Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). PATIENTS AND METHODS: We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2. RESULTS: From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). CONCLUSIONS: Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial.

Background: Several studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients' tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial. Patients and methods: The primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician's choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over. Results: Among 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm. Conclusions: The cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.

[Aplasia cutis congenita and antithyroid drugs during pregnancy: Case series and literature review]. / Aplasie cutanée congénitale et antithyroïdiens de synthèse au cours de la grossesse : série de cas et revue de la littérature.

BACKGROUND: Aplasia cutis congenita (ACC) following in utero exposure to antithyroid drugs such as methimazole/carbimazole (MTZ/CMZ) has been reported since 1972. Though currently included in MTZ/CMZ embryopathy, it remains poorly characterized and is little discussed. Having seen two cases within a short period of time, we carried out a literature review and searched the French pharmacovigilance database for notification of cases. PATIENTS AND METHODS: We performed a search of the literature in the Medline database using the following keywords: "aplasia cutis congenita", "birth skin defects", "pregnancy" and "drug". All articles reporting cases of ACC following in utero exposure to antithyroid drugs were included. All cases of ACC under antithyroid drugs reported to French pharmacovigilance centres were analysed. RESULTS: Three hundred and sixty-eight articles were retrieved and 31 were analysed, including a further 4, mentioned in selected articles, giving 59 cases of ACC under MTZ/CMZ reported in the literature and having an intrinsic accountability score of plausible or dubious. ACC was typically isolated, single, small in size, and localised on the median scalp area. Exposure occurred in the first weeks of gestation. There were 6 familial cases involving siblings. Ten ACC and MTZ/CMZ cases were reported to pharmacovigilance centres in France. DISCUSSION: Practitioners should be aware of ACC following MTZ/CMZ exposure in utero, whether it occurs in isolation or not. It is likely a teratogenic effect of MTZ/CMZ enhanced by a genetic predisposition.

Designs of preoperative biomarkers trials in oncology: a systematic review of the literature.

BACKGROUND: The identification of predictive and pharmacodynamics (PD) biomarkers of efficacy of anticancer-targeted therapies is not always straightforward. To address this problem, preoperative trials have been set up. The present study aimed at evaluating how these trials are designed. DESIGN: We retrieved all preoperative oncology trials, defined as preoperative trials having a PD end point. RESULTS: Only 56 trials met our selection criteria. Of these, 27 trials (48%) were randomized. Forty-nine trials (88%) evaluated at least a noncytotoxic agent. In 37 trials (66%), a single agent was administered. The most prevalent tumor type was breast cancer (59%). Median duration of accrual was 28 months (range: 9-98). In these trials, there was a mean of two patients included per month (range: 0-7). The date of surgery was fixed before study entry in 35 trials (62%), while surgery was set up after preoperative therapy in the remaining 21 trials (38%). In the former trials, median duration of preoperative therapy was 17 days (range: 1-112), whereas in the latter trials it ranged from 4 to 29 weeks. The primary end point was a PD end point in 26 of the 45 trials (58%) in which it was mentioned. One percent of patients could not undergo surgery as per protocol due to an adverse event. Statistically significant predictive and PD biomarkers were identified in 17 (30%) and 27 trials (48%), respectively. CONCLUSION: Preoperative biomarkers trials are infrequent but safe and feasible. These trials often permit the identification of predictive and PD biomarkers.

Detection of adeno- and lentiviral (HIV1) contaminations on laboratory surfaces as a tool for the surveillance of biosafety standards.

AIMS: As a biosafety laboratory, we survey the handling of adenovirus type 5 (Ad5) and HIV1-derived lentivirus in contained-use facilities in Switzerland to identify insufficiencies of the safety precautions taken by the laboratories. METHODS AND RESULTS: In the past 9 years, we took 430 swab samples from various types of surfaces in research laboratories. Samples were examined for Ad5 contaminations by real-time PCR and infectivity assay or for the presence of lentivirus (HIV1) nucleic acids by real-time (RT) PCR. Samples collected from centrifuges did not only contain Ad5 DNA more frequently but also exhibited higher numbers of Ad5 and lentiviral (HIV1) DNA copies than swabs from any other area of sampling. Five of ten samples containing infectious Ad5 particles or lentivirus (HIV1) RNA were found in samples taken from centrifuges. Ad5 contamination rates were higher in the tube holder and lower on the inner wall of the rotor chamber in centrifuges that were fitted with aerosol tight covers compared to centrifuges without covers. CONCLUSIONS: Our results allowed the comparison of hygiene standards of different laboratories and lead to the identification of centrifuges as hotspots for contaminations. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on our results, we propose to use the collected data as a tool for rating future swab results. Furthermore, the amount of Ad5 and HIV1-derived lentivirus DNA could serve as an indicator of the level of good laboratory practice in contained-use laboratories handling these viral vectors.

Contaminations of laboratory surfaces with Staphylococcus aureus are affected by the carrier status of laboratory staff.

AIM: As a biosafety laboratory, we take samples from surfaces in microbiological laboratories to survey the handling of micro-organisms. Whereas contaminations with other micro-organisms were rare, Staphylococcus aureus was found in the working environment of many laboratories. As 20-60% of the healthy population are carriers of S. aureus we wanted to asses the effect of carriers on our sampling results. METHODS AND RESULTS: Nasal swabs of staff members in nonmicrobiological laboratories and offices as well as surface samples from their personal work environment were taken and analysed for S. aureus DNA. In addition S. aureus strains were isolated using S. aureus-specific agar plates and analysed by randomly amplified polymorphic DNA (RAPD)-PCR and multilocus sequence typing (MLST). Our data show that contaminations with S. aureus in nonmicrobiological environments are common with 29% of the surface samples containing S. aureus DNA. In the working environment of carriers, the number of contaminations was significantly increased compared to the environment of noncarriers. CONCLUSION: The carrier status of staff members significantly affects the number of contaminations on laboratory surfaces. Therefore, even in the absence of intentional handling of S. aureus, contaminations can be detected on a substantial amount of surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: Sampling procedures need to be adapted based on these results with respect to the locations where samples are taken and the threshold for significant contaminations. Because of its wide distribution, S. aureus can serve as a marker for hygienic standards in laboratories.

Contrast-enhanced power and color Doppler ultrasonography of the pancreas in healthy and diseased cats.

BACKGROUND: The diagnosis of feline pancreatic disease is difficult, because clinical abnormalities and routine noninvasive diagnostic tests are unreliable. OBJECTIVE: The purpose of this study was to investigate by Doppler ultrasonography if vascularity and blood volume differs in the otherwise ultrasonographically normal and diseased feline pancreas. ANIMALS: Thirty-six client owned cats. METHODS: The pancreas was examined with B-mode and contrast-enhanced color and power Doppler ultrasonography. Doppler images were analyzed with a computer program: parameter fractional area represents a vascularity index and color-weighted fractional area assesses blood volume. RESULTS: Based on the B-mode findings, the pancreas was considered normal in 11 clinically healthy cats and diseased in 25 cats of which 4 were clinically healthy and 21 had clinical signs consistent with pancreatic disease. Histologic or cytologic samples were taken in all diseased pancreata. Fifteen samples were of diagnostic quality: purulent or mixed cellular inflammation (8), nodular hyperplasia (4), and neoplasia (3) were identified. Vascularity and blood volume for all Doppler methods was significantly higher in cats with pancreatic disease. Significantly higher Doppler values were detected with power Doppler than with color Doppler, and with postcontrast color and power Doppler than with precontrast Doppler technologies. CONCLUSION: Contrast-enhanced Doppler ultrasonography appears feasible in the feline pancreas. Significant differences were found between normal cats and those with evidence of pancreatic pathology. Further studies are needed to evaluate its use for the differentiation of pancreatic disorders and in cats suspected to have pancreatic disease but without B-mode ultrasonographic changes of the pancreas.

Integrated optoelectronic microprobes.

Optogenetics opened not only new exciting opportunities to interrogate the nervous system but also requires adequate probes to facilitate these wishes. Therefore, a multidisciplinary effort is essential to match these technical opportunities with biological needs in order to establish a stable and functional material-tissue interface. This in turn can address an optical intervention of the genetically modified, light sensitive cells in the nervous system and recording of electrical signals from single cells and neuronal networks that result in behavioral changes. In this review, we present the state of the art of optoelectronic probes and assess advantages and challenges of the different design approaches. At first, we discuss mechanisms and processes at the material-tissue interface that influence the performance of optoelectronic probes in acute and chronic implantations. We classify optoelectronic probes by their property of delivering light to the tissue: by waveguides or by integrated light sources at the sites of intervention. Both approaches are discussed with respect to size, spatial resolution, opportunity to integrate electrodes for electrical recording and potential interactions with the target tissue. At last, we assess translational aspects of the state of the art. Long-term stability of probes and the opportunity to integrate them into fully implantable, wireless systems are a prerequisite for chronic applications and a transfer from fundamental neuroscientific studies into treatment options for diseases and clinical trials.

[Pancytopenia related to low-dose methotrexate: study of five cases and review of the literature]. / Pancytopénie sous méthotrexate à faibles doses: étude de cinq observations et revue de la littérature.

PURPOSE: The aim of this study is to report personal experience of pancytopenia related to low-dose methotrexate and to review the literature. METHODS: We included retrospectively all cases of pancytopenia related to low-dose methotrexate (<25 mg/week), followed between January 1997 and December 2006, in the university hospital of Strasbourg, France. RESULTS: Five women, mean age 75.6 years, were included in the present study. Clinical manifestations included: symptomatic anemia (n=4), infection (n=3) and hemorrhagic manifestations (n=2); one patient had no feature. Mean hemoglobin concentration was 8,8 g/dl; mean white cell and platelet counts were 1,500 /mm(3) and 16,000 /mm(3), respectively. Potential risk factors were identified in all patients: renal failure and low serum albumin levels (n=5), anti-inflammatory drug intake (n=2), folate deficiency (n=4) and cobalamin deficiency (n=1). One patient died of septic and hemorrhagic cerebral complications. CONCLUSION: Pancytopenia related to tow-dose methotrexate is a rare but life-threatening disorder. Search and prevention of potential risk factors are required in all patients; determination of MTHFR genotype may be of several interests as folate supplementation.

Evaluation of the low-dose dexamethasone suppression test and ultrasonographic measurements of the adrenal glands in cats with diabetes mellitus.

The objectives of the study were to evaluate the low-dose dexamethasone suppression (LDDS) test and the size of the adrenal glands via ultrasonography in cats with diabetes mellitus. Twenty-two cats were enrolled in the study. In 19 cats, suppression of cortisol concentrations below 5.5 nmol/litre occurred four and eight hours after intravenous administration of dexamethasone (0.1 mg/kg). In one other cat, the cortisol concentration was also below 5.5 nmol/litre at eight hours but was 11.0 nmol/litre at four hours. The results were in agreement with those of healthy cats in a previous study. The cortisol concentrations four and eight hours after administration of dexamethasone did not differ between cats with good glycemic control (n = 8) and those with moderate to poor control (n = 12). The adrenal glands of the diabetic cats were not enlarged compared with those of healthy cats. In two diabetic cats, the LDDS test results were abnormal. One cat had a pituitary adenoma and adrenal glands of normal size as determined by ultrasonography. The size of the adrenal glands of the other cat clearly differed; histological examination of the larger adrenal gland revealed an adrenocortical adenoma. Based on our findings, the results of the LDDS test using 0.1 mg/kg of dexamethasone are normal in cats with diabetes mellitus independent of the quality of glycemic control. In addition, diabetes mellitus does not lead to a measurable increase in the size of the adrenal glands in cats. Further studies are needed to evaluate if the dexamethasone dosage used in this study is useful to diagnose mild form of hypercortisolism.

Memory of childbirth in the second year: the long-term effect of a negative birth experience and its modulation by the perceived intranatal relationship with caregivers.

OBJECTIVE: To assess the memory of various subdimensions of the birth experience in the second year postpartum, and to identify women in the first weeks postpartum at risk of developing a long-term negative memory. DESIGN, METHOD, OUTCOME MEASURES: New mothers' birth experience (BE) was assessed 48-96 hours postpartum (T1) by means of the SIL-Ger and the BBCI (perception of intranatal relationships); early postnatal adjustment (week 3 pp: T1(bis)) was also assessed. Then, four subgroups of women were defined by means of a cluster-analysis, integrating the T1/T1(bis) variables. To evaluate the memory of the BE, the SIL-Ger was again applied in the second year after childbirth (T2). First, the ratings of the SIL-Ger dimensions of T1 were compared to those at T2 in the whole sample. Then, the four subgroups were compared with respect to their ratings of the birth experience at T2 (correlations, ANOVAs and t-tests). RESULTS: In general, fulfillment, emotional adaptation, physical discomfort, and anxiety improve spontaneously over the first year postpartum, whereas in negative emotional experience, control, and time-going-slowly no shift over time is observed. However, women with a negative overall birth experience and a low level of perceived intranatal relationship at T1 run a high risk of retaining a negative memory in all of the seven subdimensions of the birth experience. CONCLUSIONS: Women at risk of developing a negative long-term memory of the BE can be identified at the time of early postpartum, when the overall birth experience and the perceived intranatal relationship are taken into account.

Resistance of human fibroblasts to c-fos mediated transformation.

Overexpression of the proto-oncogene c-fos induces transformation of primary avian and established rodent mesenchymal cells and tumor development in transgenic mice. As overexpression of Fos was also found in several human tumors of mesenchymal origin, we were interested whether c-fos is a transforming protein for human cells. Since fos genes transduced by infection competent vectors were most efficient in cellular transformation, expression cassettes of the human c-fos were introduced into a replication competent herpesvirus saimiri vector. Infection of human neonatal fibroblasts, cells of mesenchymal origin, resulted in episomal persistence of the recombinant viral genome and expression of c-fos in high excess. However careful examination for transformed phenotype failed to detect any changes in morphology, serum dependence, anchorage dependence, and life span, suggesting resistance of human mesenchymal cells against c-fos mediated transformation.

A pair of selectable herpesvirus vectors for simultaneous gene expression in human lymphoid cells.

The genome of Herpesvirus saimiri, a lymphotropic virus of non-human primates, was used to develop a vector system for transducing foreign genes into primary human T-cells and T-lymphoid cell lines. Recombinant viruses were obtained by homologous recombination of the viral genome with linearized plasmid DNA. The plasmid used contained a fragment of virion DNA, a hygromycin-B-resistance marker (HyR), and a multiple cloning site for the insertion of additional expression cassettes. The resulting recombinants were efficiently enriched and were plaque-purified. The virus mediating HyR and a H. saimiri strain carrying the Geneticin-resistance marker were used to infect the human T-lymphoid cell line Jurkat. Lymphocytes with a double-resistant phenotype were shown to contain the two different H. saimiri recombinants persisting as episomes at high multiplicity. The H. saimiri vector system will be suitable to study cooperating regulatory genes in T-lymphocytes.

Novel tetravalent and bispecific IgG-like antibody molecules combining single-chain diabodies with the immunoglobulin gamma1 Fc or CH3 region.

Although bispecific IgG molecules have been successfully applied for antibody-mediated immunotherapy of tumours, applicability is hampered by the difficulties associated with their generation. In the present study, we have used a bispecific single-chain diabody (scDb) directed against carcinoembryonic antigen and Escherichia coli beta-galactosidase as a model to generate bispecific IgG-like antibody molecules. We show that the fusion of this single-chain diabody to the Fc (scDb-Fc) or CH3 (scDb-CH3) region of the human immunoglobulin gamma1 chain results in the expression of dimeric fusion proteins exhibiting four functional antigen binding sites with increased functional affinity. This strategy represents a new and convenient way to generate IgG-like multivalent and bispecific molecules that are efficiently secreted from mammalian cells.

The pharmacokinetics of thiamphenicol in lactating cows.

The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives of 6.10 +/- 1.39 min and 1.60 +/- 0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9 +/- 0.077 ml/kg per min and the apparent volume of distribution was 1220.79 +/- 256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t1/2P) (serum to quarters), was found to be 36.89 +/- 11.14 min. The equivalent elimination half-life (t1/2E) (quarters to serum) from the milk was 3.62 +/- 1.06 h and the peak thiamphenicol concentration in the milk was 23.09 +/- 3.42 micrograms/ml at 2.5 +/- 0.32 h. After intramuscular injection, the elimination half-life was 2.2 +/- 0.40 h, the absorption half-life was 4.02 +/- 1.72 min and the peak concentration in the serum was 30.90 +/- 5.24 micrograms/ml at 23 +/- 8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59 +/- 6.87 min, the elimination half-life was 5.91 +/- 4.97 h and the mean peak concentration in the milk was 17.37 +/- 2.20 micrograms/ml at 3.4 +/- 0.22 h.

[Hyperthyroidism and immune hemolytic anemia following amiodarone therapy]. / Hyperthyroïdie et anémie hémolytique immune après traitement par amiodarone.

We report the cases of two patients who, after prolonged amiodarone therapy developed hyperthyroidism and immune haemolytic anaemia. Antibodies were of the IgG type and non-specific at elution. A search for other causes of haemolytic anaemia with positive Coombs' test gave negative results. Antiamiodarone antibodies have recently been discovered; they reflect an immunological disturbance due to this drug and might be responsible for some of the undersirable effects of amiodarone. In our patients, hyperthyroidism and haemolytic anaemia were induced by a dual mechanism: accumulation of amiodarone and induction of an effect of this drug on the immune system.

[The French pharmacovigilance system: structure and missions]. / Le réseau de pharmacovigilance français: structure et missions.

THE NETWORK: The French pharmacovigilance system is composed of a network of 31 regional pharmacovigilance centers located in convenient proximity to health care professionals. CAUSALITY ASSESSMENT: A causality assessment method is compulsory for all persons involved in pharmacovigilance in order to assess the causal relationship between an adverse effect and one or more drugs. PHARMACOEPIDEMIOLOGY: If necessary, an additional evaluation of the causal relationship is performed using pharmacoepidemiology methods. THE NATIONAL COMMISSION: A technical committee and a National Commission of Pharmacovigilance centralizes at the Agence Françiase de Sécurité Sanitaire (or AFSSAPS) and assesses all data in order to provide consensual advise to the relevant authorities on necessary measures, to prevent or reduce a drug-related adverse effect.

[Extra-pyramidal syndrome induced by donepezil]. / Syndrome extrapyramidal sous donepezil.

BACKGROUND: The cholinergic hypothesis of Alzheimer's disease is the basis of a new class of drugs: acetylcholinesterase inhibitors. These drugs have few side effects, mainly digestive disorders. CASE REPORTS: Extra-pyramidal side effects with severe gait disorders were observed in 3 patients with Alzheimer's dementia treated with donepezil. This drug was associated with paroxetine or a neuroleptic. In 2 of the 3 cases, the extra-pyramidal effects disappeared when donepezil was discontinued. DISCUSSION: Extra-pyramidal syndromes in elderly subjects with cognitive impairment are difficult to interpret. The possible causes include interactions between acetylcholinesterase inhibitors, neuroleptics and serotonine reuptake inhibitors and Lewy body dementia.

[Are nasal swabs for swine appropriate for the diagnosis of bacterial pneumonia agents?]. / Sind Nasentupfer beim Schwein zur Diagnostik bakterieller Pneumonie-Erreger geeignet?

Nasal swabs and lungs of 150 pigs with pneumonia were tested by culture at post mortem examination. The isolated agents were Pasteurella multocida (P.m.), P. haemolytica, Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Staphylococcus aureus, Streptococcus spp. and Escherichia coli. P.m. was most frequently found, and this agent only showed a significant correlation between lungs and nasal swabs. In 80.6% of pigs with P.m. in the lung the agent was detected in the nose, too. Drug resistance patterns of P.m. isolates from lungs and noses of the single animals were identical or similar, also in case of different capsular types. The examination of porcine nasal swabs for bacteria capable of causing pneumonia should be limited to P. multocida. Demonstration of agents in lung material is generally more certain.