INTEGRATIVE CANCER SUPPORT

HYPERBARIC OXYGEN IS AN IMMUNE MODULATION THERAPY 

Hyperbaric Oxygen Therapy is combined with traditional oncology enhances patients outcomes:

 * 'Hyperbaric Oxygen Therapy (HBOT) may increase the amount of oxygen in cancer cells, which may make them easier to kill with radiation therapy and chemotherapy. HBOT is a type of radiosensitizing agent and a type of chemosensitizing agent.

 ** HBOT assists immune responses to chemotherapy reducing immunosuppression and neutropenia'.

 www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45218

What is the success of traditional chemotherapy to a 5-year survival?

 - 'The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA'. 

 - 'As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival

 - 'To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.'

​The Contribution of Cytotoxic Chemotherapy to 5-year Survival in Adult Malignancies

 

OXYMED International Oncology Consultant

Dr Dawn Lemanne, MD, MPH

Board-Certified Medical Oncologist

Clinical Assistant Professor of Medicine, University of Arizona

Director, Oregon Integrative Oncology

www.oregonio.com

E: dawn.lemanne@gmail.com

Please do not hesitate to send Dr Lemanne an email with your history, medication and integrative approach assisting you.

International Integrative Oncology Hospitals

www.cancertherapies.cc Golden Sand Bay Hospital No 1, | Lichuan Dong Jie, Jinshazhou, | Guangzhou China

http://chemothermia.com/ - Integrative ChemoThermia Oncology Center - Istanbul

Dr Issels Immuno-Oncology (USA)

Issels Immuno-Oncology.PNG
Hospital food
Typical hospital food for cancer patients
'The curative and adjuvant chemotherapy to 5-year survival in adults is 2.3% in Australia.
When Chemotherapy Does More Harm than Good
http://www.independent.co.uk/life-st
Chemotherapy Use, Performance Statu
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Hyperbaric Oxygen Therapy is not provided as a cure or to treat the cancer and or diminish the spread of cancer mutation. ​ 

 * Intensive Hyperbaric Oxygen Therapy combined with Ketogenic Diet & deliberate lifestyle strategies reducing inflammatory cytokine expressions "rebooting" mitochondrial respiration.

 

HBOT is provided to assist the patient whilst undertaking conservative orthodox and complementary approaches. 

HBOT is a form of Chimeric Antigen Receptor Therapy (CAR) as HBOT elevates "anti-inflammatory cytokine gene expressions" including IL2, IL3, IL4, IL10, IL13 which are anti-cancer in immune support.

HBOT is combined with Ketogenic Diet and deliberate life style strategies reducing pro-inflammatory cytokines NFkB  (master regulator of inflammation).

 * HBOT is the 'integrative bridge' between orthodox and complementary approaches"The human frame is Oxygen dependent. Oxygen is essential to quality of life and essential to drug delivery. This multifactor internal healing response is unique" (Hooper 2014).

 ** Our focus is to 'assist and support' those with this complex illness - we encourage all individuals and family members to undertake due diligence and keep an open mind on the subject.  

​​

HBOT plus Chemo Strategy

We recommend an immediate ketogenic diet lifestyle change - no sugars and no carbohydrates

We recommend intermittent fasting on the days you are scheduled for chemotherapy and or radiation. Press Pulse - A novel therapeutic strategy for metabolic management of cancer Hyperbaric Oxygen Therapy & Ketogenic Diet (2017)

 

We encourage fasting before you attend for your scheduled HBOT sessions. Liquids and supplements are OK.

In addition, take sodium or potassium bicarbonate together with Betahydroxybuturate (Bulletproof XCT Oil) early each morning to rapidly alkalize and ketone load your blood. We encourage you to be in an elevated ph state (alkaline) which is not productive for circulating cancer cells (CTC's).

Other supportive supplements on the day attending your scheduled HBOT include: Metformin to further reduce circulating blood sugars (also reduces circulating TNFa, IL8 and NfKB etc), and consider Liposomal Turmeric and Liposomal Vitamin C to elevate the imposed oxidative and oxygen stress on the circulating cancer cells.

Cytokine blood testing will offer additional recommendations based on your individual markers.

Other important supplements: 

Ketogenic Diet (oncology diet removing all sugars and carbohydrates),

Synext (B3 nicotinic acid reboots mitochondrial respiration), 

MCT Powder (Medium Chain Triglyceride Powder), 

Berberine (inhibits sugar absorption),  

Metformin (inhibits Interleukin 8 & TNFa), 

Medical Cannabis (cytokine modulation),

Liposomal Vitamin C and Liposomal Curcumin (blocks cytokine inflammation), 

Sodium Bicarbonate (rapidly elevates blood ph alkalinity), 

Euphorbia Kansui (inhibits NFKB, cytokine modulation), 

N-Acetyl Cysteine (NAC) (inhibits cytokine inflammation), 

Low Dose Naltrexone (cytokine modulation), 

Dichloroacetate,  

Granulocyte Macrophage Colony Stimulating Factor  (GM-CSF stimulates the production, maturation and activation of three types of white blood cells (WBC): neutrophils, macrophages and dendritic cells.

Sargramostim (GM-CSF) stimulates the production and mobilization of progenitor stem cells. GM-CSF elevates

Brain Derived Neurotrophic Factors (BDNF). 

 

Peptides

BPC157,

Fatostatin

FTY720

 

The importance of supplemental Iodine

Nutrients. 2019 Jul 17;11(7). pii: E1623. doi: 10.3390/nu11071623.

Adjuvant Effect of Molecular Iodine in Conventional Chemotherapy for Breast Cancer. Randomized Pilot Study.

Moreno-Vega A1, Vega-Riveroll L1, Ayala T1, Peralta G1, Torres-Martel JM1, Rojas J2, Mondragón P1, Domínguez A2, De Obaldía R2, Avecilla-Guerrero C3, Anguiano B1, Delgado-González E1, Zambrano-Estrada X1, Cuenca-Micó O1, De La Puente Flores O1, Varela-Echavarría A1, Aceves C4.

Author information

Abstract

This study analyzes an oral supplement of molecular iodine (I2), alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7-35 days before surgery. For the Advanced group, 30 patients received I2 or placebo, along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and an absence of tumor chemoresistance. The control, I2, FEC/TE, and FEC/TE + I2 groups exhibited response rates of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients treated with the I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% versus 46%).

 * I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial to analyze chemotherapy + I2 treatment for advanced breast cancer.

Home Oxygen (Normobaric Oxygen) 

In addition to intensive HBOT we recommend Normobaric home use is recommended for all cancer patients.

 * We recommend using Liposomal Turmeric, N-Acetyl Cysteine, Liposomal Vitamin C in the nebulizer container whilst breathing 93-95% Oxygen.

1/1

Ann Lab Med. 2018 Sep;38(5):395-401. doi: 10.3343/alm.2018.38.5.395.

Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function.

Mitochondria are the powerhouses of the cell as well as the primary site of hematopoiesis, which also occurs in the cytoplasm. Hematopoietic stem cells (HSCs) are characterized by a very high turnover rate, and are thus considered to be relatively free from the age-related insults generated by mitochondria. However, HSCs are also subject to these age-related insults, including the incidence of myeloid proliferative diseases, marrow failure, hematopoietic neoplasms, and deterioration of the adaptive human immune system.

 * Recently, NAD⁺ dietary supplements, known as Niacin or vitamin B₃, including tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD⁺ precursornicotinamide riboside, have been shown to play a role in restoring adult stem cell function through the amelioration of mitochondrial dysfunction.

This insight motivated a study that focused on reversing aging-related cellular dysfunction in adult mouse muscle stem cells by supplementing their diet with nicotinamide riboside. The remedial effect of nicotinamide riboside enhanced mitochondrial function in these muscle stem cells in a SIRT1-dependent manner, affecting cellular respiration, membrane potential, and production of ATP. Accordingly, numerous studies have demonstrated that sirtuins, under nuclear/mitochondrial control, have age-specific effects in determining HSC phenotypes. Based on the evidence accumulated thus far, we propose a clinical intervention for the restoration of aged HSC function by improving mitochondrial function through NAD⁺ precursor B3 supplementation.

​Cancer resistance is driven by Mitochondrial Hypoxia

Cell respiration hypoxia (low oxygen tension) inside the tumor cell is the hallmark of solid tumors.

 * There is a clear link between "hypoxia and elevated HIF (hypoxic inducible factor) initiating the mobilization of tumor-initiating cells - a critical driver of tumor progression from primary tumors to metastases".

Cell Hypoxia, Over Expression of proinflammatory cytokines and inadequate diet drives cancer resistance

 * Metastasis occurs in the presence of Hypoxia with elevated HIF (Hypoxic Inducible Factor), associated with elevated inflammatory Cytokines (IL1, IL6, IL7, IL8) including NFkB, Tumour Necrosis Factor alpha (TNFα), GlycAS100B; chronic anaerobic and fungal infections, high carbohydrate, high glucose diet ... 

Hyperbaric Oxygen Therapy is a complementary therapy increasing the effectiveness of Chemotherapy and minimising the side effects of radiation

 * HBOT impacts cellular Oxygen tension and inflammatory cascades and 'enhances the efficacy of radiotherapy and chemotherapy for the treatment of malignant tumors'Undersea Hyperb Med. (2013).

 ** HBOT does not promote metastasis – it is the opposite - Hypoxia (lack of oxygen) increases tumorgenesis & resistance to conventional treatments - Hyperbaric Oxygen Therapy and Cancer Growth (UHMS 2003).

Int J Nanomedicine. 2018 Oct 4;13:6049-6058. doi: 10.2147/IJN.S140462. eCollection 2018.

Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment.

Graham K1, Unger E1.

Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression.

Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.

​Hyperbaric oxygen therapy as adjunctive strategy in treatment of glioblastoma multiforme.

Med Gas Res. 2018 Apr 18;8(1):24-28. doi: 10.4103/2045-9912.229600. eCollection 2018 Jan-Mar.

Glioblastoma multiforme (GBM) is the most common type of malignant intracranial tumor in adults. Tumor tissue hypoxia, high mitotic rate, and rapid tumor spread account for its poor prognosis. Hyperbaric oxygen therapy (HBOT) may improve the sensitivity of radio-chemotherapy by increasing oxygen tension within the hypoxic regions of the neoplastic tissue. This review summarizes the research of HBOT applications within the context of experimental and clinical GBM. Limited clinical trials and preclinical studies suggest that radiotherapy immediately after HBOT enhances the effects of radiotherapy in some aspects.

 * HBOT also is able to strengthen the anti-tumor effect of chemotherapy when applied together.

Overall, HBOT is well tolerated in the GBM patients and does not significantly increase toxicity. However, HBOT applied by itself as curative strategy against GBM is controversial in preclinical studies and has not been evaluated rigorously in GBM patients. In addition to HBOT favorably managing the therapeutic resistance of GBM, future research needs to focus on the multimodal or cocktail approaches to treatment, as well as molecular strategies targeting GBM stem cells.

Int J Hyperthermia. 2019 Apr 1:1-10. [Epub ahead of print]

Feasibility study of metabolically supported chemotherapy with weekly carboplatin/paclitaxel combined with ketogenic diet, hyperthermia and hyperbaric oxygen therapy in metastatic non-small cell lung cancer.

Previous evidence suggests that metabolically supported chemotherapy (MSCT), ketogenic diet, hyperthermia and hyperbaric oxygen therapy (HBOT) could all target vulnerabilities of cancer cells. This study aimed to evaluate the efficacy and the tolerability of this combination therapy in the treatment of stage IV non-small cell lung cancer (NSCLC).

METHODS:

Forty-four NSCLC patients with distant metastasis that received MSCT (administration of chemotherapy regimen following induced hypoglycemia) plus ketogenic diet, hyperthermia and HBOT combination were included in this retrospective study. Survival and treatment response rates as well as toxicities were evaluated.

RESULTS:

Overall response rate (ORR, complete response plus partial response) was 61.4%; whereas, 15.9% and 22.7% of patients had stable disease (SD) and progressive disease (PD), respectively. Mean overall survival (OS) and progression-free survival (PFS) was 42.9 months (95% CI: 34.0-51.8) and 41.0 months (95% CI: 31.1-50.9), respectively. A higher Eastern Cooperative Oncology Group (ECOG) performance status (ECOG ≥2) was associated with worse OS and PFS. Patients received chemotherapy cycles with acceptable toxicity and adverse events. No problems were encountered due to fasting, hypoglycemia, ketogenic diet, hyperthermia or hyperbaric oxygen therapy.

CONCLUSIONS:

Findings of this study suggest that MSCT combined with other modalities targeting multiple pathways and cellular vulnerabilities may bring about remarkable improvements in survival outcomes and treatment response rates in metastatic NSCLC, without additional safety concerns. Large comparative studies are warranted to draw robust conclusions.

Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.

Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma.

Augur ZM1, Doyle CM1, Li M1, Mukherjee P1, Seyfried TN1.

Introduction: Temozolomide (TMZ) is part of the standard of care for treating glioblastoma multiforme (GBM), an aggressive primary brain tumor. New approaches are needed to enhance therapeutic efficacy and reduce toxicity. GBM tumor cells are dependent on glucose and glutamine while relying heavily on aerobic fermentation for energy metabolism. Restricted availability of glucose and glutamine may therefore reduce disease progression. Calorically restricted ketogenic diets (KD-R), which reduce glucose and elevate ketone bodies, offer a promising alternative in targeting energy metabolism because cancer cells cannot effectively burn ketones due to defects in the number, structure, and function of mitochondria. Similarly, oxaloacetate, which participates in the deamination of glutamate, has the potential to reduce the negative effects of excess glutamate found in many brain tumors, while hyperbaric oxygen therapy can reverse the hypoxic phenotype of tumors and reduce growth. We hypothesize that the combinatorial therapy of KD-R, hyperbaric oxygen, and oxaloacetate, could reduce or eliminate the need for TMZ in GBM patients. 

Methods: Our proposed approach for inhibiting tumor metabolism involved various combinations of the KD-R, oxaloacetate (2 mg/g), hyperbaric oxygen, and TMZ (20 mg/kg). This combinatorial therapy was tested on adult VM/Dk mice bearing the VM-M3/Fluc preclinical GBM model grown orthotopically. After 14 days, tumor growth was quantified via bioluminescence. A survival study was performed and the data were analyzed and portrayed in a Kaplan Meier plot. Preliminary dosage studies were used and strict diet and drug administration was maintained throughout the study. 

Results: The therapeutic effect of all treatments was powerful when administered under KD-R. The most promising survival advantage was seen in the two groups receiving oxaloacetate without TMZ. The survival of mice receiving TMZ was diminished due to its apparent toxicity. Among all groups, those receiving TMZ had the most significant reduction in tumor growth. The most powerful therapeutic effect was evident with combinations of these therapies. Conclusion: This study provides evidence for a potentially novel therapeutic regimen of hyperbaric oxygen, oxaloacetate, and the KD-R for managing growth and progression of VM-M3/Fluc GBM.

Korean J Intern Med. 2018 May;33(3):541-551. doi: 10.3904/kjim.2016.334. Epub 2017 Dec 15.

Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer.

We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice.

METHODS:

Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated.

RESULTS:

Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8-hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy.

CONCLUSIONS:

Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

Adv Sci (Weinh). 2018 Jun 25;5(8):1700859. doi: 10.1002/advs.201700859. eCollection 2018 Aug.

Hyperbaric Oxygen Potentiates Doxil (Doxorubicin) Antitumor Efficacy by Promoting Tumor Penetration and Sensitizing Cancer Cells.

 * "As a result, the combination treatment (DOX-loaded liposome (Doxil) is coadministered with HBO) synergistically inhibits tumor growth, with a tumor inhibition rate of 91.5%."

- Hypoxia plays a central role in tumor biology,[1] as it not only fuels tumor development, progression, and metastasis, but also induces chemotherapy resistance both in pharmacokinetics and pharmacodynamics.[2] Hypoxia upregulates hypoxia induced factor 1 α (HIF-1 α )[3] and collagen,[4] which builds up a dense extracellular matrix (ECM) and severely limits drug delivery efficiency and antitumor efficacy.[5] Moreover, tumor cells under hypoxic condition are often caught in an inactive state and are insensitive to chemotherapeutic agents.[6]

- Therefore, overcoming hypoxia can significantly potentiate chemotherapy. To that end, various systems aiming at raising oxygen tension at hypoxic solid tumors have been urgently pursued.[7]. Hyperbaric oxygen (HBO) therapy can overcome tumor hypoxia and has been routinely utilized in clinics for many years.[8] Operating at elevated pressure, typically 2–3 atmosphere absolute (ATA), HBO increases the oxygen concentration in the plasma and therefore facilitates oxygen delivery directly. HBO is considered a safe clinical treatment and has been used for ischemia, acute carbon monoxide poisoning, nonhealing wounds, and late radiation injury.[9] As an effective approach in elevating oxygen content, HBO has already been combined with radiotherapy and photodynamic therapy for hypoxic solid tumor treatment.[10] 

- Hypoxia is a fundamental hallmark of solid tumors and helps contribute to chemotherapy resistance. Hyperbaric oxygen (HBO) therapy can overcome tumor hypoxia and promote chemotherapy antitumor efficacy; However, the simultaneous administration of some conventional chemotherapies, including doxorubicin (DOX), with HBO is considered an absolute contraindication. Here, DOX-loaded liposome (Doxil) is coadministered with HBO to assess the safety and efficacy of this combination treatment. By overcoming tumor hypoxia, HBO not only improves Doxil tumor penetration by decreasing the collagen deposition but also sensitizes tumor cells to Doxil.

- Here, for the first time, we combined two FDA approved therapies, HBO and Doxil, to synergistically potentiate Doxil antitumor efficacy. By overcoming tumor hypoxia, HBO not only decreases collagen deposition and promotes Doxil penetration into the tumor but also interrupts cancerous cell cycle arrest, rendering hypoxic tumor cells more sensitive to Doxil (see Scheme 1). Moreover, Doxil significantly mitigates the cardiotoxicity of DOX under HBO. Collectively, these results suggest that the combination of HBO with Doxil, and likely many other nanomedicines, is an effective and safe treatment modality for hypoxic solid tumors and could facilely translate to clinical trials.

As a result, the combination treatment synergistically inhibits tumor growth, with a tumor inhibition rate of 91.5%. The combination of HBO with Doxil shows neither extra side effects nor promotion of tumor metastasis. These results collectively reveal that the combination of HBO with Doxil is an effective and safe treatment modality. As both HBO and Doxil are routinely used, their combination could quickly translate to clinical trials for patients with hypoxic solid tumors.

The hypoxic area uncovered by the relative intensity of optical density (IOD) of pimonidazole significantly decreased by 90% (P < 0.001) after a single HBO treatment (Figure 1B). To further validate that the oxygenation of hypoxic tumor could indeed exert a meaningful biological effect, we quantified two important indicators in tissue hypoxia and TME, HIF-1 α , and its downstream target vascular endothelial growth factor (VEGF), after three HBO therapies.[22] The percentage of HIF-1 α  positive cells in the HBO group was 24.4 ± 5.7% and was significantly lower than that of the control group (48.5 ± 5.6%) (Figure 1C,D). A 67% reduction in the expression of HIF-1 α  was also observed with the western blotting (Figure 1E,F).

- Collectively, these findings show that HBO effectively modulates hypoxia. As a downstream target of HIF-1 α , the expression of VEGF should be mediated by HIF-1 α . Accordingly, there was an 85% reduction in expression of VEGF observed after HBO therapy, revealing that the expression of HIF-1 α is indeed decreased (Figure S3, Supporting Information). Pimonidazole, HIF-1 α , and VEGF are important prognostic markers of hypoxia in human cancer[23] and are widely used for detecting hypoxia modulation.[22,24] In this study, each of these three markers showed that HBO overcame tumor hypoxia. Similar conclusions have been drawn by using magnetic resonance imaging and oxygen electrodes.[25] Taken together, Figure 1 exhibits that HBO therapy overcomes tumor hypoxia and downregulates HIF-1 α expression, which can benefit cancer treatment.

- Deep penetration of therapeutic drugs, especially for nanotherapeutics, is a bottleneck for efficient drug delivery and potent cancer chemotherapy.[26] Because of the dense ECM and high IFP, the penetration distance of most anticancer drugs is only 3–5 cell diameters, typically less than 200 µm.[27] Few drugs are able to reach the tumor tissue core, which is often hypoxic, and kill those aggressive tumor cells. Tumor ECM consists of a highly interconnected network of collagen fibrils that become the major barrier for interstitial transportation of drugs. Thus, lowering the content of collagen fibrils would facilitate drug deep penetration.[15c] Previous studies showed clear link between tumor hypoxia and the deposition of collagen fibrils: Higgins et al. found that hypoxia-induced connective tissue growth factor (CTGF) is mainly mediated by HIF-1 α [28] and similar results were revealed in renal system[29] and in tumors.[30]  HBO reduces the amount of HIF1 α significantly, implying HBO might be able to inhibit collagen fibers deposition by interrupting HIF-1 α /CTGF/collagen pathway.

- HBO therapy reduced the deposition of collagen in tumor ECM. These results are aligned with published work which has shown that the number of collagen fibril per µm2 in tumor tissue decreased 66.7% after HBO therapy.[16] Combined with the immunohistochemistry and western blotting results of HIF-1 α , the results showed in Figure 2 demonstrate that HBO therapy decreases collagen fibril deposition through the regulation of HIF-1 α /CTGF/collagen I pathway. Decreased collagen I deposition in tumor ECM is expected to boost Doxil deep penetration and accumulation in tumor tissue.[5a,15c,32] These findings (Figures 2 and 3) clearly demonstrate that HBO opens up the dense ECM in hypoxic solid tumors and selectively benefits Doxil rather than DOX.

- To the best of our knowledge, this is the first report in which HBO therapy acts as a facilitative therapy for deep penetration of nanotherapeutics. A variety of methods have also been developed to bolster penetration of nanotherapeutics,[37] and many of these focus on degradation of tumor ECM by delivering small molecular drugs or enzymes.

- Compared with these methods, HBO uses oxygen as a drug to oxygenate hypoxic tumors and modulate ECM. Oxygen has the advantage of higher delivery and penetration efficiencies under HBO situations. Moreover, the drugs and enzymes used to degrade ECM in those methods have safety concerns that must be alleviated with clinical trials, whereas HBO has been used for many years with a proven safety profile. Collectively, our results show that HBO therapy reinforces Doxil penetration and enhances DOX accumulation at tumor tissue. These actions are beneficial for in vivo antitumor efficacy.

An Integrative Treatment Approach is Optimal

Hyperbaric oxygen therapy and cancer review 2004-2012

Target Oncol. 2012 Dec;7(4):233-42. doi: 10.1007/s11523-012-0233-x. Epub 2012 Oct 2.

Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway, ingrid.moen@biomed.uib.no.​

  • Hypoxia is a critical hallmark of solid tumors and involves enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis.

  • Hyperbaric oxygen (HBO) treatment has for centuries been used to improve or cure disorders involving hypoxia and ischemia, by enhancing the amount of dissolved oxygen in the plasma and thereby increasing O(2) delivery to the tissue. Studies on HBO and cancer have up to recently focused on whether enhanced oxygen acts as a cancer promoter or not. As oxygen is believed to be required for all the major processes of wound healing, one feared that the effects of HBO would be applicable to cancer tissue as well and promote cancer growth. Furthermore, one also feared that exposing patients who had been treated for cancer, to HBO, would lead to recurrence.

  • Recent systematic reviews on HBO and cancer have concluded that the use of HBO in patients with malignancies is considered safe.

  • To supplement the previous reviews, we have summarized the work performed on HBO and cancer in the period 2004-2012. Based on the present as well as previous reviews, there is no evidence indicating that HBO neither acts as a stimulator of tumor growth nor as an enhancer of recurrence.

  • On the other hand, there is evidence that implies that HBO might have tumor-inhibitory effects in certain cancer subtypes, and we thus strongly believe that we need to expand our knowledge on the effect and the mechanisms behind tumor oxygenation.

Int J Nanomedicine. 2018 Oct 4;13:6049-6058. doi: 10.2147/IJN.S140462. eCollection 2018.

Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment.

Graham K1, Unger E1.

Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression.

Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.

Med Sci Monit. 2018 Jun 13;24:4009-4019. doi: 10.12659/MSM.906707.

Combined Hyperbaric Oxygen Partial Pressure at 1.4 Bar with Infrared Radiation: A Useful Tool To Improve Tissue Hypoxemia?

Dünnwald T1, Held J2, Balan P3, Pecher O4, Zeiger T3, Hartig F5, Mur E6, Weiss G2, Schobersberger W1,7.

Author information

Abstract

Tissue hypoxia contributes to the pathogenesis of several acute and chronic diseases. Hyperbaric oxygen therapy (HBO) and whole-body warming using low-temperature infrared technology (LIT) are techniques that might improve hypoxemia. Combining HBO and LIT as hyperbaric oxygen therapy combined with low-temperature infrared radiation (HBOIR) might be an approach that results in positive synergistic effects on oxygenation. LIT increases blood flow and could reduce HBO-induced vasoconstriction, and hyperoxia could compensate for the increased metabolic oxygen requirements mediated by LIT. Both LIT and HBO increase the oxygen diffusion distance in the tissues. HBOIR at 0.5 bar has been shown to be safe and feasible. However, physiological responses and the safety of HBOIR at an increased oxygen (O2) partial pressure of 1.4 bar or 2.4 atmospheres absolute (ATA) still need to be determined. The hope is that should HBOIR at an increased oxygen partial pressure of 1.4 bar be safe, future studies to examine its efficacy in patients with clinical conditions, which include peripheral arterial disease (PAD) or wound healing disorders, will follow. The results of pilot studies have shown that HBOIR at an overload pressure is safe and well tolerated in healthy participants but can generate moderate cardiovascular changes and an increase in body temperature. From the findings of this pilot study, due to its potential synergistic effects, HBOIR could be a promising tool for the treatment of human diseases associated with hypoxemia.

Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma.

Melanoma Res 2018 Mar 8. Epub 2018 Mar 8.

Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA.

  • March 2018

Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials.

These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-α, interferon-α, interferon-γ], antibodies (αPD-1, αPD-L1, αTIM-3, αOX40, αCTLA-4, αLAG-3), dendritic cell-based vaccines, and chemokines (CXCR2). There are a substantial number of ongoing clinical trials using two or more of these combination therapies. Preliminary results indicate that these combination therapies are a promising area to focus on for cancer treatments, especially melanoma. The main challenges with the combination of cellular and immunotherapies are adverse events due to toxicities and autoimmunity. Identifying mechanisms for reducing or eliminating these adverse events remains a critical area of research. Many important questions still need to be elucidated in regard to combination cellular therapies and immunotherapies, but with the number of ongoing clinical trials, the future of curative melanoma therapies is promising.

Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts.

PLoS One 2017 23;12(8):e0183254. Epub 2017 Aug 23.

Department of Biomedicine, University of Bergen, Bergen, Norway.

Background: Tumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model.

Materials And Methods: 5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU).

Results: HBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model.

  • Conclusion: Despite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I.

Double-Edged Sword: Killing Cancer Cells can also Drive Tumor Growth - 1 December 2017

  • “In this study we demonstrate that chemotherapy-generated debris from dead and dying tumor cells can stimulate tumor growth, which has pivotal implications for the treatment of cancer patients,” said senior author Dipak Panigrahy, MD, Assistant Professor of Pathology in the Department of Pathology and a Scientist at the Cancer Center at Beth Israel Deaconess Medical Center. “Conventional cancer therapy designed to kill tumor cells is inherently a double-edged sword.”

  • The researchers’ further analysis revealed that chemotherapy-killed cancer cells promote growth when a lipid molecule exposed on the surface of dead and dying cells triggers the release of cytokines – proteins that regulate the body’s immune and inflammatory response.  The resulting “cytokine storm” in the tumor’s microenvironment in turn sets the stage to promote new tumor growth.

  • “This pro-tumor activity could fuel a positive feedback loop that is difficult to overcome with more aggressive cytotoxic therapy like chemotherapy and radiation,” said Panigrahy. “This may explain the inherent therapeutic limit to cancer treatments available today.”

Chemotherapy Use, Performance Status, and Quality of Life at the End of Life

JAMA Oncol. 2015;1(6):778-784. doi:10.1001/jamaoncol.2015.2378

  • Conclusions and Relevance: Although palliative chemotherapy is used to improve Quality of Life (QOL) for patients with end-stage cancer, its use did not improve Quality near Death (QOD) for patients with moderate or poor performance status and worsened QOD for patients with good performance status. The QOD in patients with end-stage cancer is not improved, and can be harmed, by chemotherapy use near death, even in patients with good performance status.

Integrative ChemoThermia Oncology Center - Istanbul

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy - Poff, Seyfried, D'Agostino 2015

  • The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+ HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer.

  • We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG + βHB + HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers​

Cancer_as_a_metabolic_disease-2017

  • Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation.​

Cancer Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer

  • This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast​. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging

Press Pulse - A novel therapeutic strategy for metabolic management of cancer Hyperbaric Oxygen Therapy & Ketogenic Diet (2017)

  • This general concept can be applied to the management of cancer by creating chronic metabolic stresses on tumor cell energy metabolism (press disturbance) that are coupled to a series of acute metabolic stressors that restrict glucose and glutamine availability while also stimulating cancer-specific oxidative stress (pulse disturbances). The elevation of non-fermentable ketone bodies protect normal cells from energy stress while further enhancing energy stress in tumor cells that lack the metabolic flexibility to use ketones as an efficient energy source. Mitochondrial abnormalities and genetic mutations make tumor cells vulnerable metabolic stress. Results: The press-pulse therapeutic strategy for cancer management is illustrated with calorie restricted ketogenic diets (KD-R) used together with drugs and procedures that create both chronic and intermittent acute stress on tumor cell energy metabolism, while protecting and enhancing the energy metabolism of normal cells.

Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer. [Int J Radiat Oncol Biol Phys. 2009]

The Ketogenic Diet and Hyperbaric Oxygen Therapy prolonged survival (by 78%) with Systemic Metastatic Cancer

Source: Research team from the Hyperbaric Biomedical Research Laboratory at the University of South Florida.

  • "Mice exposed to combined ketogenic diet and hyperbaric oxygen therapy lived 78 percent longer than mice fed a standard high-carbohydrate diet."  "When administered properly, both the ketogenic diet and hyperbaric oxygen therapy are non-toxic and may even protect healthy tissues while simultaneously damaging cancer cells," said Prof D'Agostino.

Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death Pharmaceuticals 2015

  • A major question for current cancer therapy is whether hypoxic-induced alterations in cancer cells will provide specific targets for selectively killing these cells, without affecting nearby normal cells. The recent evidence discussed below establishes a clear link between "hypoxia and the mobilization of tumor-initiating cells as a critical driver of tumor progression from primary tumors to metastases". Often by the time cancers are detected, systemic micrometastases have become established, so that targets are needed that play essential roles in metastatic cells, but which are non-essential for normal cell growth and survival.

  • Despite some improvements in cancer therapies, and surgical removal of primary tumors and draining lymph nodes, cancer recurrence and metastatic spread by residual disease remains a fundamental clinical problem, with many solid tumor types recurring at higher frequencies.

The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

 - Hypoxia and HIF (Hypoxic Inducible Factor) 

  • Tumor  hypoxia  (lack of oxygen) is a critical factor of cancer progression and the overexpression of HIF-α subunits in tumors and their metastases is associated with the aggressiveness of a majority of human cancers and correlates with poor overall survival

  • It was demonstrated previously that hypoxic cells are more aggressive and invasive with better ability to metastasize. For instance, multiple myeloma cancer cells cultured in hypoxic conditions in vitro and injected into mice were able to spread to the new bone marrow faster than the cells cultured in normoxic conditions.

  • Also, exposing an orthotopic mouse model of cervical carcinoma to a dozen cycles of 10 minutes 7% O2 , which was followed by 10 minutes of air exposure daily, increased the number of lymph node metastases. Similar observations were recorded in mice bearing sarcoma tumors, where exposure to acute hypoxia augmented the lung metastases.

  • HIF-1α was shown to be expressed in 90% of human gastric cancer biopsies at the front edge of the invading tumor compared to HIF-1α negative normal tissues. HIF inhibition significantly reduced the metastasis of gastric cancer cells in vivo, and HIF deficient cells were less motile, invasive, and adhesive in vitro. High involvement of the main hypoxic regulator, HIF-α, in all steps of metastasis led to many trials of inhibiting this molecule to diminish cancer cell trafficking thus reducing metastasis.

  • Hypoxia is one of the main features of solid tumors and was shown to correlate with poor prognosis of cancer patients. While hypoxia is lethal for many cells, a subpopulation of tumor cells is able to not only adapt to hypoxic conditions but also become resistant to chemo- and radiotherapy. The role of hypoxia in the phenomenon of therapy resistance has been acknowledged for at least 60 years. Apart from cellular adaptations influenced by hypoxia, lowered oxygenation of the tumor tissue confers chemoresistance.

  • Hypoxia causes slow-proliferating stem-cell-like phenotype of cells, decreases senescence, creates chaotic and malfunctioning blood vessels, and augments metastasis, which all together further induces therapy resistance.

  • Currently, assessment of tumor oxygenation and HIF expression pattern helps determine tumor chemo- and radio-sensitivity. It was reported that head-and-neck cancer samples with high expression of HIF-1α and HIF-2α were more resistant to chemotherapy (carboplatin) compared to biopsies with low HIF-α expression which were chemo-sensitivePatients with oropharyngeal cancer demonstrating high expression of HIF-1α had a lower chance to achieve complete remission after irradiation. 

  • In addition, irradiation was shown to induce HIF-1 activity, leading to production of angiogenic molecules such as VEGF which protects ECs from irradiation-induced apoptosis.

 

 * HIF-1 represents a valid predictive marker and therapeutic target for manipulation, in combination with chemotherapeutics and radiotherapy, in order to sensitize the cells to treatments.

 * Note: Hyperbaric Oxygen Therapy downregulates expression of HIF and other pro-inflammatory cytokines and interleukins. 

Hyperbaric oxygen therapy sensitizes nimustine treatment for glioma in mice.

Cancer Med 2016 Nov 13;5(11):3147-3155. Epub 2016 Oct 13.

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Rd, Suzhou, 215004, China.

  • November 2016

Nimustine (ACNU) has antitumor activities in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are hampered by the hypoxic microenvironment. We examined the combined effects of ACNU and HBO in a GFP transgenic nude mice bearing human glioma model. Mice inoculated with human glioma cells SU3 were randomly divided into the four groups: (A) the control group, (B) the HBOT (HBO therapy) group, (C) the ACNU group, and (D) the HBOT+ACNU group. Tumor size was measured at the indicated time intervals with a caliper; mice were sacrificed 28 days after treatment, and immunohistochemistry staining and western blot analysis were carried out. By the end of the trial, the tumor weights of groups A, B, C, and D were (P < 0.05), 6.03 ± 1.47, 4.13 ± 1.82 (P < 0.05), 2.39 ± 0.25 (P < 0.05), and 1.43 ± 0.38 (P < 0.01), respectively.

  • The expressions of TNF-α, MMP9, HIF-α, VEGF, NF-κB, and IL-1β were associated with the infiltration of inflammatory cells and the inhibition rate of tumor cells.

  • Hyperbaric oxygen therapy (HBOT) could inhibit glioma cell proliferation and inflammatory cell infiltration, and exert a sensitizing effect on ACNU therapy partially through enhancing oxygen pressure (PO) in tumor tissues and lower expression levels of HIF-1α, TNF-α, IL-1β, VEGF, MMP9, and NF-κB.

  • Further information on Nimustine go to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108775/

Hyperbaric oxygen as an adjunctive therapy in treatment of malignancies, including brain tumours.

Med Oncol. 2016 Sep;33(9):101. doi: 10.1007/s12032-016-0814-0. Epub 2016 Aug 2.

Stępień K1, Ostrowski RP2, Matyja E2.

  • Hyperbaric oxygen (HBO) therapy is widely used as an adjunctive treatment for various pathological states, predominantly related to hypoxic and/or ischaemic conditions. It also holds promise as an approach to overcoming the problem of oxygen deficiency in the poorly oxygenated regions of the neoplastic tissue. Occurrence of local hypoxia within the central areas of solid tumours is one of the major issues contributing to ineffective medical treatment. More often, HBO is used as an adjuvant treatment along with other therapeutic modalities, such as radio- and chemotherapy.

  • This review outlines the existing data regarding the medical use of HBO in cancer treatment, with a particular focus on the use of HBO in the treatment of brain tumours. We conclude that the administration of HBO can provide many clinical benefits in the treatment of tumours, including management of highly malignant gliomas. Applied immediately before irradiation, it is safe and well tolerated by patients, causing rare and limited side effects.

  • The results obtained with a combination of HBO/radiotherapy protocol proved to be especially favourable compared to radiation treatment alone. HBO can also increase the cytostatic effect of certain drugs, which may render standard chemotherapy more effective. The currently available data support the legitimacy of conducting further research on the use of HBO in the treatment of malignancies.

Hypoxia - Chronic Inflammation & Cancer 

Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways

  • There is an undeniable link between inflammation and cancer.

  • Virchow first noted that inflammatory cells are present within tumors and tumors arise at sites of chronic inflammation. This observation was made >150 years ago and led to the conclusion that inflammation significantly contributes to the development of cancer.

  • Epidemiological evidence now supports this conclusion and suggests that up to 25% of all cancers are due to chronic infection or other types of chronic inflammation (1).

  • The sources of inflammation are widespread and range from microbial and viral infections to exposure to allergens and toxic chemicals to autoimmune diseases and obesity. An acute inflammatory response is usually beneficial, especially in response to microbial infections and tissue damage. A well-regulated inflammatory response can also be anti-tumorigenic and have a role in tumor suppression (2).

  • Chronic inflammation, however, is detrimental and, among other deleterious effects, will frequently predispose cells for an oncogenic transformation.

  • Irrespective of its underlying cause, chronic inflammation can be oncogenic by various mechanisms. This includes induction of genomic instability, increasing angiogenesis, altering the genomic epigenetic state and increasing cell proliferation.

  • Over-production of reactive oxygen and nitrogen species (RONS), aberrant inflammatory cytokine and chemokine expression, increased cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NFκB) expression are just some of the molecular factors that contribute to inflammation-induced carcinogenesis.

 

  • Inflammation can alter the expression of oncogenes and tumor suppressor genes (including both protein coding genes and non-coding microRNA genes) to promote neoplastic transformation.

Relevance of hypoxia in radiation oncology: pathophysiology, tumor biology and implications for treatment.

Q J Nucl Med Mol Imaging. 2013 Sep;57(3):219-34.

  • Tumors are characterized by an inefficient and disorganized vasculature which leads to tumor regions that are transiently or chronically undersupplied with oxygen (hypoxia) and nutrients (e.g., glucose). These adverse conditions are linked to treatment resistant and metastasizing disease with poor prognosis. Radiation sensitivity is dramatically lowered in hypoxic, yet viable and clonogenic, cells since oxygen is involved in the fixation of radiation-induced DNA damage (radiobiological hypoxia), and loco-regional tumor control is adversely affected in patients with hypoxic tumors.

  • Hypoxia also leads to reduced sensitivity towards chemotherapeutics since drug delivery is reduced in hypoperfused hypoxic areas and hypoxic cells are quiescent, making drugs that target dividing cells ineffective.

Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).

Oncotarget. 2017 Jun 9;8(40):67269-67286. doi: 10.18632/oncotarget.18428. eCollection 2017 Sep 15.

  • Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.

  • Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells.

  • In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.

  • This type of metabolic Achilles' heel will allow us and others to more effectively "starve" the CSC population.

Clin Oncol (R Coll Radiol). 2004 Dec;16(8):549-60.

The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies.

Morgan G1, Ward RBarton M.

Abstract

The debate on the funding and availability of cytotoxic drugs raises questions about the contribution of curative or adjuvant cytotoxic chemotherapy to survival in adult cancer patients.

MATERIALS AND METHODS:

We undertook a literature search for randomised clinical trials reporting a 5-year survival benefit attributable solely to cytotoxic chemotherapy in adult malignancies. The total number of newly diagnosed cancer patients for 22 major adult malignancies was determined from cancer registry data in Australia and from the Surveillance Epidemiology and End Results data in the USA for 1998. For each malignancy, the absolute number to benefit was the product of (a) the total number of persons with that malignancy; (b) the proportion or subgroup(s) of that malignancy showing a benefit; and (c) the percentage increase in 5-year survival due solely to cytotoxic chemotherapy. The overall contribution was the sum total of the absolute numbers showing a 5-year survival benefit expressed as a percentage of the total number for the 22 malignancies.

RESULTS:

  • The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA.

 

CONCLUSION:

  • As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.

USA Oncology Forum 2017
Istanbul ChemoTherma Team
ChemoTherma Protocols
Istanbul ChemoTherma
Istanbul ChemoTherma
Istanbul ChemoTherma
Istanbul ChemoTherma
Istanbul ChemoTherma
Istanbul ChemoTherma
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OXYMED Case Study 7 year old - Glioblastoma Multiforme (GB4)

 

  • Jan 2017 large frontal parietal tumour with mid-line shift.

  • MRI taken after surgical resection.

  • In excess of 90% of the tumour had regrown in month following.

  • Child undertaking radiation protocols however health declining rapidly. Prognosis extremely poor.

  • Under recommendation from a USA Physician the child commences HBOT combined with strict Ketogenic Diet.

  • HBOT commences mid February 2017.

  • After 86 hours HBOT - follow up MRI.

  • Child now back at school.

  • Note (below)  Cytokine Profile testing 'before' and 'after 106-hours' HBOT.

MRI Jan 2017 : Pre HBOT
Post Surgical Resection : Pre HBOT
Post HBOT (84-hours)
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OXYMED Case Study - male age 36, Brain, Chest, Testicles, Bone Metastasis

 

  • Interval 166-hours HBOT

Pre HBOT Oct 2016
Post HBOT (166 Hours)
Post HBOT (250 hours)
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OXYMED Case Study - female age 41, Recurrent Breast Cancer, Chest, Liver, Stomach Metastasis

 

  • Before Jan 2017 and After May 2017

  • Interval 150-hours HBOT

Historical Understanding of Cancer Metabolism

Dr. Otto Warburg Nobel Prize winner

Cancer cells are known to be anaerobic, meaning they ferment oxygen rather than burn oxygen.

When the level of oxygen that gets into a normal cell becomes too low, or the ATP molecule count gets too low, a normal cell will convert into becoming anaerobic. A Nobel Prize was awarded for proving that cancer cells are anaerobic, meaning they do not burn glucose, but rather they ferment glucose in order to get their ATP energy.

  • “Over seventy-five years ago Dr. Otto Warburg published a Nobel Prize winning paper describing the environment of the cancer cell. A normal cell undergoes an adverse change when it can no longer take up oxygen to convert glucose into energy by oxidation. In the absence of oxygen the cell reverts to a primitive nutritional program to sustain itself, converting glucose, by fermentation. The lactic acid produced by fermentation lowers the cell pH (acid/alkaline balance) and destroys the ability of DNA and RNA to control cell division - the cancer cells begin to multiply unchecked. The lactic acid simultaneously causes intense local pain and destroys cell enzymes. Therefore, cancer appears as a rapidly growing outer cell mass with a core of dead cells.” 

  • In the absence of oxygen, glucose undergoes fermentation to create lactic acid. This causes the cell pH to drop from between 7.3 to 7.2 down to 7 and later to 6.5; in more advanced stages of cancer and in metastases the pH may drop to 6.0 and even 5.7.

  • Dr. Warburg stated: “But nobody today can say that one does not know what cancer and its prime cause be. On the contrary, there is no disease whose prime cause is better known, so that today ignorance is no longer an excuse that one cannot do more about prevention. That prevention of cancer will come there is no doubt, for man wishes to survive. But how long prevention will be avoided depends on how long the prophets of agnosticism will succeed in inhibiting the application of scientific knowledge in the cancer field. In the meantime, millions of men must die of cancer unnecessarily." [Nobel Prize Winner Otto Warburg in a meeting of Nobel Laureates, June 30, 1966]. http://www.cancertutor.com/

Alkalinity

Acidity generated by the tumor microenvironment drives local invasion

Departments of Cancer Imaging and Metabolism, Radiology, and Analytic Microscopy Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

  • The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion.

  • It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion.

  • In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH.

  • Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis.

  • In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 

Hypoxia Key Factor To Tumour Resistance and Tumour Proliferation

Hyperbaric Oxygenation of Hypoxic Glioblastoma Multiforme Cells Potentiates the Killing Effect of an Interleukin-13-Based Cytotoxin

  • IL13 has anti-tumour effects and when combined with HBO enhances the killing effects of Glioblastoma and other cancers.

  • Several clinical trials have been done with Hyperbaric Oxygen or hypoxic cell radiosensitizers intending to overcome the problem of the radioresistance of hypoxic tumor cells (7–9). The results of these trials have shown benefit of proper oxygenation for glioblastoma multiforme radiotherapy. 'Our results show that a recombinant cytotoxin directed against glioblastoma multiforme cells kills these cells much less efficiently under anoxic/hypoxic conditions.

  • The HBO reoxygenation brings unexpected additional rebound benefit (IL13) making glioblastoma multiforme cells even more responsive to the killing effect of a cytotoxin.'

  • The reoxygenated anoxic glioblastoma multiforme cells were 2- to 10-fold more sensitive to DT-IL13QM killing than normoxic glioblastoma multiforme cells.

  • IL-13 expression in glioblastoma multiforme cells is dependent on oxygenation status. IL-13 is up-regulated with HBO.

  • Reoxygenation causes a 'rebound' or even a further increase in protein levels of IL-13Ra2 and active furin in glioblastoma multiforme cells subjected to anoxia or hypoxia.

  • Glioblastoma Multiforme is a high-grade astrocytoma and represents the most aggressive form of brain tumors. The successful treatment of patients with glioblastoma multiforme is still a major challenge, and a median survival rate is 14.5 months since diagnosis (1). 'Similarly to other solid tumors, glioblastoma multiforme tumors exhibit resistance to radiotherapy and chemotherapy largely in part due to the hypoxic tumor microenvironment'

  • In addition to the aggressive invasive nature of glioblastoma multiforme is the unique property of tumor hypoxia (inadequate oxygen). Hypoxia is considered as an important factor affecting the efficacy of current orthodox treatments in glioblastoma multiforme (2, 3).

  • Hypoxia is an alteration of balance between cellular proliferation and oxygen supply, resulting in significantly lower oxygen levels in focal regions than those encountered in surrounding both malignant and normal tissues (4).

  • 'Hypoxia influences the behaviour of human tumor cells and empowers hypoxic tumour cells a higher resistance to radiotherapy and certain chemotherapies and a higher mutation rate and potential for a more metastatic and malignant phenotype'

  • Evidence suggests that hypoxia influences the behavior of human tumor cells and empowers hypoxic tumor cells a higher resistance to radiotherapy and certain chemotherapies and a higher mutation rate and potential for a more metastatic and malignant phenotype (2).

  • The tumor oxygenation is negatively associated with increasing grade of human astrocytomas (5).

  • Similarly to other solid tumors, glioblastoma multiforme tumors exhibit strong resistance to radiotherapy and chemotherapy due to the hypoxic tumor microenvironment (6).

  • Hyperbaric Oxygen Therapy (HBO) impacts cellular Oxygen tension and inflammatory cascades and has been shown to 'enhance the efficacy of radiotherapy and chemotherapy for the treatment of malignant tumors'. Undersea Hyperb Med. 2013.

Does Hyperbaric Oxygen Therapy Cause Cancer Spread? No The Opposite ...

Hyperbaric Oxygen does it promote growth or recurrence of malignancy (UHMS 2003)?

  • Hypoxia causes increased release of interleukin 8 (IL8) contributing to aggressive spread of cancer cells.

Austin Hospital Melbourne - Hyperbaric Oxygen Therapy & Cancer Resistance

Hyperbaric oxygen therapy for malignancy 2006, by Daruwalla J, Christophi C. University of Melbourne, Austin Hospital, Level 8 Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Victoria, 3084 Australia received international recognition and formed the basis of numerous peer reviewed studies.

Unfortunately, the Austin Hospital does NOT provide Hyperbaric Oxygen Therapy to assist cancer patients.

Why isn't the Australian Government providing HBO funding to assist patient outcomes based on this internationally acclaimed study?

HBO continues to be dictated by economic and political influences under the careful watch of pharmaceutical preferences.

Hyperbaric oxygen therapy for malignancy

World J Surg. 2006 Dec;30(12):2112-31.

Daruwalla J, Christophi C.

Department of Surgery, University of Melbourne, Austin Hospital, Level 8 Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Victoria, 3084 Australia. jurstine@pgrad.unimelb.edu.au

  • One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center.

  • Hypoxia has a major impact on various aspects of tumor cell function and proliferation.

  • Hypoxic tumor cells are relatively insensitive to conventional therapy (chemotherapy and radiation) owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome.

  • One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress.

  • This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.

Hyperbaric Oxygenation Potential Anti-Cancer Effects on Breast Cancer Cells

  • In the 2007 study, Haroon, Patel, and Al-Mehdi decided to evaluate the growth of murine breast cancer cells in the lung after hyperbaric oxygen treatment in an experimental metastasis assay. The total metastatic load in the lung is reduced after HBO - that’s one of the most significant new findings from a 2007 study ...

 

Radiotherapy after hyperbaric oxygenation in malignant gliomas

Curr Med Res Opin. 2015 Sep 28:1-8. [Epub ahead of print]

Chen JR1, Xu HZ1, Ding JB1, Qin ZY1.

  • Literature search/screening yielded eight studies for analysis. Six of the studies were single-arm in design and enrolled a total of 203 patients, of whom 142 had grade IV gliomas and 61 had grade III gliomas. In these six studies, all patients received HBO then RT. Two studies were double-arm in design, with 24 patients treated with HBO followed by RT and 26 patients treated with RT alone.

  • The findings from both the single- and double-arm studies indicated improved outcomes (survival rate, progression free survival, time to progression, response rate) with HBO and RT therapy. Reported toxicity included leucopenia, anemia, thrombocytopenia, fever, loss of appetite, constipation, nausea, vomiting, and liver dysfunction. The addition of HBO had minimal effect on toxicity or side effects; across the eight studies, only one patient with severe middle ear barotrauma had a complication directly related to HBO exposure.

  • This systematic reviews suggests that the addition of HBO to RT is tolerated and may be beneficial in patients with high-grade gliomas.

HBO & Mild Hyperthermia

Int J Hyperthermia. 2015 Jul 9:1-6. [Epub ahead of print]

Efficacy of hyperbaric oxygen therapy combined with mild hyperthermia for improving the anti-tumour effects of carboplatin

Ohguri T1, Kunugita N, Yahara K, Imada H, Uemura H, Shinya N, Youjirou G, Takashi C, Okazaki R, Ootsuyama A, Korogi Y.

The aim of this study was to evaluate the effects of hyperbaric oxygen therapy (HBO) on the enhancement of hyperthermic chemosensitisation to carboplatin at mild temperatures in experimental tumours.

METHODS:

SCCVII carcinoma in C3H/He mice was used to assess tumour growth delay. The mice received intraperitoneal injections of carboplatin.

For HBO treatment, the mice were exposed to HBO at 2.0 atmospheres of absolute oxygen for 60 min. For mild hyperthermia (HT), treatment at 41.5 °C for 30 min was performed. The tumour tissue pO2 levels were measured with a digital pO2 monitor during and immediately after treatment.

RESULTS:

The average time taken to reach a threefold relative tumour size was significantly longer after treatment with carboplatin combined with mild HT and HBO than after treatment with carboplatin and mild HT. The relative sizes of the tumours after the combined treatment were smallest when the treatment sequence was carboplatin, mild HT, and HBO.

The tumour tissue pO2 values were significantly higher immediately after mild HT followed by HBO than immediately after HBO followed by mild HT. The tumour tissue pO2 levels during mild HT and HBO generally increased, although the patterns of the increases varied.

CONCLUSION:

  • The administration of HBO increased the effects of hyperthermic chemosensitisation to carboplatin at mild temperatures on experimental tumours, particularly when given in the sequence of carboplatin, mild HT, and HBO, a finding that supports previous clinical outcomes for a novel combined therapy using carboplatin plus HT and HBO.

HBO & Vitamin C

Wien Med Wochenschr. 2015 Jun;165(11-12):251-257. Epub 2015 Jun 12.

Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

Venturelli S1, Sinnberg TW, Niessner H, Busch C.

Author information

Abstract

Intravenous application of high-dose ascorbate (vitamin C) has been used in complementary medicine since the 1970s to treat cancer patients. In recent years it became evident that high-dose ascorbate in the millimolar range bears selective cytotoxic effects on cancer cells in vitro and in vivo. This anticancer effect is dose dependent, catalyzed by serum components and mediated by reactive oxygen species and ascorbyl radicals, making ascorbate a pro-oxidative pro-drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger.

  • It further depends on HIF-1 signaling and oxygen pressure, and shows a strong epigenetic signature (alteration of DNA-methylation and induction of tumor-suppressing microRNAs in cancer cells).

 

  • The detailed understanding of ascorbate-induced antiproliferative molecular mechanisms warrants in-depth preclinical evaluation in cancer-bearing animal models for the optimization of an efficacious therapy regimen (e.g., combination with hyperbaric oxygen or O2-sensitizers) that subsequently need to be evaluated in clinical trials.

Further Clinical Research

Cureus. 2017 Jul 7;9(7):e1445. doi: 10.7759/cureus.1445.

Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer.

İyikesici MS1, Slocum AK2, Slocum A2, Berkarda FB2, Kalamian M3, Seyfried TN4.

Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion.

The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC.

J Am Chem Soc. 2016 Apr 27;138(16):5222-5. doi: 10.1021/jacs.6b01784. Epub 2016 Apr 13.

An Implantable Depot That Can Generate Oxygen in Situ for Overcoming Hypoxia-Induced Resistance to Anticancer Drugs in Chemotherapy.

Huang CCChia WT1, Chung MFLin KJHsiao CWJin CLim WHChen CCSung HW.

In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.

Diving Hyperb Med. 2016 Jun;46(2):124.

Pre-emptive treatment with hyperbaric oxygen following radiation therapy for head and neck cancer may prevent the onset of late radiation tissue injury.

Wood DBennett M.

Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer. [Int J Radiat Oncol Biol Phys. 2009]

P08.58 Impact of selected pentabromobenzylisothiourea (ZKK-3) combined with hyperbaric oxygen therapy on therapeutic response and oxygenation status of T98G glioblastoma cell line

Abstract

Introduction: Glioblastoma (GBM), the primary brain tumour derived from astroglial cells, is the most frequently diagnosed intracranial malignancy in adults. Poor prognosis for GBM patients results from high invasiveness of neoplastic cells related with faulty angiogenesis and persistent hypoxia states. In such conditions glioma cells develop radio- and chemotherapy-resistant phenotype. It is postulated that application of hyperbaric oxygen (HBO) may improve therapeutic response via refinement of tumour tissue oxygenation. The more effective therapeutic strategies are also required.

One of the novel compounds that exhibit anti-tumour properties are pentabromobenzylisothioureas.

The aim of this study was to examine whether HBO may enhance anti-tumour efficacy of selected pentabromobenzylisothiourea when both agents were administered as combined ZKK-3/HBO therapy.

Materials and Methods: Human glioblastoma T98G cell line was cultured in medium supplemented with novel isothiourea derivative - ZKK-3. The proliferation and viability of glioma cells cultured in hypoxia or hyperbaric oxygen conditions were examined. Cell proliferation was tested 24 hours after ZKK-3 addition using Nikon Inverted Microscope and Multisizer 3 Beckman Coulter. The viability assay was taken 24 and 48 hours post ZKK-3 supplementation by CellTiter 96®AQueous One Solution Cell Proliferation Assay (Promega). Hypoxia state of T98G cells was determined via the evaluation of HIF-1α protein expression using HIF-1A ELISA Kit (Thermo Scientific). Tests were performed on cells treated with ZKK-3 and cultured in various oxygen conditions: 1/ normoxia (24 hours), 2/ hypoxia (24 hours), 3/ HBO (2 ATA, 1 hour followed by 23 hours of normoxia), 4/ double hypoxia, 5/ hypoxia/HBO.

Results: Proliferation of T98G cells treated with ZKK-3 was significantly decreased after hyperbaric oxygenation in comparison to hypoxia conditions. Administration of HBO resulted also in statistically significant diminution of glioma cells’ viability.

Expression of HIF-1α in T98G cells strongly depended on oxygen conditions: in hypoxia and double hypoxia the level of protein was significantly elevated compared with normoxia, while after hyperbaric oxygenation no changes or even decrease of HIF-1α level was observed. Comparison of double hypoxia and hypoxia/HBO groups showed that HBO addition after ZKK-3 supplementation caused significant reduction of HIF-1α expression.

Conclusions: Treatment of malignant glioma cells with selected isothiourea derivative is significantly more efficient when combined with hyperbaric oxygen administration. Beneficial effect of HBO on decreasing HIF-1α expression allows to consider hyperbaric oxygenation as the way to overcome tumour hypoxia. ACKNOWLEDGEMENT: The research was supported by the KNOW-MMRC project and Foundation for the Development of Diagnostic and Therapy.


P08.58 Impact of selected pentabromobenzylisothiourea (ZKK-3) combined with hyperbaric oxygen therapy on therapeutic response and oxygenation status of T98G glioblastoma cell line.

Available from:

https://www.researchgate.net/publication/316519822_P0858_Impact_of_selected_pentabromobenzylisothiourea_ZKK-3_combined_with_hyperbaric_oxygen_therapy_on_therapeutic_response_and_oxygenation_status_of_T98G_glioblastoma_cell_line [accessed Aug 17, 2017].

Diving Hyperb Med. 2016 Jun;46(2):124.

Pre-emptive treatment with hyperbaric oxygen following radiation therapy for head and neck cancer may prevent the onset of late radiation tissue injury.

Wood D, Bennett M.

Comment on

J Am Chem Soc. 2016 Apr 27;138(16):5222-5. doi: 10.1021/jacs.6b01784. Epub 2016 Apr 13.

An Implantable Depot That Can Generate Oxygen in Situ for Overcoming Hypoxia-Induced Resistance to Anticancer Drugs in Chemotherapy.

Huang CC, Chia WT1, Chung MF, Lin KJ, Hsiao CW, Jin C, Lim WH, Chen CC, Sung HW.

Author information

  • 1Department of Orthopaedics, National Taiwan University Hospital, Hsinchu Branch , Hsinchu 30013, Taiwan, ROC.

Abstract

In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels.

Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.

Urology. 2016 Apr 25. pii: S0090-4295(16)30110-8. doi: 10.1016/j.urology.2016.04.015. [Epub ahead of print]

Evaluation of Hyperbaric Oxygen Therapy in the Treatment of Radiation-induced Hemorrhagic Cystitis.

Mougin J1, Souday V2, Martin F1, Azzouzi AR1, Bigot P3.

Author information

  • 1Department of Urology, Angers University Hospital, France.

  • 2Department of Medical Intensive Care and Hyperbaric Medicine, Angers University Hospital, France.

  • 3Department of Urology, Angers University Hospital, France. Electronic address: pibigot@chu-angers.fr.

Abstract

OBJECTIVE:

To evaluate the efficacy of hyperbaric oxygen therapy (HBO) in the treatment of postradiation hematuria (PRH) and to identify the predictive factors for a successful outcome.

MATERIALS AND METHODS:

We conducted a retrospective study and included all patients with PRH treated with HBO in a university hospital center between January 2003 and December 2013. We studied the patients' clinical characteristics, radiotherapy indication, treatments preceding HBO, the grade of hematuria diagnosed based on the Common Terminology Criteria for Adverse Events classification v 4.03 and the efficacy of HBO. The success of HBO was defined as the total or partial resolution of hematuria.

RESULTS:

We included 71 patients with a median age of 72 (39-87) years. PRHs were severe (grade ≥3) in 50 (70.4%) of the cases. Radiotherapy was indicated in the treatment of prostate cancer in 61 (85.9%) patients. The median length of time between hematuria and HBO was 8 (1-154) months. Prior to HBO, 46 (64.8%) patients underwent electrocoagulation of the bladder. HBO sessions were compounded by 9 cases of barotraumatic otitis, 5 cases of transient visual disturbance, and 1 case of finger paresthesia. On average, 29 (3-50) sessions were carried out. Treatment was effective in 46 (64.8%) patients, 37 (52.1%) of whom were completely cured. A hematuria grade of less than 3 was a predictive factor in the successful treatment (P = .027). Median follow-up was 15 (1-132) months.

CONCLUSION:

HBO completely resolves PRH in 52.1% of cases. Prolonged patient follow-up is required to confirm the efficacy of this treatment.

Cochrane Database Syst Rev. 2016 Apr 28;4:CD005005. doi: 10.1002/14651858.CD005005.pub4.

Hyperbaric oxygen therapy for late radiation tissue injury.

Bennett MH1, Feldmeier J, Hampson NB, Smee R, Milross C.

Author information

  • 1Department of Anaesthesia, Prince of Wales Clinical School, University of NSW, Sydney, NSW, Australia.

Abstract

BACKGROUND:

Cancer is a significant global health problem. Radiotherapy is a treatment for many cancers and about 50% of people having radiotherapy will be long-term survivors. Some will experience late radiation tissue injury (LRTI) developing months or years later. Hyperbaric oxygen therapy (HBOT) has been suggested as a treatment for LRTI based upon the ability to improve the blood supply to these tissues. It is postulated that HBOT may result in both healing of tissues and the prevention of problems following surgery.

OBJECTIVES:

To assess the benefits and harms of HBOT for treating or preventing LRTI.

SEARCH METHODS:

We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 11), MEDLINE, EMBASE, DORCTIHM and reference lists of articles in December 2015. We also searched for ongoing trials at clinicaltrials.gov.

SELECTION CRITERIA:

Randomised controlled trials (RCTs) comparing the effect of HBOT versus no HBOT on LRTI prevention or healing.

DATA COLLECTION AND ANALYSIS:

Three review authors independently evaluated the quality of the relevant trials using the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and extracted the data from the included trials.

MAIN RESULTS:

Fourteen trials contributed to this review (753 participants). There was some moderate quality evidence that HBOT was more likely to achieve mucosal coverage with osteoradionecrosis (ORN) (risk ratio (RR) 1.3; 95% confidence interval (CI) 1.1 to 1.6, P value = 0.003, number needed to treat for an additional beneficial outcome (NNTB) 5; 246 participants, 3 studies). There was also moderate quality evidence of a significantly improved chance of wound breakdown without HBOT following operative treatment for ORN (RR 4.2; 95% CI 1.1 to 16.8, P value = 0.04, NNTB 4; 264 participants, 2 studies). From single studies there was a significantly increased chance of improvement or cure following HBOT for radiation proctitis (RR 1.72; 95% CI 1.0 to 2.9, P value = 0.04, NNTB 5), and following both surgical flaps (RR 8.7; 95% CI 2.7 to 27.5, P value = 0.0002, NNTB 4) and hemimandibulectomy (RR 1.4; 95% CI 1.1 to 1.8, P value = 0.001, NNTB 5). There was also a significantly improved probability of healing irradiated tooth sockets following dental extraction (RR 1.4; 95% CI 1.1 to 1.7, P value = 0.009, NNTB 4).There was no evidence of benefit in clinical outcomes with established radiation injury to neural tissue, and no randomised data reported on the use of HBOT to treat other manifestations of LRTI. These trials did not report adverse events.

AUTHORS' CONCLUSIONS:

These small trials suggest that for people with LRTI affecting tissues of the head, neck, anus and rectum, HBOT is associated with improved outcome. HBOT also appears to reduce the chance of ORN following tooth extraction in an irradiated field. There was no such evidence of any important clinical effect on neurological tissues. The application of HBOT to selected participants and tissues may be justified. Further research is required to establish the optimum participant selection and timing of any therapy. An economic evaluation should be undertaken.

Lancet Oncol. 2016 Feb;17(2):224-33. doi: 10.1016/S1470-2045(15)00461-1. Epub 2015 Dec 17.

Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.

Glover M1, Smerdon GR2, Andreyev HJ3, Benton BE3, Bothma P4, Firth O5, Gothard L6, Harrison J7, Ignatescu M2, Laden G8, Martin S6, Maynard L9, McCann D10, Penny CE2, Phillips S10, Sharp G6, Yarnold J11.

Author information

  • 1Hyperbaric Medicine Unit, St Richard's Hospital, Chichester, UK.

  • 2DDRC Healthcare, Plymouth, UK.

  • 3The GI Unit, The Royal Marsden NHS Foundation Trust, London, UK.

  • 4Whipps Cross University Hospital, Leytonstone, London & East of England Hyperbaric Unit, Great Yarmouth, UK.

  • 5London Diving Chamber, Hospital of St John and St Elizabeth, London, UK.

  • 6Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.

  • 7North West Emergency Recompression Unit, Murrayfield Hospital, Wirral, UK.

  • 8North of England Medical and Hyperbaric Services, Spire Hull & East Riding Hospital, Kingston-upon-Hull, UK.

  • 9Clinical Trials and Statistics Unit at the Institute of Cancer Research, London, UK.

  • 10The Diver Clinic, Poole, UK.

  • 11Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. Electronic address: John.yarnold@icr.ac.uk.

Abstract

BACKGROUND:

Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies.

METHODS:

HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066.

FINDINGS:

Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related.

INTERPRETATION:

We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed.

FUNDING:

Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.

Cancer Radiother. 2016 Jun 21. pii: S1278-3218(16)30081-6. doi: 10.1016/j.canrad.2016.04.003. [Epub ahead of print]

[Hyperbaric oxygen and radiotherapy: From myth to reality].

[Article in French]

Espenel S1, Raffoux C2, Vallard A1, Garcia MA3, Guy JB1, Rancoule C1, Ben Mrad M1, Langrand-Escure J1, Trone JC1, Pigne G1, Diao P1, Magné N4.

Abstract

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.

Sci Transl Med. 2015 Mar 4;7(277):277ra30. doi: 10.1126/scitranslmed.aaa1260.

Immunological mechanisms of the antitumor effects of supplemental oxygenation

Hatfield SM1, Kjaergaard J1, Lukashev D1, Schreiber TH2, Belikoff B1, Abbott R1, Sethumadhavan S1, Philbrook P1, Ko K1, Cannici R1, Thayer M1, Rodig S3, Kutok JL3, Jackson EK4, Karger B5, Podack ER2, Ohta A1, Sitkovsky MV6.

Abstract

Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine.

We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice.

  • Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell- and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.

Cancer Res. 2014 May 15;74(10):2655-62. doi: 10.1158/0008-5472.CAN-13-3696. Epub 2014 Apr 28.

Releasing pressure in tumors: what do we know so far and where do we go from here? Hyperbaric Oxygen Therapy review

Ariffin AB1, Forde PF2, Jahangeer S2, Soden DM2, Hinchion J3.

Author information

  • 1Authors' Affiliations: Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork; and Department of Cardiothoracic Surgery, Cork University Hospital, Wilton, Cork, IrelandAuthors' Affiliations: Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork; and Department of Cardiothoracic Surgery, Cork University Hospital, Wilton, Cork, Ireland.

  • 2Authors' Affiliations: Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork; and Department of Cardiothoracic Surgery, Cork University Hospital, Wilton, Cork, Ireland.

  • 3Authors' Affiliations: Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork; and Department of Cardiothoracic Surgery, Cork University Hospital, Wilton, Cork, Ireland john.hinchion@hse.ie.

Abstract

Tumor interstitial pressure is a fundamental feature of cancer biology. Elevation in tumor pressure affects the efficacy of cancer treatment. It causes heterogenous intratumoral distribution of drugs and macromolecules. It also causes the development of hypoxia within tumor bulk, leading to reduced efficacy of therapeutic drugs and radiotherapy.

Tumor pressure has been associated with increased metastatic potential and poor prognosis in some tumors. The formation of increased pressure in solid tumors is multifactorial. Factors known to affect tumor pressure include hyperpermeable tortuous tumor vasculatures, the lack of functional intratumoral lymphatic vessels, abnormal tumor microenvironment, and the solid stress exerted by proliferating tumor cells.

 

Reducing this pressure is known to enhance the uptake and homogenous distribution of many therapies. Pharmacologic and biologic agents have been shown to reduce tumor pressure. These include antiangiogenic therapy, vasodilatory agents, antilymphogenic therapy, and proteolytic enzymes. Physical manipulation has been shown to cause reduction in tumor pressure. These include irradiation, hyperbaric oxygen therapy, hyper- or hypothermic therapy, and photodynamic therapy. This review explores the methods to reduce tumor pressure that may open up new avenues in cancer treatment.

Q J Nucl Med Mol Imaging. 2013 Sep;57(3):219-34.

Relevance of hypoxia in radiation oncology: pathophysiology, tumor biology and implications for treatment.

Busk M1, Horsman MR.

Tumors are characterized by an inefficient and disorganized vasculature which leads to tumor regions that are transiently or chronically undersupplied with oxygen (hypoxia) and nutrients (e.g., glucose). These adverse conditions are linked to treatment resistant and metastasizing disease with poor prognosis. Radiation sensitivity is dramatically lowered in hypoxic, yet viable and clonogenic, cells since oxygen is involved in the fixation of radiation-induced DNA damage (radiobiological hypoxia), and loco-regional tumor control is adversely affected in patients with hypoxic tumors. Hypoxia also leads to reduced sensitivity towards chemotherapeutics since drug delivery is reduced in hypoperfused hypoxic areas and hypoxic cells are quiescent, making drugs that target dividing cells ineffective. Fortunately, clinical attractive imaging and gene-expression based technologies that allows pre- and during treatment assessment of tumor hypoxia are now available. These technologies may identify patients suitable for established or emerging hypoxia-targeting treatments and, equally important; they allow us to monitor the efficacy of such intervention and may thus pave the way for effective individualized treatment. In the current review, we address 1) the causes and consequences of tumor hypoxia, 2) technologies that allow assessment of tumor hypoxia in individual patients and 3) current status of hypoxia-targeting treatments.

Undersea Hyperb Med. 2013 Jul-Aug;40(4):351-62.

Potential roles of hyperbaric oxygenation in the treatments of brain tumors

Kohshi K, Beppu T, Tanaka K, Ogawa K, Inoue O, Kukita I, Clarke RE.

  • Division of Hyperbaric Medicine and Emergency Medicine, University Hospital of the Ryukyus, Okinawa, Japan. kohshi@med.u-ryukyu.ac.jp

Abstract

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain.

HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas.

The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

Target Oncol. 2012 Dec;7(4):233-42. doi: 10.1007/s11523-012-0233-x. Epub 2012 Oct 2.

Hyperbaric oxygen therapy and cancer-a review - Hypoxia is a hallmark of solid tumors.

Summary of the hypoxia-induced factors influencing cancer growth and progression

Source

Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway, ingrid.moen@biomed.uib.no.

Abstract

Hypoxia is a critical hallmark of solid tumors and involves enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis.

Hyperbaric oxygen (HBO) treatment has for centuries been used to improve or cure disorders involving hypoxia and ischemia, by enhancing the amount of dissolved oxygen in the plasma and thereby increasing O(2) delivery to the tissue. Studies on HBO and cancer have up to recently focused on whether enhanced oxygen acts as a cancer promoter or not. As oxygen is believed to be required for all the major processes of wound healing, one feared that the effects of HBO would be applicable to cancer tissue as well and promote cancer growth. Furthermore, one also feared that exposing patients who had been treated for cancer, to HBO, would lead to recurrence. Nevertheless, two systematic reviews on HBO and cancer have concluded that the use of HBO in patients with malignancies is considered safe. To supplement the previous reviews, we have summarized the work performed on HBO and cancer in the period 2004-2012. Based on the present as well as previous reviews, there is no evidence indicating that HBO neither acts as a stimulator of tumor growth nor as an enhancer of recurrence.

  • On the other hand, there is evidence that implies that HBO might have tumor-inhibitory effects in certain cancer subtypes, and we thus strongly believe that we need to expand our knowledge on the effect and the mechanisms behind tumor oxygenation.

World J Gastroenterol. 2015 Oct 21;21(39):11168-78. doi: 10.3748/wjg.v21.i39.11168.

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy.

Tsukinaga S1, Kajihara M1, Takakura K1, Ito Z1, Kanai T1, Saito K1, Takami S1, Kobayashi H1, Matsumoto Y1, Odahara S1, Uchiyama K1, Arakawa H1, Okamoto M1, Sugiyama H1, Sumiyama K1, Ohkusa T1, Koido S1.

Author information

Abstract

AIM:

To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms' tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II-restricted WT1 peptides combined with chemotherapy.

METHODS:

During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity (DTH) test.

RESULTS:

Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (≥ 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.

CONCLUSION:

Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.

Cancers (Basel). 2011 Jun 27;3(3):2811-26. doi: 10.3390/cancers3032811.

Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer

Mukaida N, Sasakki S, Popivanova BK.

Source

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. naofumim@kenroku.kanazawa-u.ac.jp.

Abstract

The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer.

Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-kB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines.

The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice.

PLoS One. 2013 Nov 11;8(11):e78728. doi: 10.1371/journal.pone.0078728. eCollection 2013.

NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma

McFarland BC1, Hong SW, Rajbhandari R, Twitty GB Jr, Gray GK, Yu H, Benveniste EN, Nozell SE.

Author information

  • 1Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Abstract

Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance.

In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo.

We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness.

Int J Clin Oncol. 2013 Mar 5. [Epub ahead of print]

Old but new methods in radiation oncology: hyperbaric oxygen therapy

Ogawa K, Kohshi K, Ishiuchi S, Matsushita M, Yoshimi N, Murayama S.

Source

Department of Radiation Oncology, Osaka University, 2-2 D10, Yamadaoka, Suita, Osaka, 565-0871, Japan, kogawa@radonc.med.osaka-u.ac.jp.

Abstract

The presence of hypoxic tumor cells is widely regarded as one of the main reasons behind the failure to control malignant tumors with radiotherapy treatments. Since hyperbaric oxygenation (HBO) improves the oxygen supply to the hypoxic tumor cells, HBO therapy has previously been used in combination with simultaneous radiotherapy to treat malignant tumors.

In some clinical trials, significant improvements in local control and survival have been seen in cancers of the head and neck and the uterine cervix. However, the delivery of simultaneous HBO therapy and radiotherapy is both complex and time-consuming, with some trials reporting increased side effects. As a result, the regimen of HBO therapy in combination with simultaneous radiotherapy has yet to be used as a standard treatment for malignant tumors. In recent years, however, radiotherapy immediately after HBO therapy has been emerging as an attractive approach for overcoming hypoxia in cancer treatment. Several studies have reported that radiotherapy immediately after HBO therapy was safe and seemed to be effective in patients with high-grade gliomas. Also, this approach may protect normal tissues from radiation injury. To accurately estimate whether the delivery of radiotherapy immediately after HBO therapy can be beneficial in patients with high-grade gliomas and other cancers, further prospective studies are warranted.

Br J Pharmacol. 2013 Feb;168(3):591-606. doi: 10.1111/bph.12008.

Interleukins in glioblastoma pathophysiology: implications for therapy

Yeung YT1, McDonald KL, Grewal T, Munoz L.

Author information

  • 1Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.

Abstract

Despite considerable amount of research, the poor prognosis of patients diagnosed with glioblastoma multiforme (GBM) critically needs new drug development to improve clinical outcomes.

  • The development of an inflammatory microenvironment has long been considered important in the initiation and progression of glioblastoma; however, the success of developing therapeutic approaches to target inflammation for GBM therapy has yet been limited.

Here, we summarize the accumulating evidence supporting a role for inflammation in the pathogenesis of glioblastoma, discuss anti-inflammatory targets that could be relevant for GBM treatment and provide a perspective on the challenges faced in the development of drugs that target GBM inflammation. In particular, we will review the function of IL-1β, IL-6 and IL-8 as well as the potential of kinase inhibitors targeting key players in inflammatory cell signalling cascades such as JAK, JNK and p38 MAPK.