Abstract. Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible. To determine the potential causes of these toxicities, polymorphic variants of cytidine deaminase, the primary enzyme involved in the hepatic metabolism of GCB, were assessed. The homogeneous c.435TT variant was detected in one patient and a heterozygotic c.435CT variant in two, one of whom additionally harbored a heterozygotic c.79AC variant. IntroductionGemcitabine (GCB) is an anticancer agent widely used alone or in combination with other cytotoxics in the treatment of various malignancies including non-small cell lung cancer (NSCLC), pancreatic, bladder, breast, ovarian, prostate cancer, and cholangiocarcinoma (1). GCB toxicity is generally mild, transitory and rarely dose limiting. Most common side effects include laboratory alterations, such as myelosupression, transaminase elevation, mild proteinuria and hematuria, whereas symptomatic toxicities are usually well controlled and not life threatening (2-4). Factors increasing GCB toxicity include its combination with platinum derivatives or taxanes, liver and kidney diseases, and alcohol abuse (5-10). There are no evidence-based and generally accepted recommendations for dose modifications of GCB, and clinical decisions are typically made based on empirical grounds.The main enzyme involved in hepatic metabolism of GCB is cytidine deaminase (CDA), encoded by the CDA gene located in locus 1p36. 2-35 (11-15). Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18-31).We describe here severe toxicity in four patients treated with GCB used alone or in combination with cisplatin. For each case, the probability of adverse drug reaction probability was assessed using the Naranjo scale described in the study by Naranjo et al (32). In the search of potential toxicity causes, we performed in all cases evaluation of CDA polymorphisms. Case 1.A 67-year-old-woman was diagnosed with poorly differentiated tubule-solid gallbladder adenocarcinoma invading the liver and spreading to the greater omentum. The patient reported recurrent pain in the upper abdomen, but was otherwise in a fairly good condition [World Health Organization Performance Status (WHO PS) 2], with body mass index of 18.6 and no apparent active inflammatory symptoms. Serum alanine transaminase (ALT) and a...
Gallbladder cancer (GBc) is a highly malignant tumor with poorly understood etiology. An insight into phenotypic features of this malignancy may add to the knowledge of its carcinogenesis and pave the way to new therapeutic approaches. We assessed the expression of female sex hormone receptors (eRα, eRβ, PR), connective tissue growth factor (CTGF) and HER2 in GBC, and adjacent normal tissue (nt), and determined their prognostic impact. immunohistochemical (iHc) expression of all biomarkers was performed in formalin-fixed, paraffin-embedded specimens in 60 Caucasian GBC patients (51 women and 9 men). ERβ, cytoPR and CTGF expression were found in 89%, 27%, 91% of GBC, and in 63%, 87%, 100% of NT, respectively. No ERα expression was found in GBC and NT. Strong (3+) HER2 expression by iHc or HER2 amplification was seen in five GBC (10.4%). A positive correlation was found between HER2 and CTGF and ERβ expression in GBc and matched nt. in the multivariate analysis, patient age >70 years, tumor size and ERβ expression in GBc was highly predictive for oS (p = 0.003). The correlation between HER2, CTGF and ERβ expression in GBc and nt may indicate the interaction of these pathways in physiological processes and gallbladder pathology. Gallbladder cancer (GBC) is an aggressive malignant tumor originating from epithelial cells of the mucous membrane. The etiology of GBC is poorly understood, and its global prevalence is characterized by considerable regional variations 1-4. The highest incidence is reported in Chile, India, Pakistan, Bolivia, Central Europe, Israel, and in Native Americans and Americans of Mexican origin 1-4. The risk of developing GBC is higher in patients with chronic inflammatory processes caused by gallstones with resulting calcification of the gallbladder wall ("porcelain gallbladder"), and with infections such as Salmonella typhi or Salmonella paratyphi 3-5. GBC is about two to six times more common in women compared to men, and its incidence steadily increases with age 1-5. Estrogens are key signaling molecules that regulate various physiological processes and play a major role in many pathological conditions, such as hormone-dependent cancers. Expression of female sex hormone receptors in GBC has been analyzed in a few studies including mainly Asian populations, and provided inconsistent results 6-14. Several small studies demonstrated overexpression of human epidermal growth factor receptor type 2 (HER2) and HER gene amplifications or mutations 15-27. Connective Tissue Growth Factor (CTGF) was found to be expressed in various stages of the GBC carcinogenesis 28. GBC carries a poor prognosis and most patients succumb to their disease. An insight into phenotypic features of this tumor may add to the knowledge of its carcinogenesis and pave the way to new therapeutic approaches. In the present study we investigated the expression of female sex hormone receptors: estrogen receptor alpha (ERα), ER beta (ERβ) and progesterone (PR), as well as CTGF and HER2 in a relatively large group of Caucasian GBC pat...
Introduction. Tissue microarray (TMA) technique has been widely used, especially in immunohistochemical assays of new prognostic and predictive markers. The main objections raised by its opponents are the small amount of sampled material and the associated risk of inadequate assessment of analysed expression, resulting from the potential heterogeneity of tumour tissue. Material and methods. This study evaluated the compatibility of biomarker expression in two independent tissue cores, 1.5 mm in diameter, obtained by TMA technique from patients with gallbladder cancer (ERb, cytoPgR, HER2, CTGF) and ovarian cancer (PTEN, BCL2, PIK3CA, IGF1R). Comparison of the expression of individual biomarkers between cores was performed using the intraclass correlation coefficient (ICC), assuming a kappa < 0.4 as a weak, ≥ 0.4 as sufficient, ≥ 0.6 as good, and ≥ 0.75 as optimal correlation, and Kendall's tau test-ICC package. Results. Evaluation of biomarker expression in the primary tumour was performed in 60 patients with gallbladder cancer and in 64 patients with high-grade serous ovarian cancer. Additionally, in patients with follicular cancer, the expression of the tested markers was assessed in the epithelium free from neoplastic malignancy. In both tumours, a good or sufficient level of homogeneity was observed in the expression of the analysed biomarkers between tissue cores. The correlation coefficient for the expression of individual markers in gallbladder cancer and adhering healthy tissue was: 0.68 (95%
We are reporting a case of a 55-year-old woman who was diagnosed as having a non-functioning pancreatic neuroendocrine neoplasm (NF-PNEN), the World Health Organization (WHO) low grade (G1) with liver metastases. In the staging process the Then, due to disease progression -radioisotope therapy with b-emitter Yttrium-90 ( 90 Y). Based on this experience and on the review of the literature, we recommend that the discrepancy between the imaging studies could be due to heterogeneity of proliferation rate and somatostatin receptors (SSTR) expression within a primary PNEN and metastases. Therefore in such cases of advanced PNEN WHO G1 in the lack of response to everolimus and octreotide LAR administration isotope therapy without a prior chemotherapy should be considered as a palliative treatment according to ESMO Clinical Practice Guidelines and Polish Network of Neuroendocrine Tumors.
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