Capecitabine-induced severe adverse events-therapeutic drug monitoring and DPYD-gene analysis are recommended.

In this report, two cases of patients with severe adverse events after an adjuvant treatment with capecitabine are described in detail. The first patient suffered from a severe ileocolitis, where ultimately intensive care treatment, total colectomy and ileum resection was necessary. The second patient experienced a toxic enteritis, which could be managed conservatively. Post-therapeutic DPYD genotyping was negative in the former and positive in the latter case. Patients can be categorised in normal, moderate and poor DPYD metabolisers to predict the risk of adverse events of capecitabine treatment. Guidelines in various European countries recommend pretherapeutic DPYD genotyping, whereas it is not recommended by the National Comprehensive Cancer Network in the USA. Irrespective of DPYD genotyping, strict therapeutic drug monitoring is highly recommended to reduce the incidence and severity of adverse events.

Baseline characteristics and patterns of care in testicular cancer patients: first data from the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS).

BACKGROUND: The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations. OBJECTIVE: The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment. RESULTS: Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5¬â€’5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines. CONCLUSION: It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures. TRIAL REGISTRATION NUMBER: NCT02229916 (Clinicaltrials.gov).

Functional inactivation of NF2/merlin in human mesothelioma.

The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2) which is located on chromosome 22q12 and mutations in this gene have been found in 40% of mesothelioma. Mutations including deletions and insertions lead to truncated and inactivated merlin. Experimental animal models indicate that disruption of the NF2 signalling pathway, together with a deficiency in ink4a, is essential for mesothelioma development. Our hypothesis was that in human mesothelioma without detectable NF2 mutations, regulators of NF2/merlin activity such as CPI-17 would be altered. CPI-17 is an oncogene inhibiting the NF2/merlin phosphatase which is necessary to maintain NF2/merlin activity. Samples obtained from 44 mesothelioma, 3 asbestosis patients and 6 normal pleura from non-asbestos related disease patients were analyzed. Truncated NF2 transcripts or presence of isoform II only were observed in 11 mesothelioma samples. In all other mesothelioma samples only NF2 isoform I or isoforms I and II were detected. 18 mesothelioma and 1 normal pleura samples also expressed splicing variant delE2/3. Unexpected variants in addition to wild-type were identified in 24 mesothelioma samples. NF2 protein was either truncated or phosphorylated on Ser 518 in primary cultures derived from 25 tumors. CPI-17 expression was significantly increased in tumor samples without deleted NF2 compared to normal pleura and tumor expressing truncated NF2. Our results support the hypothesis that the disruption of NF2 signalling is essential for the development of human mesothelioma. In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17.