A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells

Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by uuresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes

Serum insulin-like growth factor 1 correlates with the risk of nodal metastasis in endocrine-positive breast cancer

Increased insulin-like growth factor (igf) signalling has been observed in breast cancer, including endocrine-responsive cancers, and has been linked to disease progression and recurrence. In particular, igf-1 has the ability to induce and promote lymphangiogenesis through the induction of vascular endothelial growth factor C (vegfc). In the present study, we analyzed serum and tumour samples from 60 patients with endocrine-positive breast cancer to determine the expression and the possible relationship of circulating igf-1, igf binding protein 3 (igfbp3), and vegfc with the presence of lymphatic metastasis and other immunohistochemical parameters. The analysis revealed a clear and significant correlation between high basal levels of igf-1, igfbp3, and vegfc and lymph node metastasis in endocrine-responsive breast cancer. In addition, expression of those molecules was significantly higher in breast cancer patients than in healthy control subjects. Those findings may enable more accurate prediction of prognosis in patients with breast cancer

A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant

Introduction: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD ∗2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence. Patient concerns: A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment. DIAGNOSIS: After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0. Interventions: As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient’s death. Outcomes: After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease. Conclusions: Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization. Abbreviations: 5,10-MTHF = 5,10-Methylenetetrahydrofolate, 5-FU = 5-fluorouracil, AEs = Adverse events, CDA = cytidinedeaminase, CES = carboxylesterase, CPIC = Clinical Pharmacogenetics Implementation Consortium, CRC = colorectal cancer, CT = computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, DPD = dihydropyrimidine dehydrogenase, DPYD = dihydropyrimidine dehydrogenase gene, DPYD-AS = DPYD activity score, ECOG = Eastern Cooperative Oncology Group, EDTA = ethylenediaminetetraacetic acid, FdUMP = 5-fluoro-20-deoxyuridine-50-monophosphate, HFS = hand-foot syndrome, HGB = hemoglobin, INB = incremental net benefit, INR = International Normalized Ratio, mCRC = metastatic colorectal cancer, MTHFR = Methylene Tetrahydrofolate Reductase, NEU = Neutrophils, PCR = polymerase chain reaction, PLT = Platelets, SNPs = single-nucleotide polymorphisms, TSER = thymidylate synthase enhancer region, TYMP = thymidine phosphorylase, TYMS = thymidylate synthase, VNTR = variable number of tandem repeat, WBC = white blood cells

Acute leukaemia in patients treated for Hodgkin's disease

Fourteen acute non-lymphoid leukaemias (ANLL) were identified among 947 consecutive patients with Hodgkin's disease (HD) treated in five collaborating centres in Italy between January 1969 and December 1979. Leukaemia developed 12-118 months after the diagnosis of HD and was always preceded by a pre-leukaemic phase. The karyotype of the leukaemic cells was studied in nine of the 14 patients and was abnormal in seven cases. Bone marrow agar cultures were performed in five of the 14 patients and were abnormal in every case. The actuarial risk of developing ANLL at 10 years was 6.2% for combined therapy, 4.8% for salvage therapy and 2.2% for chemotherapy alone. No case of ANLL was documented among 136 patients treated with radiotherapy alone. One patient developed acute promyelocytic leukaemia following treatment with ABVD and radiotherapy. Both univariate and multivariate analyses seem to demonstrate that the induction therapy modality is a significant variable in development of secondary acute leukaemia. The recognition of a significant risk of ANLL in patients treated for HD should create changes in treatment policy