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Mechanism of hypercalcemia in HL has long been suggested to involve extra-renal activation of 1α-hydroxylase leading to production of 1, 25(OD)2 Vitamin D3 or Calcitriol, an active metabolite of Vitamin D, which leads to increased re-absorption of calcium and phosphate from intestine, increased osteoclast activation and bone resorption as well as increased phosphate re-absorption in renal tubules

Hypercalcemia of malignancy involves three mechanisms: 1. Humoral hypercalcemia mediated by PTHrP—seen in solid tumors like breast cancer and adult T cell leukemia/lymphoma (ATLL), 2. Direct osteoclast mediated bone resorption due to bony metastasis—seen in solid tumors and multiple myeloma, 3. Calcitriol mediated hypercalcemia—seen in Hodgkin’s and non-Hodgkin’s lymphoma as well as granulomatous disorders like tuberculosis, sarcoidosis, leprosy and disseminated Candidiasis

Hypercalcemia in HL is rare and its incidence has been reported as 0.9, 1.6 and 5.4 % in different series

The source of 1α-hydroxylase in HL has been postulated as monocytes and macrophages infiltrating the tumor akin to tuberculosis or sarcoidosis and is stimulated by IFN-γ secreted by T-lymphocytes

Like sarcoidosis, patients with HL exhibit increased sensitivity to Vitamin D supplements and sunlight, which have been found to precipitate hypercalcemia in these patients

Classical biochemical profile in Calcitriol mediated hypercalcemia include: an elevated calcium, normal/slightly elevated phosphate, normal 25(OH) Vitamin D, suppressed PTHrP and PTH, elevated Calcitriol and a normal/increased tubular reabsorption of phosphate

not been associated with a poorer prognosis and tends to subside after treatment of the underlying disease

The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis

The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8

four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders

growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy

glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population

blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively

glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”

Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death

changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy

lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes

the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis

these metabolic disturbances would be expected to remain extant after therapeutic interventions

accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients

Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)

liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis

cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress

pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels

ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors

Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)

Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals

In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid

Ascorbate is required for maintaining iron in the ferrous state

In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects

Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical

In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical

e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2

Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant