Lymphoma with hypercalcemia

A prospective survey was carried out to determine the incidence of hypercalcemia in hospitalized patients with lymphoma. Serum calcium determinations were carried out during 440 admissions on 152 patients, most of whom had widespread lymphoma. Forty-one of the 152 patients died, all having had calcium levels recorded on that admission. Two of the 152 patients (1.3%) were found to have hypercalcemia. By comparison hypercalcemia occurred in 6 of 34 patients (17.6%) with multiple myeloma.Hypercalcemia is uncommonly associated with lymphoma but may be seen particularly in centres where many patients with this disease are treated. Hypercalcemia readily responds to therapy and is a reversible cause of morbidity, but when associated with lymphoma it usually indicates widespread disease. The mechanism of hypercalcemia is unknown but there is strong evidence for humoral factors that may or may not be related to parathyroid hormone.     

Nephrogenous cyclic adenosine monophosphate levels in normocalcemic cancer patients: its significance

We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic patients with documented cancer of various organs and cell types. NcAMP levels were elevated in 17 (28%) and decreased in 13 (21%) of the cancer patients. Both high and low NcAMP levels were seen within the various cancer groups. There was a significant correlation (r = 0.383, P less than 0.01) between NcAMP and serum parathyroid hormone (PTH) levels, suggesting that tumor-related factors affecting NcAMP , may be partially related to native PTH. Alternatively, these factors might be altering the effect of endogenous PTH on renal tubules. A significant negative correlation was also observed between NcAMP and tubular maximum for phosphate (r = -0.356, P less than 0.02) suggesting that either cAMP per se or factors affecting NcAMP alter phosphate excretion. Follow up serum calcium data was available on 48 of the 61 patients. Subsequent hypercalcemia developed independent of the initial nephrogenous cAMP levels. It therefore appears that NcAMP elevation and development of hypercalcemia are two separate paraneoplastic phenomena.     

Circulating angiogenesis regulators in cancer patients

BACKGROUND/AIMS: To date, numerous studies have demonstrated that several angiogenesis regulators circulate in the blood and may function as endocrine factors in cancer patients. This review aims to give a comprehensive insight into the possible clinical value of circulating angiogenesis regulators, mainly basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), angiogenin, pleiotrophin, thrombospondin (TSP) and endostatin (ES) in cancer patients. METHODS: A computerized (MEDLINE) and a manual search based on the reference lists of the publications were performed to identify articles published on this topic. RESULTS: In a detailed literature search, approximately 100 publications were found up to the end of 1999. Circulating angiogenic factors such as bFGF, VEGF, HGF and angiogenin have been evaluated not only as diagnostic and/or prognostic factors but also as predictive factors in cancer patients. On the other hand, little is known about the clinical significance of negative regulators. Neither the source nor the mechanism of protein externalization has been clarified in detail. CONCLUSIONS: Although there are no known factors with established clinical utility, circulating angiogenesis regulators may be useful in several situations. They could be used to determine the risk of developing cancer, to screen for early detection, to distinguish benign from malignant disease, and to distinguish between different types of malignancies. In patients with established malignancies such factors might be used to determine prognosis, to predict the response to therapy, and to monitor the clinical course. Further investigations are warranted to assess the specific utility of each factor.     

Hepatocyte growth factor activators, inhibitors and antagonists and their implication in cancer intervention

Hepatocyte growth factor (HGF), otherwise known as scatter factor (SF), has been demonstrated over the past decade to elicit a number of functions that may be tumorigenic, and enhance the invasive/metastatic nature of cancer cells. Clinical studies have also demonstrated that HGF/SF, together with its receptor, cMET, is closely related to the disease progression and prognosis of patients with cancer. The past few years have seen the identification of numerous inhibitors and antagonists to the action of HGF/SF. These factors have demonstrated a possible role in minimising the action of HGF/SF on cancer cells, and may be of therapeutic value in the future. This article overviews the activators, inhibitors, and antagonists to HGF/SF and discusses the possible implications in cancer therapy.     

Effect of intravenous bisphosphonates on release of basic fibroblast growth factor in serum of patients with cancer-associated hypercalcemia

Basic fibroblast growth factor (bFGF) is a potent tumor angiogenesis factor and normal constituent of bone extracellular matrix which does not normally circulate in serum of nonpregnant adult humans. We examined the effects of acute administration of intravenous bisphosphonates on release of bFGF in human serum. Twenty seven men and women (mean age, 64 yr) with cancer-associated hypercalcemia, the majority of whom had osseous metastases, were treated once with an intravenous bisphosphonate. Nearly all twelve patients with elevated baseline serum bFGF ranging from 5-27 pg/mL showed significant decreases in serum bFGF (2-7 days) after iv bisphosphonate treatment. The mathematical product of the patients' initial serum bFGF and intial serum calcium concentration, the 'Ca x bFGF product', was significantly negatively (r = -0.91, P < 0.001) correlated with the acute change in serum bFGF level. No consistent relationship was observed between serum bFGF and serum parathyroid hormone related peptide (PTHrP) levels in the hypercalcemic cancer patients. In a subset of patients with non-hematological malignancies and low baseline serum bFGF, acute changes in serum bFGF were significantly negatively (r = -0.66, P < 0.01) correlated with acute change in serum calcium concentration. These results indicate that release of bFGF in serum of patients with cancer-associated hypercalcemia likely depends predominantly on increased bone resorption. Acute change in low serum levels of bFGF in patients with cancer-associated hypercalcemia treated with intravenous bisphosphonates may be physiologically inversely regulated by acute change in the serum calcium concentration.     

Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome which is characterized by hypercalcemia resulting from secretion by tumors of a circulating bone-resorbing factor. Evidence suggests that in many instances this factor is an adenylate cyclase-stimulating protein which shares features with, but is distinct from, parathyroid hormone (PTH). The current report describes the purification to homogeneity from a humoral hypercalcemia of malignancy-associated tumor of a novel, basic, highly potent PTH-like adenylate cyclase-stimulating protein. This factor differs from previously described PTH-like factors with respect to size, amino acid composition, and specific activity.     

Activation of signal pathways and the resistance to anti-EGFR treatment in colorectal cancer

Colorectal cancer is the third most common cancer with a 5-year survival rate of less than 10%. It is caused by alterations of multiple signal pathways which are affected by both genetic and environmental factors. In some cases, EGFR is important in the carcinogenesis of colorectal cancer suggesting anti-EGFR therapy may be a potential treatment option. However, in other cases it is not effective, which may be related to its down-stream targeted gene mutations. KRAS is highly emphasized in the literature but other mutations like Src, PIK3CA, and BRAF may also be important. Furthermore, obesity may decrease the effectiveness of anti-EGFR treatment as it increases the risk factors for colorectal cancer. Using next-generation sequencing technology, it may be possible to identify all gene mutations in an individual with colorectal cancer. Therefore, gene mutations affecting anti-EGFR therapy in colorectal cancer patients can be identified.     

Hypercalcemia Secondary to Gastrointestinal Stromal Tumors: Parathyroid Hormone-Related Protein Independent Mechanism?

ObjectiveHypercalcemia is a common paraneoplastic manifestation of many malignancies like breast, ovarian, and squamous-cell cancers of head and neck; however, there have been only a few case reports of hypercalcemia associated with gastrointestinal stromal tumors (GISTs). We report a case of GIST presenting with hypercalcemia without any osseous metastasis and provide a literature review regarding the mechanisms of hypercalcemia and therapeutic strategies.MethodsWe present a report of case and a review of the relevant literature.ResultsA 52-year-old woman with history of localized breast cancer in remission and a pelvic 13 × 12 cm GIST with peritoneal, liver, and lung metastases presented with hypercalcemia of 14.3 mg/dL (8.5-10.5 mg/dL). Parathyroid hormone-related protein (PTHrP) was undetectable, intact parathyroid hormone (PTH) was appropriately low at 1 pg/mL (10-65 pg/mL), and 1,25 dihydroxy vitamin D (1,25 OH₂ vit D) was elevated at 131 pg/mL (18-78 pg/mL) with normal renal function. Calcium responded transiently to tyrosine kinase inhibitor therapy and bisphosphonates but within a year, she expired due to tumor progression.ConclusionGIST is a rare cause of hypercalcemia. In addition to PTHrP expression, direct tumor production of 1,25(OH)₂ vit D or 1-α hydroxylase enzyme resulting in activation of 25-hydroxy vitamin D may be an alternative mechanism in GIST-related hypercalcemia. Therapy with tyrosine kinase inhibitors and bisphosphonates is recommended, though prognosis is poor. Further investigations are needed to characterize the etiology and management of hypercalcemia in these patients. (Endocr. Pract. 2013;19: e158-e162)     

Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.     

Current therapeutic options for gastric adenocarcinoma

Gastric cancer inflicts significant health issues globally despite its declining incidence. The disease is known to be diagnosed at its advanced stages also corresponding with a poor prognosis for patients. The integral therapeutic choices to cure advanced gastric cancer have progressed swiftly in modern days. The preface of molecularly targeted therapeutic techniques would potentiate the personalized approach depending on patient-specific and tumor-specific features, exasperating the advantages of chemotherapy. Here we have reviewed the modern therapeutics such as immune therapy, chemotherapy, m-RNA based therapeutics, alongside evaluating the influence of age, sex and comorbidities-like factors on the occurrence of gastric cancer. Gastric cancer therapy consolidated target agents comprising inhibitors of programmed death-1(PD-1), human epidermal growth factor receptor 2 (HER2), mRNA, and epidermal growth factor receptor (EPGF). A combination of trastuzumab to platinum-mediated chemotherapy evolved has a typical front-line therapy in advanced gastric cancer. An attempt has been made to epitomize the contemporary-modern research on targeted therapy for advanced gastric cancer.     

Breast-conserving therapy versus modified radical mastectomy: socioeconomic status determines who receives what--results from case-control study in Tianjin, China

Background: Despite anecdotal evidence linking socioeconomic status and choices on surgical management in breast cancer patients in China, no scientific evaluations have ever been conducted. The objective of this study was to evaluate patient factors that influence patients’ treatment options between breast cancer patients receiving breast-conserving therapy (BCT) and modified radical mastectomy (MRM). Methods: A total of 268 stage I–II breast cancer patients treated with BCT in Tianjin Cancer Hospital, from January 2005 to January 2007, were compared with 200 randomly selected breast cancer patients (controls) treated with MRM. A personal health questionnaire (PHQ) was used to assess the factors that may affect the surgical decision making. Chi-squared test and multiple logistic regressions were used to examine factors associated with BCT. Results: BCT patients who were younger and were more likely to live in urban areas had medical insurance, higher levels of education and family income. Patients with medical insurance coverage were approximately six times more likely to receive BCT than patients without medical insurance after controlling for other potentially confounding factors. Similar results were also observed for family income. The observed differences cannot be explained by clinical aspects of their disease, such as tumor stage, estrogen receptor, and lymph node involvement. Conclusion: Breast cancer patients’ socioeconomic status, rather than their clinical condition, is the predominant factor in determining whether a breast cancer patient receives BCT or not. These results provide a snapshot on how socioeconomic status influences cancer care provision in China. Future efforts should be made towards reducing discrepancies in treatment options for cancer patients caused by social class and socioeconomic status.     

Vitamin D and prostate cancer

Vitamin D and its metabolites are best known for their actions in calcium and bone metabolism. However, epidemiological studies have suggested that an increased prostate cancer risk is associated with decreased production of vitamin D. In vitro and in vivo studies have shown that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25D), inhibits proliferation of cancer cells derived from multiple tissues, including the prostate. Although the mechanisms underlying the growth inhibitory effects of 1,25D have not been fully elucidated, in prostate cancer cells 1,25D reduces cell growth via a number of cellular pathways, including cell cycle arrest, induction of apoptosis, and altered activation of growth factor signaling. The hypercalcemia induced by 1,25D in vivo limits its use clinically as a therapeutic agent. However, several 1,25D analogs have been developed that reduce prostate tumor growth in rodent xenograft models without causing hypercalcemia. Additional studies are required in order to determine whether these 1,25D analogs will be useful therapeutic agents for the treatment of prostate cancer.     

Prognostic significance of elevated endothelin-1 levels in patients with colorectal cancer

BACKGROUND: Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. METHOD: Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes' stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. RESULTS: Three variables, age, Dukes' tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes' C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. CONCLUSION: Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.     

Gut hormones with activity to modulate cellular growth

Recent progress in cancer research revealed that gut hormones have the activity to regulate the cellular growth of cancer cells. Gastrin, cholecystokinin and vasoactive intestinal peptide were demonstrated to stimulate the growth of gastric cancer cells, pancreatic cancer cells and colon cancer cells, respectively. Accordingly, it is possible to assume that these gut hormones may play an important role in the progression of these cancers. Further studies will be required to clarify the role of gut hormones as physiological growth factors in gastrointestinal tissues. The other aspect of gut hormones related with cellular growth is their role as autocrine growth factors. Gastrin-releasing peptide (GRP) is classified as a gut hormone with the structural similarity with amphibian bombesin. Several reported findings indicate that GRP functions as an autocrine growth factor for human small cell lung carcinoma; a monoclonal antibody for GRP is now applied for the therapy of this cancer. It is important to find out other gut hormones functioning as autocrine growth factors.     

Radioguided Parthyroidectomy is Successful in 98.7% of Selected Patients

ObjectiveTo examine an individualized approach to patients with primary hyperparathyroidism (PHPT) in an effort to identify factors that would differentiate patients who can be treated with radioguided parathyroidectomy (RP) from those that require more extensive parathyroid exploration (PE) using intraoperative parathyroid hormone (IOPTH) measurement and to compare rates of recurrent and persistent hypercalcemia.MethodsA total of 100 patients were retrospectively studied. Patients with positive single photon emission computed tomography (SPECT) scans underwent surgeon-performed sonography (SPS) followed by RP. Patients with negative or equivocal SPECT scans underwent PE utilizing SPS as a guide and IOPTH. The success rate, recurrence and persistence rates, and rate of bilateral exploration were compared.ResultsSeventy-five percent of patients with PHPT had a positive SPECT scan and underwent RP, whereas 25% of patients had a negative SPECT scan and underwent PE with IOPTH utilizing SPS as a guide. Persistent hypercalcemia was noted in 1 patient (1.3%) and recurrent hypercalcemia in 2 patients (2.6%) in the RP group, whereas no persistent hypercalcemia was noted in the group undergoing PE utilizing SPS and IOPTH. Overall, 89% of patients were cured with unilateral surgery.ConclusionPatients with positive SPECT scans may undergo RP with an expected cure rate of 98.7%. Patients with negative SPECT scans should undergo SPS followed by PE using IOPTH and can expect a cure rate near 100%. Properly selected patients may undergo RP, with low rates of persistent (1.3%) and recurrent (2.6%) hypercalcemia. (Endocr Pract. 2014;20:305-309)     

Biochemical markers of endothelial activation in primary hyperparathyroidism.

Patients with primary hyperparathyroidism (PHPT) have impaired vasodilation both dependent and independent of endothelium. The aims of our study were to measure three different biochemical markers of endothelial activation, i. e., plasma thrombomodulin, soluble(s) E-selectin, and von Willebrand factor, in PHPT patients before and one year after successful parathyroidectomy, and to distinguish the potential effect of hypercalcemia and/or high parathyroid hormone from that of major cardiovascular risk factors (diabetes mellitus, hyperlipidemia, hypertension, obesity, smoking habit) on endothelial function. Twenty consecutive patients with PHPT subdivided into two groups according to the absence (n = 8) or presence (n = 12) of one or more risk factors, and fifteen healthy normocalcemic subjects were studied. Baseline thrombomodulin levels were similar in the groups with and without risk factors, and in controls. In contrast, sE-selectin and von Willebrand factor were higher in PHPT patients with risk factors than in those without risk factors (p < 0.05 and p < 0.01, respectively) and controls (p < 0.01). Neither thrombomodulin nor sE-selectin changed after parathyroidectomy in either PHPT group. Plasma von Willebrand factor decreased (p < 0.01) in patients without risk factors, while persisting at high levels in patients with risk factors. In conclusion, in spite of a limitation due to the small number of patients, our study suggests that classic cardiovascular risk factors seem to be the main determinants for the high plasma levels of sE-selectin and vWF in PHPT. Together with unaltered thrombomodulin and sE-selectin levels, a plasma vWF decrease after parathyroidectomy might reflect a specific mechanism of its endothelial calcium- and/or PTH-stimulated secretion in some PHPT patients without risk factors. Whether a vWF reduction after parathyroidectomy may be used as a biochemical index for improved endothelial function in PHPT patients without risk factors has yet to be demonstrated in larger studies.     

Anti-tumor activity of calcitriol: pre-clinical and clinical studies

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.     

Unconventional cancer remedies.

Unproven and disproven remedies continue to abound for illnesses for which conventional treatment is only partially effective. This is particularly true with cancer, for which up to 50% of patients may be receiving unorthodox therapy. This article examines unconventional cancer remedies, their adverse effects, their common factors and the basis for their appeal, as well as what motivates and characterizes patients who choose these treatments. Also discussed is an approach that may be used by the conventional physician for patients who are likely to seek unorthodox treatment. This approach will help patients make the best decision about their treatment and protect them from the hazards of unconventional remedies.