Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors.

PURPOSE: Wilms tumor gene 1 (WT1), a zinc-finger transcription factor essential for testis development and function, along with other genes, was investigated for their role in the pathogenesis of testicular germ cell tumors (TGCT). METHODS: In total, 284 TGCT and 100 control samples were investigated, including qPCR for WT1 expression and BRAF mutation, p53 immunohistochemistry detection, and massively parallel amplicon sequencing. RESULTS: WT1 was significantly (p < 0.0001) under-expressed in TGCT, with an increased ratio of exon 5-lacking isoforms, reaching low levels in chemo-naïve relapsed TGCT patients vs. high levels in chemotherapy-pretreated relapsed patients. BRAF V600E mutation was identified in 1% of patients only. p53 protein was lowly expressed in TGCT metastases compared to the matched primary tumors. Of 9 selected TGCT-linked genes, RAS/BRAF and WT1 mutations were frequent while significant TP53 and KIT variants were not detected (p = 0.0003). CONCLUSIONS: WT1 has been identified as a novel factor involved in TGCT pathogenesis, with a potential prognostic impact. Distinct biologic nature of the two types of relapses occurring in TGCT has been demonstrated. Differential mutation rate of the key TGCT-related genes has been documented.

[Treatment with sunitinib and hypothyroidism--a case report and overview of literature]. / Liecba sunitinibom a hypotyreóza--kazuistika a prehl'ad literatúry.

In the article the authors present the case of a patient with clear cell renal carcinoma, where after nephrectomy local metastases appeared. The treatment of choice was sunitinib. After 20 cycles of therapy heavy hypothyroidism was verified which required substitution by thyroxine. Elevated levels of TSH appeared in up to 70% and hypothyrodism in up to 40% of thus treated patients. Also described is the mechanism of action of sunitinib. There seems to exist a correlation between the "adverse effects" of the drug and a better result of the therapy of cancer, however, prospective studies are absent. Most experts agree that the thyroid function during treatment with sunitinib needs to be monitored.

Symptomatic osteoradionecrosis of pelvic bones in patients with gynecological malignancies-result of a long-term follow-up.

The aim of this study was to assess the incidence and risk factors of pelvic fractures as a result of radiation therapy in women with gynecological cancer. We retrospectively reviewed 3530 female patients treated at our institute between 1980 and 1998 with megavoltage radiation with or without brachytherapy for cancer in the pelvic area. Eligible were patients with vulvar, vaginal, cervical, endometrial, and fallopian tube cancer. Median follow-up was 88 months (range 0-240). Emphasis was put on treatment-related and patient-related risk factors. Of the eligible 3155 patients, 15 developed symptomatic bone fracture caused by osteoradionecrosis, which makes an overall incidence of 0.44% The diagnosis was based on anamnesis, clinical course, and X-ray or computed tomography images. Median time of onset was 44 months (range 6-197). All patients had pain as the first symptom. The only independent predictive factor for developing osteoradionecrosis seemed to be preexistent osteoporosis. Other risk factors that are related to osteoporosis include higher age, postmenopausal status, or steroid treatment. We did not find any significant treatment-related predictive factor for pelvic osteoradionecrosis. Patients with osteoporosis are probably at the highest risk for developing osteoradionecrotic fractures after pelvic radiotherapy. More studies are needed to find out other endogenous predictive factors.

Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy.

BACKGROUND: Anthracycline-induced cardiotoxicity has led to the adoption of empirical dose limits that may restrict continued use of anthracyclines among patients who might benefit. Dexrazoxane, a cardioprotective agent, has been shown to reduce the risk of anthracycline-associated cardiotoxicity when given from first dose of anthracycline. This study sought to confirm the benefit of dexrazoxane in patients at high risk of cardiotoxicity due to prior anthracycline use. PATIENTS AND METHODS: A total of 164 female breast cancer patients, previously treated with anthracyclines, received anthracycline-based chemotherapy either with (n = 85) or without (n = 79) dexrazoxane for a maximum of six cycles. RESULTS: Compared with those receiving anthracycline alone, patients treated with dexrazoxane experienced significantly fewer cardiac events (39% versus 13%, P < 0.001) and a lower and less severe incidence of congestive heart failure (11% versus 1%, P < 0.05). Tumor response rate was unaffected by dexrazoxane therapy. The frequency of adverse events was similar between groups and there were no significant between-group differences in the number of dose modifications/interruptions. CONCLUSION: Dexrazoxane significantly reduced the occurrence and severity of anthracycline-induced cardiotoxicity in patients at increased risk of cardiac dysfunction due to previous anthracycline treatment without compromising the antitumor efficacy of the chemotherapeutic regimen.

[Treatment of early stages of ovarian carcinoma. Evaluation of experience at the Institute of Radiation Oncology over a 10-year period (1983-1993)]. / Lécba casných stadií karcinomu ovaria. Zhodnocení zkuseností Ustavu radiacní onkologie za období deseti let (1983-93).

The authors evaluated in a retrospective study the therapeutic results of ovarian carcinoma stage FIGO I (68 patients) and FIGO II (28 patients) attained in the Institute of Radiation Oncology, Prague during the ten-year period from 1983-1993. Total survival and survival without relapse within five years are 77% in stage I and 74% in stage II. The corresponding values of five-year survival without relapse were 56% and 58% resp. Despite the fact that the therapeutic results are comparable with data in the literature, a great shortcoming is the inadequate documentation of the initial laparotomy and the very general histopathological finding, moreover without grading, in a great proportion of the patients. The authors emphasize that these shortcomings make a reliable indication of adjuvant therapy impossible, in particular in early stages of ovarian carcinoma. Despite repeated references to this shortcoming these mistakes have persisted for several decades.

Subcutaneous interleukin-2 in combination with vinblastine for metastatic renal cancer: cytolytic activity of peripheral blood lymphocytes.

Eight patients with progressive metastatic renal cell carcinoma were selected for one course of subcutaneous recombinant interleukin-2 (IL-2) plus vinblastine (VBL) treatment lasting for seven weeks. Seven of the eight patients were evaluable for response, eight for toxicity. Peripheral blood lymphocytes (PBL) from the evaluable patients were isolated and frozen prior to, during, and after the treatment courses; kinetics of their cytolytic activity was assessed and compared under standard conditions in 51Cr microcytotoxicity assay with natural killer (NK)-sensitive and NK-resistant human tumor targets. Among the evaluable patients treated, there was 1 partial responder (10+ months, regressions occurred in lung, retroperitoneal lymph nodes and adrenal metastases) and 3 patients achieved a stable disease (10+, 10+, 5+ months). Systemic toxicity was mild to moderate with treatment-limiting adverse effects in one patient (severe thrombocytopenia, grade IV). In the IL-2-treated patients, the cytolytic activity of PBL directed against NK-sensitive targets rapidly decreased during the first week of IL-2 treatment, approaching the negative values on day 10. Then the cytolytic activity was slowly increasing and reached its maximum within another two weeks. Afterwards, the cytolytic activity of PBL was again decreasing and the approximate values of the initial cytolysis were reached after 6-8 weeks. In contrast, with NK-resistant targets such characteristic kinetics of PBL cytolytic activity was not observed. The kinetics of PBL-mediated cytolysis was similar in IL-2-responders and non-responders, so that no correlation of in vivo and in vitro effects of subcutaneous IL-2 and VBL treatment could be established.