High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations.

Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeutically relevant BRAF mutations in NMZL. Sets of somatic mutations that could help to discriminate NMZL from other closely related small B-cell lymphomas were uncovered and tested on unclassifiable small B-cell lymphoma cases, in which clinical, morphological, and phenotypical features were equivocal. Application of targeted gene panel sequencing gave at many occasions valuable clues for more specific classification.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

This corrects the article DOI: 10.1038/bjc.2014.209.

[Doctor, I'm hot! Managing the effects of menopause in patients with breast cancer]. / Docteur, j'ai chaud! Gestion des effets de la menopause chez les patientes atteintes d'un cancer du sein.

The incidence of breast cancer is rising up, but the mortality rate is decreasing, leading to a growing number of survivors. Most of these women are postmenopausal at diagnosis or will reach menopause following anti-cancer treatments. Most of them have hormone-sensitive tumors and will receive an anti-hormonal treatment. Endocrine therapy is associated with many adverse effects, including a worsening of climacteric symptoms with a negative impact on quality of life and therefore a suboptimal therapeutic adherence. Some supportive therapies can alleviate these adverse effects and should be offered to patients.

Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

[PARP inhibitors: new therapeutic agents in breast and ovarian cancer]. / Inhibiteurs de la PARP: nouvelle arme thérapeutique pour les cancers du sein et de l'ovaire.

PARP inhibitors are novel drugs under development in oncology, particularly against breast and ovarian cancer. They act on the DNA repair mechanisms in synergy with the loss of BRCA function of the tumor cells, thereby inducing a genetic instability that leads to cell death. The clinical benefit of PARP inhibitors has been demonstrated for breast and ovarian cancer in BRCA germline mutation carriers. Their use in sporadic triple negative breast cancers, that share similarities with BRCA1 mutated tumors, is currently investigated with encouraging preliminary results.

[Impact of breast MRI and PET-CT in breast cancer staging]. / Apport de l'IRM mammaire et du PET-CT dans le bilan initial du cancer du sein.

The preoperative staging of breast carcinoma determines the type of surgery. Mammography and echography are considered standard. Even though, breast MRI shows better performance for evaluation of the size of the tumor and for detection of additional foci of the tumor. Breast MRI appears to lead to more extensive surgery or increased numbers of mastectomy. But it remains unclear whether breast MRI contributes to reduce positive surgical margins, local recurrences and whether it increases survival. Because of the low predictive positive value, every MRI finding should be confirmed by core needle biopsy. PET-CT has the best sensibility for the detection of distant metastasis but should only be used in very high risk patients.

Is cisplatin required for the treatment of non-small-cell lung cancer? Experience and preliminary results of a phase I/II trial with topotecan and vinorelbine.

Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade, paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, and topotecan have been introduced into the clinic. These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5-1.0 mg/m(2)/day x 5) and i.v. vinorelbine (20-30 mg/m(2)/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75-1.0 mg/m(2)/day and i.v. vinorelbine of 25 mg/m(2)/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m(2)) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC.

[False rubella diagnosis in pregnancy by IgM enzyme immunoassay]. / Falsche Rubella-Diagnose in der Schwangerschaft aufgrund eines IgM-Enzymimmunoassays.

On the basis of a case report of a false-positive rubella diagnosis in early pregnancy the interpretation of positive IgM is discussed. A primigravida at 14 weeks of gestation showed rubella-specific IgM in an enzyme immunoassay. This result could not be confirmed by an alternative method (hemagglutination-inhibiting test after separating the serum by density gradients into different immunoglobulin classes and removal of the IgG with protein A). The immunological status corresponded with a past rubella infection or with the status after vaccination (IgG-positive). It is therefore recommended to use an additional method in the presence of IgM, especially if an interruption of the pregnancy has to be considered. In the course of the examination a recent cytomegalovirus infection could be detected.

[Post-transfusion hepatitis in the Zürich region]. / Posttransfusionshepatitis in der Region Zürich 1979-1983.

In the years 1979 to 1983 approximately 350,000 units of blood were transfused in the area of Zurich. During the same period 45 cases of posttransfusion hepatitis were reported. In 12 of these cases transfusion could be excluded as cause of the hepatitis. In another 26 cases it was not possible to prove a connection between the blood transfusion and the hepatitis. Only in 7 cases was blood transfusion proved to be responsible for posttransfusion hepatitis: in 3 cases blood positive for HBs-Ag was transfused. In 3 other cases donors who had donated HBs-Ag negative blood developed hepatitis-B shortly after their blood donation: it is assumed that their blood at the time of donation was carrying infectious hepatitis-B-virus particles at a concentration too small to be detected by routine HBs-Ag screening. In one case only was transmission of non-A-non-B-hepatitis virus suspected. Due to improved HBs-Ag-screening, the incidence of posttransfusion hepatitis has been reduced by nearly 70% during the last 10 years. Nevertheless, efforts must continue to reduce the incidence of this important transfusion complication.