Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the “THERAPY”phase 1-2 trial

To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first-line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m², then 250mg/m²). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7–6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.     

Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms

Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.     

Translation and Cultural Validation of the WERF EPHect Endometriosis Patient Questionnaire into Canadian French

ObjectiveTo produce a culturally validated Canadian French version of the Standard EPHect Endometriosis Patient Questionnaire (EPQ-S) from the World Endometriosis Research Foundation (WERF).MethodsWe studied 17 premenopausal women who were seen for pelvic pain symptoms or suspicion of endometriosis at the gynaecology clinic of the CHU de Québec – Université Laval (Québec City, Canada). Participants completed the French language version of the questionnaire at their first visit, and the validation took place about 1 week later.ResultsAll 22 of the invited women agreed to participate, of whom 17 were reached for the validation. The mean age of participants was 38.9 years, and 15 (88%) had a confirmed diagnosis of endometriosis. Fourteen participants (82%) found the questionnaire clear and relevant. The average length of time to complete the questionnaire was 36.25 ± 10.8 minutes. The validation process resulted in the addition of lines at the end of each section to allow space for specific comments and some clarifications with respect to timelines.ConclusionThis study validated a Canadian French version of the EPHect questionnaire. With such validation studies, differences in language and culture will no longer be a barrier to large national and international studies on endometriosis, leading to high-quality research and breakthroughs for millions of individuals living with this disease.     

Impact of Comorbidities on Hospital-Acquired Infections in a Geriatric Rehabilitation Unit: Prospective Study of 252 Patients

ObjectivesHospital-acquired infections (HAIs) remain a major source of morbidity and mortality in long-term care units, despite advances in antimicrobial therapy and preventive measures. Our aim was to investigate risk factors for HAIs, especially in the elderly, and to describe the relationship between comorbidities (number, severity, and specific diseases) and HAIs using a comprehensive inventory of comorbidities.DesignProspective cohort studySettingGeriatric rehabilitation unit in a university hospital in the Paris metropolitan area.ParticipantsParticipants were 252 consecutive patients aged 75 years or older (mean age, 85 ± 6.2 years) and admitted between 2006 and 2008.MeasurementsSurveillance of HAI was conducted. A complete inventory of comorbidities was done using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Potential risk factors were evaluated in 2 risk models, one with HAI acquisition, CIRS-G, activities of daily living score less than 10, and at least 1 invasive procedure (yes/no) and the other with HAI acquisition and specific invasive procedures and diseases.ResultsOf the 252 patients, 97 experienced HAIs, for an incidence of 5.6 infections per 1000 bed-days. The most common HAI sites were the respiratory tract (48%; 65/136) and urinary tract (37%; 51/136). The CIRS-G global score and comorbidity index were higher in patients with than without HAIs. Among HAI categories, respiratory and urogenital diseases were more prevalent in the group with HAIs. In the model combining CIRS-G, activities of daily living score less than 10, and at least 1 invasive procedure, independent risk factors for HAI were CIRS-G index (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.13–2.11; P = .005) and invasive procedures (OR, 5.18; 95% CI, 2.77–9.71; P < .001). In the model including specific procedures and diseases, independent risk factors for HAI were intravenous catheter (OR, 7.39; 95% CI, 2.94–18.56; P < .001), urinary catheter (OR, 3.33; 95% CI, 1.40–7.88; P = .006), gastrointestinal endoscopy (OR, 3.69; 95% CI, 1.12–12.16; P = .03), pressure sores (OR, 2.52; 95% CI, 1.04–6.10; P = .03), and swallowing impairment (OR, 3.37; 95% CI, 1.16–9.74; P = .02).ConclusionsThis study identified several important risk factors for HAIs. There is a need for HAI prevention via the implementation of infection-control programs, including surveillance, in rehabilitation units.     

MRSA Harboring mecA Variant Gene mecC, France

We describe human cases and clustered animal cases of mecA(LGA251)-positive methicillin-resistant Staphylococcus aureus in France. Our report confirms that this new variant has a large distribution in Europe. It may represent a public health threat because phenotypic and genotypic tests seem unable to detect this new resistance mechanism.     

State of the art: Could nursing mothers be vaccinated with attenuated live virus vaccine?

Recently two cases of vaccine-associated neurologic disease have been reported in breastfed infants whose mothers had received live attenuated yellow fever vaccine. These two cases have focused attention on the transmission of attenuated yellow fever vaccine virus from mother to infant via breastfeeding, and more generally of all other live attenuated viruses used to immunize nursing mothers. This article provides an overview of the rare literature on possible virus excretion in breast milk after vaccination of nursing mothers with live attenuated virus vaccine and on cases of infection via breastfeeding in infants whose mothers had been vaccinated postpartum. Before implementing postpartum vaccination in a nursing mother, the vaccinator needs to weigh up the risk of transmission to and adverse effects in the baby from live vaccine virus against the beneficial effects of the vaccine for the mother, taking into account her need for vaccination.     

Lamivudine therapy of chronic hepatitis B in three groups of patients: non transplanted patients, liver recipients, and kidney recipients

OBJECTIVE: As conflicting results have been observed by some authors in liver recipients, the aim of the study was to evaluate lamivudine therapy in 3 groups of patients with chronic hepatitis B: non-transplanted patients, liver and kidney recipients.METHODS: All patients were studied for clinical symptoms, hepatic enzymes, hepatitis B virus (HBV) serology, serum HBV DNA load, and HBV polymerase genotype (mutations associated with lamivudine resistance).RESULTS: During the 48-144 week-long follow-up (mean: 75 weeks), 23 non-transplanted patients, 5 liver and 6 kidney recipients were studied. A sustained biochemical and virological response was obtained in 19 out of the 23 non-transplanted patients and in 4 of 6 kidney recipients, while the 5 liver recipients did not respond. After the development of lamivudine resistance, mutations rtM204V and rtL180M were detected in all studied patients, mutation rtM207I in one, with similar results from traditional nucleotide sequencing and a commercial line probe assay.CONCLUSION: The poor response to lamivudine in liver recipients requires further studies.     

Cytogenetic study of 30 patients with multiple myeloma: comparison of 3 and 6 day bone marrow cultures stimulated or not with cytokines by using a miniaturized karyotypic method

Cytogenetics in multiple myeloma (MM) cases are generally difficult to perform due to the low proliferation index of malignant plasma cells (PC) in most cases. Although IL-6 and GM-CSF stimulate the in vitro proliferation of malignant plasma cells, their usefulness for improving cytogenetic results in multiple myeloma patients remains questionable, because results which compare various culture conditions in a sufficient number of patients are not available. By using a miniaturized karyotypic method, we compared in 30 multiple myeloma patients the number and percentage of clonal abnormal mitoses obtained from 3 and 6 d bone marrow cultures performed without or with two combinations of cytokines: IL-6 + GM-CSF or IL-6 + GM-CSF + IL-2 + IL-4 + TNFα . The percentage of patients with an abnormal karyotype, which varied with the Durie and Salmon stage of the disease, as well as the type of numerical and structural karyotypic abnormalities that we detected, were in agreement with published results. The detection of clonal karyotypic abnormalities was better after 3 d of culture without cytokine than in all other culture conditions. The higher percentage of patients at all stages of MM with an abnormal karyotype in our study (76.6%) than in previous ones (20% to 60%) is largely explained by the large number of mitoses analysed in six different culture conditions due to the use of a miniaturized karyotypic method.