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MRI

Innovative MRI without Toxic Gadolinium Contrast Media

PreNuvo: Innovative MRI Technology

High-resolution radiology is used in oncology for both diagnoses as well as screening and monitoring. Because cancer cell physiology is metabolically different from healthy cells, contrast media are preferentially taken up by cancer cells allowing for more precise imaging.

Magnetic Resonance Imaging (MRI)  was invented in the 1980s.  It is a magnetic technology and does not expose patients to ionizing radiation, but to magnetic fields.  Hence it is considered safer than exposure to the damaging, oncogenic ionizing radiation found in X-Rays and PET and CT scans

Say No to Gadolinium
The most commonly used contrast medium used with MRI imaging to enhance resolution is Gadolinium. Gadolinium is a  magnetic metal that is engineered into a nanoparticle solution and injected into the vein.

Gadolinium can damage both nephrons and neurons and is not completely excreted leading to toxic load over time.  Because cancer patients may have multiple scans per year over many years, exposure to Gadolinium can become damaging and increasingly toxic. Gadolinium also acts as a calcium channel blocker and even at low concentrations can interfere with the contraction of smooth, skeletal, and cardiac muscle, nerve impulses, and blood coagulation. 

MRI-Man

Furthermore, there is a syndrome called Gadolinium deposition disease that is a gadolinium storage condition for which the long-term effects are not well understood.  A common adverse effect of Gadolinium exposure and retention is renal fibrosis.

Patients should discuss the risks of ALL contrast media with the radiology team to evaluate risks and benefits and be fully informed before proceeding with any scan.  Because all contrast media has toxicity, the opportunity to have a high-resolution scan without the use of Gadolinium contrast media is a very important innovation.

Patients with compromised cardiovascular, renal and neurologic function should use cautions before authorizing the performance of any scan without a full understanding of toxicity, risks, and benefits of contrast media

What if A High-Resolution MRI was possible without toxic contrast media?

PreNuvo has developed a High-Resolution MRI Scan that does not require the use of Gadolinium contrast media.

As with all technologies, MRI technology is advancing. Prenuvo is a company on the forefront of MRI Innovation bringing new safe and effective techniques not requiring contrast medium for high-resolution whole-body imaging, making accurate diagnosis possible.

Prenuvo uses innovative new hardware, software, and sequencing to create more detailed comprehensive images along with the use of Artificial Intelligence to enhance accurate analysis in less time.  Prenuvo claims a 0.7% false-positive rate due to the higher resolution, often decreasing the need for additional follow-up imaging, biopsies, or surgeries.  All without the use of Gadolinium or any other contrast media.

A more comfortable patient-centric experience:
A whole-body scan at Prenuvo typically takes 60 minutes compared to 5 hours for a conventional MRI.  The scanner itself is wider and more open and less claustrophobic with fresh air vents.  The machine is much quieter as opposed to the loud clanking of the conventional MRI.  The design also allows the patient’s head to remain outside of the scanner for most of the scan.  Innovative design and technology also solve many of the issues that lead to stress and anxiety for the patient that is common with MRI scans.  Additionally, a headset and a music menu are provided to support relaxation.

For a faster, safer, less toxic, and highly accurate MRI without contrast, I recommend that you explore the use of prenuvo.com for your patients.

(NB: I have no financial relationship whatsoever with  Prenuvo.)

Selected References:

resveratrol

Resveratrol, Estrogen and Breast Cancer

Phytochemical Aromatase Inhibition

Estrogen Receptor Positive is a prevalent form of breast cancer that has been effectively treated by targeting the proliferative estrogen pathway. .   Typically pre-menopausal women will be given SERMS (Selective Estrogen Receptor Modifiers such as Tamoxifen) which blocks the effect of circulating estrogen on receptor binding, thus inhibiting estrogen stimulation and function.  Tamoxifen and SERMS also have significant adverse effects:  increasing thrombosis, endometrial proliferation, and cancer stem cells.   

resveratrol-cancer

Another category of hormonal therapies includes SEEMS ( Selective Estrogen Enzyme Modulators, such as Aromatase Inhibitors) including letrozole and Arimidex, which block the conversion of androgens to estrogens in the tissue by inhibiting the aromatase enzyme. SEEMS are primarily recommended to post-menopausal women.  While most studies on resveratrol and its impact on cancer metabolism are murine or cell studies, the evidence is compelling.   Most human studies have been focused on the cell-protective, anti-aging, anti-oxidant and anti-inflammatory properties of resveratrol. Here we take a look at the aromatase inhibition properties of resveratrol.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phytochemical that belongs to the stilbenoids group of phytophenols.  It is a natural plant compound found in the skin of red grapes, red wine, red grape juice, Japanese Knotweed (Polygonum cuspidatum), and in small amounts in some berries such as blueberries, mulberries, lingonberries, bilberries, red currants, cranberries and in small amounts in pistachios and peanuts. 

In one study both resveratrol, as well as melatonin, were found to be aromatase inhibitors and to have an inhibitory effect equivalent to letrozole, a commonly prescribed aromatase inhibitor drug.

Although this was true in cell culture, it has not been seen in human studies, primarily due to the fact that resveratrol has a low absorption rate when taken orally.   

Estrogen receptor-positive Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.

 

Another cell culture study demonstrated that resveratrol could inhibit aromatase at both the enzyme and mRNA expression levels and that there was a significant transcriptional control of the CYP19 gene which promotes cell proliferation in breast tissue. The research concluded that these phytochemicals can be used to target allosteric binding sites on the aromatase enzyme.

A more recent study demonstrated the anti-proliferative effect on Estrogen Receptor positive (ER+)  breast cancer cells by effectively targeting allosteric binding sites on the aromatase enzyme by resveratrol, chrysin, and apigenin. The study also included berberine and pomiferin as promising phytochemical aromatase inhibitors.  High-quality berberine is readily available and has a broad range of therapeutic actions including impacting over 20 pathways involved in cancer cell metabolism, inflammation, and bacterial pathogen control.  

Wang Y, Lee KW, Chan FL, Chen S, Leung LK. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci. 2006 Jul;92(1):71-7. doi: 10.1093/toxsci/kfj190. Epub 2006 Apr 11. PMID: 16611627.

A similar study showed that resveratrol can inhibit the CYP19 promoter gene via transcriptional control by reducing estradiol mRNA abundance through aromatase inhibition.  This leads to an anti-proliferative effect.

Wang Y, Ye L, Leung LK. A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol. Toxicology. 2008 Jun 27;248(2-3):130-5. doi: 10.1016/j.tox.2008.03.017. Epub 2008 Mar 29. PMID: 18462857.

The research on the impact of resveratrol on estrogen receptor-positive breast cancer proliferation and aromatase inhibition has fueled the development of several “enhanced” more bioactive resveratrol steroid analogues which may be more effective and have greater absorption than the form found in nature. 

In my clinical experience, resveratrol is a weak aromatase inhibitor and does not offer the level of protection provided by pharmaceuticals, but is also well-tolerated and without many of the adverse effects of aromatase inhibitors drugs. (Joint pain, fatigue, sleep disruption, vaginal dryness, hot flashes).  I will give 3-5 grams of pure resveratrol powder daily in 2 divided doses. To overcome the low absorption rate of resveratrol.  I always give it a high-fat food such as nut butter or full-fat yogurt and mix in cinnamon and ginger not only to improve the taste but also to enhance digestion and absorption.  This may be a good option for women who stop taking aromatase inhibitors due to unacceptable side effects negatively impacting their Quality of Life. Pharmacologic dosing of resveratrol can offer a mild aromatase inhibitory protective effect to these women along with over 50 additional pathways contributing to health and longevity.

Alhadrami HA, Sayed AM, Melebari SA, Khogeer AA, Abdulaal WH, Al-Fageeh MB, Algahtani M, Rateb ME. Targeting allosteric sites of human aromatase: a comprehensive in-silico and in-vitro workflow to find potential plant-based anti-breast cancer therapeutics. J Enzyme Inhib Med Chem. 2021 Dec;36(1):1334-1345. doi: 10.1080/14756366.2021.1937145. PMID: 34139914; PMCID: PMC8759730.

Kang H., Xiao X., Huang C., Yuan Y., Tang D., Dai X., Zeng X. Potent aromatase inhibitors and molecular mechanism of inhibitory action. Eur. J. Med. Chem. 2018;143:426–437. doi: 10.1016/j.ejmech.2017.11.057. - DOI - PubMed

Sainsbury R. The development of endocrine therapy for women with breast cancer. Cancer Treat. Rev. 2013;39:507–517. doi: 10.1016/j.ctrv.2012.07.006. - DOI - PubMed

Zhao H., Zhou L., Shangguan A.J., Bulun S.E. Aromatase expression and regulation in breast and endometrial cancer. J. Mol. Endocrinol. 2016;57:R19–R33. doi: 10.1530/JME-15-0310. - DOI - PMC - PubMed

copper-drive

How does Copper Drive Cancer Progression?

Key Takeaways:

This initiation of Angiogenesis is one of the steps of disease progression and acceleration, Creating an environment where this is contained is very powerful.

  • Controlling Copper and Angiogenesis is a mechanism
  • No one ever dies of a primary tumor for the most part, it is metastatic disease that kills the cancer patients
  • The more we can contain tumor progression, travel and desize, patients can live with metastatic disease for quite a long time, if we can control it
  • There's no kill rate to the tumor cell when you inhibit Angiogenesis, by any means whether it's a drug or copper culation
  • If we lower copper in a patient whose had a good reduction of their tumor burden, by any means, surgery, chemotherapy and immunotherapy... And then we track their copper, keeping copper in the lowest quartile of normal, usually their disease does not progress.
  • You reduce Inflammation when you reduce copper

cancer-patient-cancer-doctor

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breast-bone-cancer

The Link between Bone Density and Breast Cancer Risk

Understanding and Monitoring Risk Factors

Bone density, or bone mineral density ( BMD ), is the amount of bone mineral in bone tissue.  Bone mineral density (BMD) is a lifetime marker of estrogen exposure in a woman's body and has been associated with increased breast cancer risk. Estrogen is a crucial factor in maintaining bone density and gradually decreases over age. While there are many factors that influence bone density and bone health, the presence of estrogen contributes to the capacity of bone to continuously remodel and maintain the dynamic balance between bone resorption and bone formation.  A woman’s exposure to estrogen over the life cycle may contribute to her risk of breast cancer.

breast-cancer

Bone density measurement is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.  There is a clear association between poor bone density and a higher probability of fracture.  There is a clear association between poor bone density and low estrogen levels.  Conversely, there is a clear association between increased and healthy bone density and higher estrogen levels.

pink-ribbonScreening for risk of breast cancer should ALSO include assessment of estrogen levels and bone density along with well-recognized risk factors which include first degree relatives, obesity, increased visceral fat, smoking, alcoholism, early menarche, late menopause, sedentary lifestyle, hormone replacement therapy, and prolonged estrogen exposure, increased density of breast tissue. 

I would also add exposure to environmental endocrine disruptors and imbalances in the intestinal microbiome influencing estrogen metabolism.  

Breast density and bone density are related to endogenous and exogenous estrogen exposure in a woman’s body.  There is a correlation between estrogen exposure, high breast density, high bone density, and increased risk of breast cancer.

Bone is living metabolically active tissue. “Bone remodeling is the process by which bone is renewed to maintain bone strength and mineral homeostasis. Remodeling involves continuous removal of discrete packets of old bone, replacement of these packets with newly synthesized proteinaceous matrix, and subsequent mineralization of the matrix to form new bone begins before birth and continues until death.  Bone remodeling increases in perimenopausal and early postmenopausal women and then slows with further aging, but continues at a faster rate than in premenopausal women. Bone remodeling is thought to increase mildly in aging men.”  Normal Bone Anatomy and Physiology 10.2215/CJN.04151206

Engaging in a health model for all patients includes assessing and managing bone health to promote healthy bone over the life cycle. A health model for cancer patients, due to the typically older age demographics will inherently include a large population of patients already at risk for loss of bone mass, osteopenia and osteoporosis. Screening for bone mineral density and managing bone health should be part of whole-person, whole health care. Taking a thorough history that includes family history, bone health and bone mineral density can bring attention to patients at higher risk for low bone density and fracture as well as patients with a higher risk of estrogen driven breast cancers.

Bone density measurement is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.  There is a clear association between poor bone density and higher probability of fracture.  There is a clear association between poor bone density and low estrogen levels.  Conversely there is a clear association between increased and healthy bone density and higher estrogen levels.

The Most Common Risk Factors for Low Bone Density and Primary Considerations for a Bone Density Test include:

bone-density 

  • Females age 65 or older
  • Males aged 70 or older
  • People over age 50 with
    • previous bone fracture from minor trauma
    • rheumatoid arthritis
    • low body weight
    • a parent with a hip fracture
  • Individuals with vertebral abnormalities
  • Individuals receiving, or planning to receive, long-term glucocorticoid therapy
  • Individuals with primary hyperparathyroidism
  • Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy
  • Individuals receiving androgen deprivation therapy 
  • Individuals with a history of eating disorders

Additional factors that are related to the risk of low bone density and the need for assessment include smoking, alcohol intake, long-term use of corticosteroid drugs, sedentary or convalescent lifestyle, protein status, mineral status, digestion, and absorption function, chronic inflammation and vitamin D status.  

For cancer patients and survivors also consider periods of poor nutrition, calorie, protein status, convalescence, lack of exercise, effect of hormonal therapies, oophorectomy, orchiectomy, chemotherapy, immunotherapy, treatment induced thyroiditis, gastritis, enteritis and colitis,  chronic pain impacting appetite, digestive and absorptive dysfunction, surgical loss of gastrointestinal organs and function as contributors to risk of loss of bone density and as well as multiple and varied adverse effects of cancer physiology and cancer treatments upon nutritional status and active lifestyle.

Selected References 

Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008 Nov;3 Suppl 3(Suppl 3):S131-9. doi: 10.2215/CJN.04151206. PMID: 18988698; PMCID: PMC3152283.

Fraenkel M, Novack V, Mizrakli Y, Koretz M, Siris E, Norton L, Shafat T, Geffen DB. Bone mineral density in women newly diagnosed with breast cancer: a prospective cohort study. NPJ Breast Cancer. 2022 Feb 17;8(1):21. doi: 10.1038/s41523-022-00388-z. PMID: 35177701; PMCID: PMC8854387.

Zain NM, Seriramulu VP, Chelliah KK. Bone Mineral Density and Breast Cancer Risk Factors among Premenopausal and Postmenopausal Women A Systematic Review. Asian Pac J Cancer Prev. 2016;17(7):3229-34. PMID: 27509955.

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breast-cancer

Should PreMenopausal Breast Cancer Patients Receive Endocrine Therapy?

 

Endocrine Therapy Provides TwentyYear Benefit in ER+ Breast Cancer

Integrative and Individualized cancer care is the best cancer care and yields the best long term outcomes. Making individualized care decisions and including a health model, not just a disease model and following the OutSmart Cancer® Diet Guidelines are core principles of the OutSmart Cancer® System.

Two years of adjuvant endocrine therapy in premenopausal patients with estrogen receptor-positive (ER+) breast cancer can reduce the risk of recurrence at 20 years, according to a study published in the Journal of Clinical Oncology. (2)  This study is meaningful because many oncologists recommend five to ten years of endocrine therapy.  This study clearly demonstrates that only two years is sufficient to significantly reduce risk of breast cancer recurrence 20 years after completion of conventional oncology treatment.  This study also demonstrates that women who are candidates for and who do not receive endocrine therapy have worse outcomes. 

Furthermore this study demonstrates that women with low genomic risk should receive tamoxifen and women with high genomic risk should receive goserilin for best long term outcomes.

By including an integrative approach utilizing the health principles of the OutSmart Cancer® System, we can further manage the side effects of these treatments and support healthy function and quality of life for these women.

OUTSMART CANCER SYSTEM® Integrative Approach and Health Focussed Model

chinese-characterEspecially supportive to management of adverse menopausal effects of endocrine therapy include acupuncture therapy(3), copper free bone mineral formula and optimized Vitamin D as well as traditional Chinese Herbal Tonics

 that nourish yin and blood and support kidney qi to modulate menopausal symptoms without estrogenic effects such as Er Xian Tang (Two Immortals Formula)  and also formulas to address hormone depletion related mood dysregulation, depression and irritability such as Shu Gan Tang (Buplerum and Evodia Combination) to harmonize the liver qi and relieve stagnation of blood and emotions.  Furthermore, patients with estrogenic cancers should be given guidance on restricting estrogenic foods from their diets as part of a lifelong plan to prevent recurrence. For example,  both red meat (7) and alcohol (6) are known carcinogens linked to promotion of breast cancer and should be restricted.  Following the OutSmart Cancer® Diet Guidelines is recommended 

Monitoring for complications of endocrine therapies

Patients receiving Tamoxifen therapy  (an oral selective estrogen receptor modifier) should have semi-annual uterine ultrasound to measure endometrial thickness to assess risk of uterine hyperplasia and neoplasm as a risk of tamoxifen therapy.

Patient receiving goserilin  (an injectabl luteinizing hormone releasing hormone antagonist administered subcutaneously either every month or every 3 months) should monitor bone density by having a baseline DEXA bone density scan at inception and at 2 years and also Urine N-Telopeptide assay to monitor rate of loss of bone minerals due to medical menopause and estrogen blockade.

Results of Study

Researchers observed significant improvements in long-term distant recurrence-free interval (DRFI) for patients who received goserelin alone, tamoxifen alone, or the combination of goserelin and tamoxifen, when compared with patients who did not receive endocrine therapy. 

However, combination goserelin and tamoxifen did not improve DRFI when compared with either agent alone.

Researchers assessed the 20-year benefit of endocrine therapy by analyzing data from the Stockholm trial (1990-1997). The analysis included 584 patients with ER+ breast cancer. The median age at baseline was 47 (range, 26-55) years, 91% of patients had progesterone receptor-positive tumors, and 88% had HER2-negative tumors.

Patients were randomly assigned to 2 years of goserelin (n=155), tamoxifen (n=135), combined goserelin and tamoxifen (n=149), or no adjuvant endocrine therapy (n=145).

In a multivariable analysis, any endocrine therapy was associated with a significant improvement in long-term DRFI, when compared with no endocrine therapy. 

There was a significant improvement in DRFI with goserelin alone (hazard ratio [HR], 0.49; 95% CI, 0.32-0.75), tamoxifen alone (HR, 0.57; 95% CI, 0.38-0.87), and goserelin plus tamoxifen (HR, 0.63; 95% CI, 0.42-0.94). 

However, there was no significant long-term benefit from the combination of goserelin plus tamoxifen, when compared with either agent alone. There was a significant interaction between goserelin and tamoxifen (P =.016). 

The researchers also assessed the long-term benefit of endocrine therapy in patients with low genomic risk (n=305) and those with high genomic risk (n=158). 

Patients with low-risk genomics had a significant improvement in DRFI with tamoxifen (HR, 0.24; 95% CI, 0.10-0.60), and patients with high-risk genomics had a significant improvement in DRFI with goserelin (HR, 0.24; 95% CI, 0.10-0.54).

Patients with high-risk genomics had significantly worse DRFI when tamoxifen was added to goserelin (HR, 3.36; 95% CI, 1.39-8.07). The interaction between goserelin and tamoxifen was significant in high-risk patients (P =.006) but not in low-risk patients (P =.080). 

“This study demonstrates long-term benefit from 2 years of adjuvant endocrine therapy in ER-positive premenopausal patients,” the researchers concluded. “Furthermore, it suggests long-lasting benefit from tamoxifen in genomic low-risk patients with long-term risk of distant recurrence, whereas genomic high-risk patients have early risk and benefit from goserelin.”

Isoflavones genistein and daidizen are phytochemicals derived from soy act  that act as MILD selective estrogen receptor modulators. These isoflavones need to be taken in very high doses on a long term basis to achieve a clinical impact and are mild in comparison to pharmaceuticals.  A recommended daily dose of genistein is 1000mg 3x/day

This study will help us support patients in making educated and informed choices and in making sure that their oncologists are practicing in accordance with the most current research and guidelines and that patients 

 

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Using Phytochemicals

Using Phytochemicals Synergistically with Chemotherapy to Improve Efficacy and Outcomes

 

The role of polyphenols in overcoming drug resistance. 

In a paper published in January 2022, Maleki Dana et al, engage in a thorough review of multiple polyphenols which, when used concurrently with chemotherapy, can inhibit the development of chemo-resistance, rendering treatment more effective and for a longer duration of time.    

Most oncologists are wary of negative drug-herb, drug nutrient interactions. 

 

polyphenols-fruits

This review shows that we can use polyphenol phytochemicals synergistically with chemotherapy treatments to support efficacy and outcomes.

 

The Outsmart Cancer® System is an Integrative Cancer Care model seeking to develop highly individualized care plans that include the best therapeutic approaches and tools from multiple disciplines, combining a disease focused targeted pathology model with a whole biosystem health model to support the best outcomes for patients.

 

Acquired drug resistance has become a challenge that may result in treatment failure.  Multiple factors contribute to chemo-resistance in cancer cells. Acquired drug resistance occurs when cancer cells fail to respond to a previously effective treatment.  Intrinsic  chemo-resistance occurs when a pre-existing factor causes a drug to be inefficient or ineffective.

 

Due to the inherent heterogeneity of tumors, subpopulations of cells may develop resistance while other subpopulations remain sensitive to treatment.  

This is the rationale for using multiple agents which impact multiple signally pathways and receptors to target a wide array of heterogeneous cells.  This is also the rationale for using multiple nutriceuticals, botanicals and phytochemicals concurrently to address multiple signaling pathways and functions.

In this excellent review paper the author focuses on the multiple synergistic functions of polyphenols citing multiple studies.

 

Polyphenols from medicinal plants and food plants form a large part of our Materia Medica. Polyphenols include several subclasses such as catechins, flavonoids, flavones, flavonols, anthocyanins, isoflavones, curcuminoids, chalcones and phenolic acids. These natural compounds are widely found found in deeply pigmented fruits, vegetables, cocoa, seeds and green and black teas,

 

Not only do polyphenols inhibit multiple pathways and mechanisms of drug resistance, but also act to  confront many of the Hallmarks of Cancer, thus inhibiting and controlling the activity and viability of malignant cells.

 

The multiple functional roles of

  • Resveratrol
  • EGCG Epigallocatechin gallate
  • Curcumin 

are discussed and examined in depth examining multiple pathways, mechanisms of action and dosing.

Also discussed are additional well researched polyphenols, many of which are sourced from food plants as well as medicinal plants including

  • Quercetin 
  • Baicalin
  • Baicalien
  • Apigenin
  • Chrysin
  • Luteolin
  • Kaempferol

Mechanisms which lead to drug resistance in tumor cells

Malignant cells are highly adaptive and respond to toxic stressors such as chemotherapeutic drugs in the tumor micro-environment in service to their own survival.  Essential malignant cells are “smart” and they can not only co-opt normal physiologic and metabolic functions within cells to respond to the presence of toxic drug therapies.

  • Decreased Drug Uptake by tumor cells
  • Drug Efflux from tumor cells (membrane pumps)
  • Alterations in drug metabolism
  • Epigenetic Modification and Signaling
  • Inhibition of Programmed Cell death via apoptosis, autophagy and necrosis in tumor cells
  • Alterations in DNA repair 
  • Activity of Cancer Stem Cells
  • Redox Capacity of cells in response to oxidative stress
  • Alterations in Epithelial to Mesenchymal Transition, Invasion and Metastatic Progression

Not only are polyphenols capable of addressing the common Hallmarks of Cancer, but they can also inhibit the multiple ways that malignant cells seek to survive in the face of drug therapies.  

 

Therefore, we should strategically combine chemo-therapeutic  agents with selected polyphenols to both enhance therapeutic effect as well as inhibit the development of drug resistance. 

 

This leads to greater therapeutic benefit, increased duration of action as well as skillful management of adverse effects.

I encourage you to read this paper in detail for a deep and detailed review of the mechanisms of these pleomorphic multitaskers polyphenols.  The polyphenols mentioned in this paper have a history of wide use and safety.

 

Our role is to both eradicate and inhibit neoplastic cells as well as nurture and support the health of the patient.  This is at the heart of the OutSmart Cancer® System.

 

References

 

The Role of Polyphenols in Overcoming Cancer Drug Resistance: A Comprehensive Review 

Maleki Dana et al

Cellular and Molecular Biology Letters (2022) 27:1

https://doi.org/10.1186/s11658-021-00301-9

 

Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg, 2011

https://doi.org/10.1016/j.cell.2011.02.013

 

Revisiting the hallmarks of cancer

Fouad YA, Aanei C.. Am J Cancer Res. 2017 May 1;7(5):1016-1036. PMID: 28560055; PMCID: PMC5446472.

 

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Clinical Pearl-cancer

Clinical Pearl: Chemotherapy Reduces Magnesium to Dangerously Low Levels

 

Hypomagnesia occurs in 29-100% of cancer patients receiving chemotherapy.

Magnesium deficiency is common in cancer patients, especially those receiving chemotherapy.  Magnesium is the second most abundant intracellular cation after potassium. It is involved in >600 enzymatic reactions in the body.

Hypomagnesia induces  fatigue , mitochondropathy (compromised mitochondrial function )and risk for neuropathy, nephropathy as well as abnormal cardiovascular function (arrhythmia, hypertension) immune dysfunction, headache and altered bone and Vitamin D metabolism.  Hypomagnesia is associated with nausea, vomiting, headache, myalgia, constipation, anxiety, insomnia and depression, all common complaints of cancer patients.

Long term and extreme hypomagnesia promotes cancer treatment related fatigue, cortical blindness, insulin resistance, prolonged QT interval, hypertension, seizures, tremor, psychiatric disturbances, migraine headaches and is associated with chronic inflammation and oxidative stress.

Magnesium status declines with age.

As cancer patients are typically over 50 years old, hypomagnesia may be present long before diagnosis. Pre-menopausal women and athletes also have higher needs of magnesium and may be deficient. 

This may influence the tumor microenvironment towards carcinogenesis, tumorogenesis, proliferation and progression.

Both oral and intravenous repletion relieve many of the hypomagnesia related adverse effects.

Adverse effects can be prevented by supplementing with magnesium in advance of as well as after chemotherapy. In a health model, keep patients replete with Magnesium at times to optimize function, prevent deficiency syndromes and adverse symptoms of chemotherapy.

Monitoring and Management of Magnesium Status

All patient care plans include oral Magnesium Glycinate Chelate

Daily Dose: 600-900mg daily in capsule, liquid or powder form

(Glycinate and Bis-Glycinate chelates are more well absorbed and less likely to have a laxative effect than other forms of magnesium chelate). Excess oral magnesium can lead to diarrhea. Spread out oral dosing over 3-4 doses per day to achieve repletion without loose stool.

Extreme Hypomagnesia can be quickly repleted by intravenous infusion.

All patients are monitored for Serum RBC Magnesium to assess magnesium status every 3-6 months long-term and monthly during active chemotherapy.

Serum Magnesium is not a reliable indicator of Magnesium deficiency.

Dietary Sources of Magnesium include:

Almonds, cashews, brazil nuts, pumpkin seeds, flaxseeds, cocoa, avocados, dark leafy greens, seaweed

 

Chemotherapeutic agents that induce hypomagnesia:

Platinum Chemotherapy Agents : Oxaliplatin, Cisplatin, Carboplatin and

Taxanes:  paclitaxel (Taxol) nab-paclitaxel (Abraxane), docetaxel (Taxotere),Cabazitaxel (Jevtana).

Vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine.

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Biomarker Lactic Acid Dehydrogenase Predicts Cancer Progression and Overall Survival

Aberrant metabolism and inefficient fuel production are characteristic of tumor cells, which are dominated by aerobic glycolysis, increased lactate production, and a higher uptake of glucose (the Warburg effect). Elevated LDH is a marker of these aberrant metabolic processes in cancer cells. High serum LDH levels are associated with poor prognosis in patients with cancer and predict progression and overall survival.

Aerobic glycolysis was described for the first time about a century ago by Otto H. Warburg who showed that cancer cells metabolize glucose differently than normal cells (Warburg effect) and that tumors derive energy mainly from the conversion of glucose to lactic acid and minimally via cellular respiration involving oxygen. Tumors produce massive amounts of the aerobic glycolysis waste product, lactic acid. This is evidence of deregulated metabolism, hence the understanding of cancer as a  “disorder of cellular metabolism”.  Lactic Acid itself may promote the growth and spread of cancer cells, especially at high concentrations by changing the tumor microenvironment.

Lactate dehydrogenase (LDH) is an enzyme that catalyzes the reduction of pyruvate to lactate at the end of the glycolytic pathway.

The normal range for LDH is 100-333 u/L, with levels greater than 245 u/L considered to be in the upper quartile of normal.  Elevated LDH, above 245 u/L, is suggestive of early carcinogenesis, tumor cell proliferation, tumor progression, and poor prognosis.

LDH is often highly elevated in aggressive forms of cancer and hematological malignancies including melanoma, lymphoma, acute leukemia, seminoma germ cell, pancreatic, gastric, lung, renal cell, nasopharyngeal, esophageal, cervical, and prostate cancers.

The OutSmart Cancer System® recognizes cancer as a metabolic syndrome and leverages the abnormal metabolism of tumor cells to exert influence over the tumor microenvironment and the behavior of tumor cells. Attending to the Cancer Terrain is a fundamental approach for influencing cancer cell metabolism.  

EGCG, a catechin found in Green Tea (H. Camellia sinensis) has been identified as an agent which inhibits LDH activity in normal and low oxygen environments by influencing the conversion of pyruvate to lactate at the end of the glycolytic pathway.  This may deprive cancer cells of their preferred fuel, glucose, and metabolites, including lactate that produces a favorable environment for malignant proliferation, growth, and progression. Recommended Therapeutic Dose 1-3 grams daily.

Monitoring trends in LDH is a method of both identifying abnormal cellular metabolism found in many solid and hematologic malignancies and is also of value in identifying early signs of recurrence as well as disease progression.

For patients achieving remission, during the first two years after completion of cancer treatment, LDH and other biomarkers of the Cancer Terrain are monitored every 3 months.  Thereafter, every six months for 3-10 more years to track and identify early signs of recurrence.  

For patients living with cancer as a chronic illness, LDH and biomarkers of the Cancer Terrain are monitored every 3 months to track evidence of recurrence and treatment resistance.

 

Learn more about monitoring the Cancer Terrain and the Tumor Microenvironment.
Receive training in Dr. Nalini’s OUTSMART CANCER SYSTEM ®. www.aiiore.com

By using biomarkers of the Cancer Terrain and cellular metabolism, it is possible to identify trends that allow for early intervention. LDH is one of the most valuable and reliable biomarkers reflecting the active presence of the aberrant physiology of tumor cells and is prognostic and predictive of progression and overall survival in cancer patients.

 

Selected References:

Oral Cancer AIIORE Blog

Phytochemicals in Oral Cancer Prevention and Therapy

Oral cancers originate in the oral cavity and may spread to the neck and throat and local lymph nodes and can metastasize. These cancers are most commonly squamous cell carcinomas and are often very aggressive.

Cancers of the oral cavity, head, and neck are linked to drinking alcohol, smoking tobacco, betel nut chewing, human papillomavirus infection, and nutritional deficiencies.

Phytochemicals are a useful adjunct therapy for both prevention and therapy.

The continuous increase in cancer cases, the failure of conventional chemotherapies, and the excessive toxicity of chemotherapies demand alternative cancer treatments.

Phytochemicals can inhibit or antagonize factors, which are dysregulated in cancer cells and may enhance the effects of conventional therapy or could be developed into a stand-alone therapy*

Phytochemicals may exert their chemopreventive properties by blocking the critical events of tumor initiation and promotion, thereby reversing the premalignant stage. Phytochemicals may also prevent tumorigenesis by inhibiting or slowing tumor progression or promoting cell differentiation. Furthermore, phytochemicals can enhance innate immune surveillance and improve the elimination of transformed cells.”**

Phytochemicals that impact multiple pathways active in the development, growth, progression, and spread of oral cancers include

Phytochemicals in Oral Cancer
  • Black Raspberry anthocyanins
  • Green Tea Catechins (EGCG, EGC, ECG)
  • Curcuma longa (curcuminoids) (tumeric)
  • Alliums: Garlic and Onions (allicin, s-allylcysteine)
  • Resveratrol 3,4’,5-trihydroxy-trans-stilbene
  • Lycopene carotenoid (tomatoes, red bell peppers)
  • Astaxaxanthin and Canthaxanthin  carotenoid xanthophylls  (green leafy vegetables)
  • Bromelain cysteine protease (pineapple)

For a detailed and thorough discussion of risk factors, etiologies, signs and symptoms, histopathology, molecular mechanisms and therapeutic interventions in oral, head, and neck cancers see: 

*Tzu-Ying Lee , Yu-Hsin Tseng Review : Biomolecules  The Potential of Phytochemicals in Oral Cancer Prevention and Therapy: A Review of the Evidence 2020 Aug 6;10(8):1150. doi: 10.3390/biom10081150

** Kotecha R., Takami A., Espinoza J.L. Dietary phytochemicals and cancer chemoprevention: A review of the clinical evidence. Oncotarget. 2016;7:52517–52529. doi: 10.18632/oncotarget.9593.

 

The Connection Between Breast Cancer and The Environment

Breast Cancer is the most commonly diagnosed malignancy in women.

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There is a continually expanding and compelling volume of data linking breast cancer to exposure to environmental toxins, radiation and endocrine disrupters lead to increased incidence of breast cancers.

When taking a thorough history of our patients we must include a review of their “Exposome”

Genetic and Genomic factors, Reproductive history, lifestyle factors such as weight, alcohol consumption, smoking and lack of physical exercise all contribute to increased risk profiles. Socioeconomic status as well as psychological health and resilience, all influence outcomes. Racial and ethnic minorities are often exposed to a disproportionately higher level of environmental toxins in the US. Immigrants may have lived in areas where there are no environmental regulations or controls.

Exposures to common chemicals found in products used every day contribute to a lifetime burden of toxic chemicals. The greatest rise in the incidence of breast cancers occurred in the decades after World War II when there were exponential increases in the use of herbicides, pesticides, plastics, cosmetics and body care products.

Cancer is often a perfect storm of genetics and environment. While studies are done on single agents, the reality is that we are living in a toxic chemical soup in modern life exposing us to a myriad of chemicals from multiple sources on a daily basis.

A common chemical BPA (Bisphenol A) is an endocrine disruptor. Exposure to BPA early in life contributes to breast displasias later in life due to its impact on mammary gland gene expression. BPA is found in plastics, linings of canned food containers and credit card receipts.

Limit exposure to plastics, polycarbonate food and water containers and canned foods to reduce BPA exposures. Breastfeeding women should be cautious as BPA is found in human breast milk.

Parabens, p-hydroxybenzoic acid esters, are widely used preservatives in personal care products and cosmetics. Parabens are endocrine disruptors. Parabens enable the Hallmarks of Cancer, characteristics of tumor cell survival and proliferation through multiple pathways. Parabens are also found in human breast milk. Parabens bind to estrogen receptors, inhibit apoptosis, promote proliferation, angiogenesis and metastasis. A lifelong commitment to avoiding all products that contain parabens will dramatically reduce exposures. Many European countries have banned the use of parabens. European made products are often paraben free as well as select brands made in the US.

Visit the Environmental Working Group Cosmetics Data base https://www.ewg.org/skindeep/ for a list of safe and not so safe products.

Single Nucleotide Polymorphisms in P450 enzymes, particularly CYP1BI metabolism. Mulitple methylation pathways also influence detoxificaton pathways and estrogen metabolism.

A healthy microbiome, particularly rich in Bifidobacteria and butyrate support normal estrogen conjugation and excretion. MANY breast cancer treatments contribute to dysbiosis, increased inflammation and alterations in estrogen metabolism and mood.

Pelvic and Abdominal radiotherapy, surgeries, chemotherapy agents, steroids, antibiotics administered to cancer patients and compromise gut health, immunity and inflammation control. Increasing butryate in the intestines improves the health of the microbiome.

Butyrate and the health of intestinal microbiome can be easily increased by ingesting 6-8 grams of soluble fibers daily. The Onion-Garlic family and the Brassica-Cabblage family vegetables are high in soluble fibers.

The use of oral contraceptives, fertility drugs and hormone replacement therapy all alter breast tissue. Thus, medical care itself leads to nosocomial trends in breast cancer. Patients BEWARE!!!

Many pesticides and herbicides cause endocrine disruption. Commercial production of many animal food sources including the additional of estrogens and growth hormones to feed.

Patients should be well versed and take a tour of their home room by room to identify toxic, endocrine disrupting chemical exposures.

Patients can be overwhelmed when we give them a long list of products and foods to avoid.

In our clinic we employ nutritional health coaches to assist patients in successfully implementing a lifestyle and diet that reduces exposures to estrogenic environmental chemicals.

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