Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

[Methodology and long-term follow-up of drug induced side effects in children (cancer, leukemia, AIDS, growth hormone)]. / Méthodologie et pratique du suivi à long terme des effets indésirables des médicaments chez l'enfant (cancers, leucémies, SIDA, hormones de croissance).

Long-term follow up for medicines used in children is necessary in some therapeutic areas. Long-term effects (e.g. in cancer) may be detected many years after the treatment period. Growth, development and maturation specific to children can make these effects particularly harmful. The development plan of a paediatric drug should include, long term follow up on the basis of pharmacological-toxicological and safety data. These aspects should be taken into account when modifying the protocol (lower dosage, withdrawal of some associations etc). The follow up period may be very long, as in cancer (e.g. second tumour after treatment for cancer). A cohort is the best choice for this follow up, but other alternatives may be useful, including a specific follow-up Unit. Long-term follow-up is nevertheless difficult and expensive, manpower-dependent and the risk of failure is great especially in the teenage years.

Assessment of viral loads in patients with chronic hepatitis C with AMPLICOR HCV MONITOR version 1.0, COBAS HCV MONITOR version 2.0, and QUANTIPLEX HCV RNA version 2.0 assays.

The correlation between response to antiviral therapy and pretreatment viral load in patients with chronic hepatitis C has prompted the development of quantitative assays to measure viral load. The aim of our study was to assess the clinical relevance of the newly developed semiautomated PCR system COBAS HCV MONITOR version 2.0 in comparison with (i) the AMPLICOR HCV MONITOR version 1.0 assay, which underestimates RNA concentration of hepatitis C virus (HCV) genotypes 2 to 6, and (ii) the QUANTIPLEX HCV RNA version 2.0 assay, which achieves equivalent quantification for each HCV genotype, with samples from 174 patients diagnosed with chronic hepatitis C before therapy. The level and range of quantification measured with AMPLICOR HCV MONITOR version 1.0 were 1 log lower than when measured with the COBAS HCV MONITOR version 2.0, at 0.261 x 10(6) RNA copies/ml (range, 0.001 x 10(6) to 2.50 x 10(6) RNA copies/ml) and 4.032 x 10(6) RNA copies/ml (range, 0.026 x 10(6) to 72.6 x 10(6) RNA copies/ml), respectively. The two assays showed a poor correlation (r(2) = 0.175). The level and range of quantification were similar when measured with the COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays, at 3.03 x 10(6) RNA copies/ml (range, 0.023 x 10(6) to 72.6 x 10(6) RNA copies/ml) and 4.91 Meq/ml (range, 0.200 to 49.5 Meq/ml), respectively. The two assays showed a strong correlation (r(2) = 0. 686) for each HCV genotype. The duration of treatment (6 or 12 months) is modulated according to HCV genotype and viral load. Our results indicate that COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays showing an equal dynamic range for each HCV genotype are suitable tools to assess patients before therapy.

Salivary gland lymphomas in patients with Sjögren's syndrome may frequently develop from rheumatoid factor B cells.

OBJECTIVE: Patients with Sjögren's syndrome (SS) have an increased risk of developing monoclonal B cell non-Hodgkin's lymphomas (MNHL), which frequently occur in the salivary glands (SG). The transition from the benign lymphocyte infiltrate of the gland that characterizes SS to MNHL is not well understood. Previous sequence analyses of the expressed variable (V) region genes have supported the theory that the surface Ig (sIg) plays an important role in the initial expansion of nonmalignant B cell clones and in lymphomagenesis. However, the antigenic specificities of these B cells were unknown. We describe the specificities of the Ig expressed by 2 cases of MNHL that developed in the SG of 2 patients with SS. METHODS: The expressed V genes were amplified by polymerase chain reaction from biopsy specimens, sequenced, and subcloned into eukaryotic expression vectors. The constructs were transfected into P3X63-Ag8.653 cells to obtain 2 monoclonal cell lines, each secreting 1 of the sIg expressed by the MNHL. These IgM were tested by enzyme-linked immunosorbent assay and immunofluorescence against a panel of antigens potentially implicated in SS. RESULTS: Our main finding was that the Ig products of the neoplastic B cells were rheumatoid factors (RF). Contrary to expectations, they did not react with nuclear or cytoplasmic antigens, double-stranded DNA, self antigens commonly bound by natural autoantibodies, or SG tissue. CONCLUSION: Previous analyses of V gene use have provided indirect evidence that SG MNHL may frequently express RF. We demonstrate that this hypothesis is true in the 2 patients we studied. Large-scale studies will be needed to establish the exact frequency of RF specificity among SS-associated MNHL.

Effects of corticosteroids on HCV infection.

The risk factors for clinical recurrent hepatitis C in liver transplant recipients are not clearly defined. It has been suggested that the corticosteroids included in the treatments of patients undergoing allograft rejection might induce acute hepatitis by increasing HCV replication. In this study we investigated the effects of corticosteroid boluses on HCV viremia in liver allograft recipients treated for acute rejection. Since we had previously developed a model of HCV replication in peripheral blood mononuclear cells (PBMC) in vitro, we also studied the effects of corticosteroids on HCV replication in vitro. A transient peak of HCV viremia was observed in patients treated with corticosteroid boluses for an acute allograft rejection. In the cell cultures, corticosteroids induced an increase of the total amount of viral RNA detectable. Our results demonstrate that corticosteroids induce an increase of hepatitis C virus replication in vivo and in vitro.

[Prenatal diagnosis of viral infections. A two year study in Strasbourg]. / Diagnostic prénatal des infections virales. Bilan de deux années d'activité à Strasbourg.

We report here the results of a 2-year study on the prenatal diagnosis of viral infections in Strasbourg. This screening was carried out by virus isolation, by PCR assay, or by detection of IgM fetal antibody for 98 pregnant women at risk of transmitting one of the viruses that causes fetal disease such as parvovirus B19 (B19), Herpesviruses [cytomegalovirus (CMV), varicella-zoster virus, herpes simplex virus] and rubella virus. A viral etiology was proven in 7 out 98 cases: PCR applied to B19 DNA detection was positive in 5 amniotic fluids (AF), 2 fetal serums and one ascitic liquid. The diagnosis of 2 cases of CMV infection was obtained by both PCR and virus isolation in AF from twins fetuses. The detection of specific IgM in maternal serum or fetal serum is useful to achieve the diagnosis but serological tests on other samples have no efficiency. No virus was found in any other specimen, but the genome of Toxoplasma gondii was detected by PCR in 1 of 17 AF samples analyzed at the Institut de Parasitologie. These findings show that PCR assay is a sensitive method for the positive diagnosis of intrauterine infection and promises to careful follow-up of the pregnancy.

AIDS primary central nervous system lymphoma: molecular analysis of the expressed VH genes and possible implications for lymphomagenesis.

AIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longer efficient in these lymphoma B cells. Taken together, our results suggest that distinct Ags could be recognized by the BCR of the lymphoma cells in different patients and that, if the Ags are responsible for the brain localization of these B cells bearing mutated BCR, other factors must be involved in B cell transformations in primary central nervous system lymphoma.

High prevalence of GB virus C/hepatitis G virus RNA in patients infected with human immunodeficiency virus.

Prevalence of GBV-C/HGV was determined in a cohort of HIV-infected patients, via a reverse transcription-polymerase chain reaction detection of RNA in serum, amplifying the NS5 region of GBV-C/HGV genome. GBV-C/HGV RNA was detected in 143 (37.7%) of 379 patients, with similar results in the different HIV risk groups: 25/56 (44.6%) in intravenous drug users, 66/161 (41%) in homo- and bisexual men, 35/108 (32.4%) in heterosexual patients, 6/20 (30%) in transfusion recipients (P=0.41). There was no difference according to the presence or absence of hepatitis C virus infection. In univariate analysis, GBV-C/HGV genome prevalence was lower in patients over 50 years old (18.2%), compared to other age groups (20-29 years: 34.2%; 30-39 years: 44.3%; 40-49 years: 36.7%, P=0.03), as well as in patients with normal CD4 cell count (29.2% vs. 45.4% between 200-500/mm3, and 35.3% below 200 CD4/mm3, P=0.012) and individuals with a chronic hepatitis B. However, in the multivariate analysis, the only prognostic factor of GBV-C/HGV RNA positivity was the presence of a chronic hepatitis B, compared to the absence of any HBV marker, or a previous exposition to HBV (presence of anti-HBc and/or anti-HBs, absence of HBsAg), or the presence of anti-HBs alone.

Recurrent varicella pneumonia complicating an endogenous reactivation of chickenpox in an HIV-infected adult patient.

We report the case of an adult patient with acquired immune deficiency syndrome (AIDS) presenting with acute dyspnoea and cutaneous disseminated lesions suggestive of an atypical varicella. The chest radiograph and the computed tomography (CT)-scan revealed a miliary pneumonia. On a previous serum sample varicella-zoster (VZV)-specific serum immunoglobulin (Ig)G titre was 1/200. A high dose acyclovir treatment was effective, but recurrences occurred twice when the treatment was discontinued. During the first recurrence the polymerase chain reaction (PCR) detected the presence of VZV in the bronchoalveolar lavage (BAL) sample. These findings confirmed the diagnosis of secondary varicella with pulmonary involvement. Secondary varicella pneumonia has not been reported in a human immunodeficiency virus (HIV)-infected adult until now. The use of PCR on a BAL sample was very useful in this case because viral culture remained negative. Recurrences of the varicella pneumonia suggested that a maintenance treatment was required in this deeply immunocompromised patient.