CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF), is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS). This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU) exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV) has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl)-5,10,-methylenepteroyl-monoglutamate calcium salt) is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies

From the Bench to Bedside: Biological and Methodology Considerations for the Future of Companion Diagnostics in Nonsmall Cell Lung Cancer

Companion diagnostics are an emerging and exciting field in the care of oncology patients. These tests accompany standard diagnostic investigations in cancer patients and function as an aid in treatment decision making. A great number of new compounds are under clinical and laboratory testing in nonsmall cell lung cancer (NSCLC). As the variety of therapeutic options expands in the various settings of the disease, it becomes apparent that specific and sensitive molecular tests are necessary to define the subsets of patients who are going to derive clinical benefit. Testing for epidermal growth factor receptor (EGFR) somatic mutations for the appropriate administration of tyrosine kinase inhibitors is just the beginning. Anaplastic lymphoma kinase (ALK) fusion protein detection and molecular histology classification are promising candidate predictors for clinical benefit from crizotinib and pemetrexed, respectively. This paper summarizes such diagnostics and discusses unanswered questions concerning underlying biology and standardization issues

Use of Supportive Care for Symptom Management in Pancreatic Cancer: Application of Clinical Research to Patient Care

In this paper, we will be discussing Abstracts #9061, #9062, #9065, #9072 and #9097 presented at the recent 2012 American Society of Clinical Oncology (ASCO) Annual Meeting. All of these abstracts explore innovative ways to control symptoms in cancer patients. We are hopeful that these methods are able to be used in symptomatic pancreatic cancer patients.Image: Oncology Unit, Medical School of Athens, Sotiria Hospital. Athens, Greece

Translational Research. New Findings and Potential Future Applications in Pancreatic Adenocarcinoma

 The current achievements in pancreatic cancer diagnosis and treatment are disappointing for patients and clinicians alike. Still, in the dawn of 2012, most patients are diagnosed at a late stage where cure is not feasible, with the majority going to succumb within the same year of diagnosis. Thus, the only hope for early and diagnosis and radical treatment is the invention of diagnostic and prognostic tests which might predict accurately patients who may develop this disease and those who have the most aggressive potential, so clinician adopt the appropriate strategy. In this paper we summarize the findings from the three most interesting research abstract as presented at the 2012 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. In particular, we focus on Abstract #160 which shows the diagnostic utility of microRNA serum profiling in pancreatic cancer patients, on Abstract #201 which suggests a potential prognostic role of transforming growth factor (TGF)-beta pathway in advanced pancreatic cancer, and on Abstract #165 which shows that protein S100A4 might be a new, potentially useful, predictive biomarker of gemcitabine efficacy.

The Role of EGFR Inhibitors in the Treatment of Metastatic Anal Canal Carcinoma: A Case Series

Anal cancer patients who have exhibited disease progression after having received all approved drugs pose a major therapeutic challenge. In addition to cytotoxic agents, novel targeted agents are being developed and have an established role in the treatment of many solid tumors, including colon cancer. However, their role in anal cancer is yet to be determined. Most anal malignancies are squamous cell carcinomas often strongly expressing epidermal growth factor receptors (EGFRs). Targeting the latter seems to result in favorable changes in tumor growth. We present three cases of refractory anal cancers, treated with EGFR inhibitors, after having received the recommended chemotherapy regimens. We conclude that EGFR inhibitors may play a vital role in the treatment of anal cancer and we suggest that large trials are be conducted in order to clarify their efficacy and to improve therapeutic management

Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder that is characterized by a variable clinical phenotype. Matched donor bone marrow transplantation is currently the only curative therapeutic option. We present the case of a 24-year-old male who was diagnosed at the age of seven with Wiskott-Aldrich syndrome. He did not respond to intravenous gammaglobulin and he experienced recurrent pulmonary infections despite prophylactic antibiotics. The patient had no matched donor. At the age of nine, he was submitted to splenectomy and his platelet count was normalized. Fifteen years later, the patient remains asymptomatic with a normal platelet count. He is still receiving prophylactic antibiotics and no bleeding episodes or septic complications have been reported. This case demonstrates that splenectomy can represent a safe therapeutic option in selected WAS patients, provided that there is a tight follow-up program, patient education and adherence to guidelines regarding post-splenectomy prophylaxis

Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered

DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS

ABSTRACT Objectives: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Methodology: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13 C uracil breath test (UraBT). Results: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 -0.18nmol/ min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2', 3', 5'-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients revealed 1 to be DPD-deficient (DOB 50 of 112.8; PDR of 49.4%) and borderline normal values (DOB 50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients (28%). Conclusions: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique