Nivolumab immunotherapy rechallenge for progressive laryngeal squamous cell carcinoma after failure of conventional treatment: A CARE case report.

OBJECTIVE: Analysis of rechallenge with nivolumab as 5th-line therapy for locally and nodally failed laryngeal squamous cell carcinoma following conventional therapeutic modalities: radiotherapy, surgery and chemotherapy. OBSERVATION: A 70-year-old male, with local and nodal progression of laryngeal squamous cell carcinoma after treatment with chemoradiotherapy and surgery, was initially treated for recurrence with carboplatin, 5-fluorouracile (FU) and cetuximab, followed by second-line nivolumab, and then two lines of conventional chemotherapy with paclitaxel and cetuximab followed by carboplatin and cetuximab. He underwent rechallenge with nivolumab in 5th line, achieving 12months' response, ongoing at the time of writing, and 42.5months' survival since initiation of exclusive systemic management after failure of conventional treatment. CONCLUSION: This case report highlights the benefit of nivolumab rechallenge in 5th line following previous failure as stand-alone therapy in 2nd line for a patient with laryngeal squamous cell carcinoma locally and nodally uncontrolled after conventional treatment. Clinical trials evaluating the efficacy of this approach are necessary to assess its contribution, as it is currently not a standard therapeutic option.

Harmful impact of treatment refusal in T3-4M0 endolaryngeal squamous cell carcinoma candidates for total laryngectomy: A STROBE analysis.

PURPOSE: To evaluate the consequences of treatment refusal in total laryngectomy (TL) candidates with T3-4M0 endolaryngeal squamous cell carcinoma (SCC). MATERIALS AND METHODS: A retrospective observational study was conducted in an inception cohort of 576 isolated T3-4M0 endolaryngeal SCC candidates for TL consecutively managed between 1970 and 2019 in a French university teaching hospital. The main endpoint was survival time and cause of death in 2 groups. Group A, 4.5% of the cohort, consisted of 26 patients who declined any laryngeal treatment. Group B consisted of 550 patients who accepted TL. Accessory endpoints were causes of TL refusal and associated variables. The STROBE guideline was applied. The significance threshold was set at P<0.005. RESULTS: One-and 3-year actuarial survival estimates increased significantly (P<0.0001) from 39% and 15% in group A, to 83% and 63% in group B, respectively. In group A, 92% of causes of death implicated index SCC progression, whereas in group B intercurrent disease, metachronous second primary, locoregional and/or metastatic SCC progression and postoperative complications accounted for 37%, 31%, 29%, and 2%, respectively. The actuarial survival estimates within group A increased significantly (P=0.0003) from 0% at 1-year in patients managed with isolated supportive care to 56% in patients managed with chemotherapy (reaching 0% at 5years). Reasons for TL refusal were fear of surgery, refusal of tracheostoma, loss of physiologic phonation, and certain comorbidities. Age and chronologic period correlated significantly with TL refusal. Median age decreased (P<0.001) from 69years in group A to 58 years in group B. Percentage TL refusal increased (P<0.0001) from 2% to 11% before and after start 1990, respectively. CONCLUSION: The current study determined loss of survival with refusal of any laryngeal treatment including TL, noted benefit of chemotherapy associated to supportive care, and discussed the possible contribution of immunotherapy.

European research platform IPANEMA at the SOLEIL synchrotron for ancient and historical materials.

IPANEMA, a research platform devoted to ancient and historical materials (archaeology, cultural heritage, palaeontology and past environments), is currently being set up at the synchrotron facility SOLEIL (Saint-Aubin, France; SOLEIL opened to users in January 2008). The new platform is open to French, European and international users. The activities of the platform are centred on two main fields: increased support to synchrotron projects on ancient materials and methodological research. The IPANEMA team currently occupies temporary premises at SOLEIL, but the platform comprises construction of a new building that will comply with conservation and environmental standards and of a hard X-ray imaging beamline today in its conceptual design phase, named PUMA. Since 2008, the team has supported synchrotron works at SOLEIL and at European synchrotron facilities on a range of topics including pigment degradation in paintings, composition of musical instrument varnishes, and provenancing of medieval archaeological ferrous artefacts. Once the platform is fully operational, user support will primarily take place within medium-term research projects for `hosted' scientists, PhDs and post-docs. IPANEMA methodological research is focused on advanced two-dimensional/three-dimensional imaging and spectroscopy and statistical image analysis, both optimized for ancient materials.

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRbeta-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique.

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRbeta) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRbeta-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRbeta-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRbeta-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRbeta-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRbeta-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRbeta-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.

First principles NMR calculations of phenylphosphinic acid C6H5HPO(OH): assignments, orientation of tensors by local field experiments and effect of molecular motion.

The complete set of NMR parameters for (17)O enriched phenylphosphinic acid C(6)H(5)HP( *)O(*OH) is calculated from first principles by using the Gauge Including Projected Augmented Wave (GIPAW) approach [C.J. Pickard, F. Mauri, All-electron magnetic response with pseudopotentials: NMR chemical shifts, Phys. Rev. B 63 (2001) 245101/1-245101/13]. The analysis goes beyond the successful assignment of the spectra for all nuclei ((1)H, (13)C, (17)O, (31)P), as: (i) the (1)H CSA (chemical shift anisotropy) tensors (magnitude and orientation) have been interpreted in terms of H bonding and internuclear distances. (ii) CSA/dipolar local field correlation experiments have allowed the orientation of the direct P-H bond direction in the (31)P CSA tensor to be determined. Experimental and calculated data were compared. (iii) The overestimation of the calculated (31)P CSA has been explained by local molecular reorientation and confirmed by low temperature static (1)H-->(31)P CP experiments.

Serum amyloid A protein-related mRNA expression in herpes simplex virus type 2-transformed hamster cells.

A nearly full-length cDNA very similar to murine serum amyloid A protein was cloned from herpes simplex virus type 2-transformed hamster cells. The expression of mRNA was constitutive in these cells and could be superinduced by conditioned medium. Higher rates of nuclear runoff transcription in transformed and induced cells indicated some regulation at the transcriptional level.

NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis.

Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.

Identification of a proliferation-related transcript with an elevated expression in the mid-gestation mouse embryo.

Polyadenylated RNA enriched in transformation specific sequences from hamster embryo fibroblast cells transformed by HSV-2 was used to construct a cDNA library. A cDNA clone (pKG4) contained a sequence which was upregulated in HSV-2 transformed cells and also in fibroblastic cell lines transformed by SV40 and 3-methylcholanthrene. The expression of the KG4 sequences in HSV-2-transformed cells was found to be modulated by the growth state of the cells. In confluent cells its level was reduced 5-times compared to the homologous RNAs from exponentially growing cells. Expression of the KG4 sequence was also examined in mouse embryos from day 8 onwards and in adult tissues. During development, KG4 is expressed at all times examined. However, there is a dramatic increase in expression on day 11. In adult tissues, a low and variable level of expression was observed. These findings suggest that the KG4 sequence is related to cellular proliferation.

Influence of solid solution formation on polarity: molecular modeling investigation of the system 4-chloro-4'-nitrostilbene/4,4'-dinitrostilbene.

Growth-induced polarity formation in solid solutions composed of dipolar 4-chloro-4'-nitrostilbene molecules and nonpolar 4,4'-dinitrostilbene molecules was investigated by means of two molecular modeling procedures. Calculation of the mixing energy in the bulk structures predicted solid solution formation within the whole composition range. Computation of the interaction energies present at growing surfaces allowed the distribution coefficient as well as the fraction of dipoles in either the up or down orientation to be calculated by a mean-field model. Miscibility and polarity were found to vary for the faces (hkl) investigated, leading to crystals composed of sectors with different compositions and polarities. The present study highlights the fact that a solid solution crystal may not be a homogeneous entity and that surface effects arising during slow growth can have an impact on solid state properties.

Progressive MRI abnormalities in late recurrence of Sydenham's chorea.

We report four cases of adult recurrence of Sydenham's chorea (SC). The first episodes all followed childhood tonsillopharyngitis. Many years later, subsequent episodes appeared after the triggering circumstances: throat or cutaneous infection, pregnancy, childbirth, contraceptive treatment or stress. Other inflammatory diseases were ruled out and streptococcal serology was weakly positive. Magnetic Resonance Imaging (MRI) revealed focal areas of T2 hypersignal in the caudate nucleus, the pallidum, the putamen and the white matter. One year later, repeat MRI variously gave evidence of the persistence, disappearance or even new appearance of abnormalities. Specific features of SC recurrence in the adult may include: a personal history of chorea after a throat infection during childhood; a second episode of isolated chorea with or without slight neuropsychological disorders; streptococcal serology weakly positive; focal hypersignals involving the basal ganglia; the triggering circumstances. Since SC is considered to be an autoimmune disease, the progressive MRI abnormalities suggest that certain circumstances may trigger the reactivation of persistent immune disorders.

Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia.

Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.

A novel high throughput screening assay for HCV NS3 helicase activity.

A novel assay for measurement of Hepatitis C virus (HCV) NS3 helicase activity was developed using Flashplate technology. This assay involves the use of a DNA duplex substrate and recombinant HCV NS3 produced in Escherichia coli. The DNA duplex consisted of a pair of oligonucleotides, one biotinylated, the other radiolabeled at their respective 5' termini. This DNA duplex was immobilized, via the biotin molecule, on the surface of a neutravidin-coated SMP103 Flashplate (NEN Life Science Products). Helicase activity results in the release of the radiolabeled oligonucleotide, which translates in signal reduction with respect to control wells. Biochemical characterization of the HCV NS3 helicase activity was performed using this assay. We demonstrated that the NS3-mediated unwinding is proportional to both the amount of DNA substrate in the well, and to the NS3 concentration in the reaction. Most of the NS3-mediated unwinding was achieved in the initial 60 min of incubation. As expected the reactions were ATP-dependent and found to be affected by the concentration of MgCl(2), MnCl(2), KCl, EDTA, and by pH. We found this assay to be highly reproducible since only slight variation was observed when a total of 68 helicase reactions were performed on one plate. Therefore, this Flashplate helicase assay is fast, convenient and reproducible. These criteria make it suitable for high throughput screening of potential NS3 helicase inhibitors.

Performance study of cementitious systems containing zeolite and silica fume: effects of four metal nitrates on the setting time, strength and leaching characteristics.

The aim of this study is to investigate the effect of four metal nitrate contaminants, namely chromium, manganese, lead and zinc on the mechanical and leaching characteristics of cement-based materials. For this purpose, three different matrices made of: (i) Portland cement, (ii) Portland cement and silica fume, and (iii) Portland cement and natural zeolite were studied. The effects of metals on the stabilised/solidified (S/S) product characteristics were monitored by measuring: (i) setting time, (ii) compressive strength, (iii) acid neutralisation capacity (ANC), and (iv) solubility of the metal contaminants as a function of pH. The results of both mechanical and leaching tests showed the importance of the contaminant/matrix couple considered. Setting time was accelerated in presence of chromium, while in presence of manganese, lead and zinc it was delayed. However, for the last two contaminants, a 10% replacement of cement by silica fume and zeolite, markedly accelerated the setting time compared to the cement-only matrix. Although the early strength development was adversely affected in presence of all four contaminants, the long-term strength was less affected compared to the control materials. Although the ANC of the materials was not markedly affected by the presence of contaminants, the nature of the matrix did modify the ANC behaviour of the solidified materials. The increased strength and reduced ANC observed in the presence of silica fume are both due to pozzolanic reaction. The type of matrix used for solidification did not affect the solubility of the four metal contaminants. Overall, the results showed that the use of blended cements must be carried out with care and the performance assessment of waste-containing cement-based materials must take into consideration both the mechanical and leaching characteristics of the systems.

The effect of storage in an inert atmosphere on the release of inorganic constituents during intermittent wetting of a cement-based material.

Monolithic waste materials (e.g. Portland cement treated wastes) in many field scenarios do not remain continuously saturated, but experience intermittent wetting interspersed with periods of storage in an unsaturated environment. During storage, the matrix may loss moisture to the environment, promoting precipitation or redistribution of species. In addition, the matrix may react with the surrounding atmosphere through carbonation or oxidation. Upon subsequent leaching, changes in the chemical and physical composition incurred over the storage interval can influence the release of inorganic species. Current assessment approaches, which use continuous leaching data to project release over some assessment interval, do not allow for changes in leachability resulting from intermittent wetting and storage. Thus, this study evaluates the effect of storage intervals in an inert atmosphere on subsequent release of inorganic species from a synthetic Portland cement matrix. Tank leaching in deionized water was interspersed with storage at three relative humidity (RH) levels (nominally 0, 50 and 100% RH) in a 100% nitrogen atmosphere. Leaching data from the three intermittent wetting cases were compared to continuous leaching for the release of structural species (Ca, OH), highly soluble species (Na, K, Cl) and pH-dependent species (As, Cd, Pb). The RH of storage environment, which acted as a boundary condition for the drying process, influenced the precipitation of species within dried pores and relaxation of pH and concentration gradients within water-filled regions. Gradient relaxation resulted from continued mass transport within saturated pores over the storage interval and was most evident when storage was conducted at 98% RH. However, when storage RH promoted drying of the matrix, the effect of gradient relaxation was balanced by precipitation. When release was normalized to total leaching time, relaxation of concentration gradients of highly soluble species resulted in greater cumulative release for the intermittently wetted cases than in the case of continuous leaching. The release of pH-dependent constituents was controlled by relaxation of the pH gradient and species solubility as a function of local pore water pH. Application of a current assessment protocol to estimate intermittent wetting release resulted in either over or underestimation of actual cumulative release, depending on the nature of the constituent of interest. These results imply that long-term constituent release from Portland cement-based waste forms should not be made by simple correction of saturated release assessments because alterations to the matrix leachability induced by the storage environment need to be considered.

Development and characterization of a bispecific single-chain antibody directed against T cells and ovarian carcinoma.

Bispecific antibodies with specificity for tumor antigen and CD3 have been shown to redirect the cytotoxicity of T cells against relevant tumor. Our objective was to generate single-chain bispecific antibodies (bsSCA) that could retarget mouse cytotoxic T lymphocytes (CTL) to destroy human ovarian carcinoma in a xenogeneic setting. A bsSCA, 2C11 x B43.13, was constructed by genetic engineering and expressed in mammalian cells. Molecular characteristics, binding properties, and ability to retarget CTL were studied. Western blot analysis showed that the product is a 65-kDa protein. Purification of antibodies could be done by single-step affinity chromatography using protein L-agarose with an unoptimized yield of 200 microg/L. BsSCA 2C11 x B43.13 was capable of binding to mouse CD3 and human CA125 as detected by FACS analysis of EL4 and OVCAR Nu3H2 cells, respectively. It could also bridge activated splenic T cells and human ovarian carcinoma as demonstrated by a bridge FACS assay. Redirected mouse CTL could mediate human target cell lysis in a 20-h 51Cr release assay despite that they are xenogeneic. Prolonged incubation of redirected CTL and tumor targets resulted in a dramatic reduction in tumor cell number. CD28 co-stimulation enhanced redirected CTL function in both types of assays. BsSCA 2C11 x B43.13 thus can be used as a preclinical immunotherapeutic model for human ovarian cancer in a xenogeneic setting.

[Pulsatile vaginal expansion: Case report of an internal iliac aneurysm detected after an injury]. / L'expansion pulsatile du vagin: à propos d'un cas d'anévrysme iliaque interne révélé par un traumatisme.

After a pelvic trauma, in a 78 years old women, systematic radiograms showed a polycyclic mass in the left side of the pelvis. This finding was confirmed by B-mode ultrasound echography. The vaginal touch found a pulsatile and expanding mass. At surgery, the diagnosis of a fissuring aneurysm of the internal iliac artery was confirmed, and a curative treatment was undertaken. Reviewing the literature, the authors emphasize the diagnostic usefulness of rectal and vaginal touch, and the importance of an early diagnosis using noninvasive imaging techniques. Surgery is the only treatment for isolated internal iliac aneurysms.

Leaching assessment of road materials containing primary lead and zinc slags.

Characterisation of the leaching behaviour of waste-containing materials is a crucial step in the environmental assessment for reuse scenarios. In our research we applied the multi-step European methodology ENV 12-920 to the leaching assessment of road materials containing metallurgical slag. A Zn slag from an imperial smelting furnace (ISF) and a Pb slag from a lead blast furnace (LBF) are investigated. The two slags contain up to 11.2 wt% of lead and 3.5 wt% of zinc and were introduced as a partial substitute for sand in two road materials, namely sand-cement and sand-bitumen. At the laboratory scale, a leaching assessment was performed first through batch equilibrium leaching tests. Second, the release rate of the contaminants was evaluated using saturated leaching tests on monolithic material. Third, laboratory tests were conducted on monolithic samples under intermittent wetting conditions. Pilot-scale tests were conducted for field testing of intermittent wetting conditions. The results show that the release of Pb and Zn from the materials in a saturated scenario was controlled by the pH of the leachates. For the intermittent wetting conditions, an additional factor, blocking of the pores by precipitation during the drying phase is proposed. Pilot-scale leaching behaviour only partially matched with the laboratory-scale test results: new mass transfer mechanisms and adapted laboratory leaching tests are discussed.

Leaching of inorganic contaminants from cement-based waste materials as a result of carbonation during intermittent wetting.

Characterization of the leaching behavior of wastes is a crucial step in the environmental assessment for reuse or disposal scenarios. The release of inorganic contaminants from waste materials is typically evaluated by tank leaching of continuously water-saturated material. However, materials, in many field or management scenarios, experience cyclic wetting and drying under varied environmental conditions (i.e. variable relative humidity, atmospheric CO2 or CO2 from biologic activities). During periods of storage in an unsaturated environment, many processes may occur that can influence the release potential and release rate of inorganic constituents. The research presented here was carried out to examine how the phenomena of carbonation during drying influence the release of inorganic contaminants from Portland cement-based materials during cyclic wetting and storage. Batch equilibrium leaching tests were used to determine constituent solubility as a function of pH. Dynamic leaching tests on monolithic material were carried out to determine the rate of constituent release as a function of leaching time and intermittent storage conditions. This paper presents the results observed for three typical waste constituents, arsenic, cadmium and lead.

[Toxic syndrome induced by neuroleptics: report of 7 cases]. / Le syndrome malin des neuroleptiques: à propos de 7 cas.

Seven cases of malignant syndrom due to neuroleptic drugs are reported, three of them in patients receiving long-acting medication. The authors point out the seriousness of such accidents, two of seven cases leading to death. Clinical features consist mainly of hyperthermia which can be erroneously attributed to infectious disease. Muscular hypertonicity is often associated with hyperthermia. Tetanus was evoked for two patients. In the absence of satisfactory physiopathologic explanation, treatment is merely symptomatic, based on intensive care. So far, this type of accident has been little known; it was important to focus our attention on it.

[Direct detection of toxoplasma in the aqueous humor by gene amplification]. / Détection directe de toxoplasmes dans l'humeur aqueuse par amplification génique (PCR).

For immunocompetent patients, ocular toxoplasmosis is the most frequent infectious cause of chorioretinal inflammation. Nowadays, the laboratory diagnosis of ocular toxoplasmosis requires serological tests and anterior chamber puncture to detect the local production of specific antibodies. The authors describe a new technique to detect toxoplasma in aqueous humor by a polymerase chain reaction in which the target is a 88 bp specific rDNA fragment. 31 patients were concerned (23 highly suspect of ocular toxoplasmosis and 8 controls). The presence of the parasite in aqueous humor was found in 7 cases. No false positive was detected. The sensitivity of the test is reduced by the poor volume of the sample. The combination of this technique with Desmont's coefficient gives a better positive predictive value. We emphasize the pathophysiological value of this technique by suggesting the presence of tachizoites in the anterior chamber. According to our knowledge, this finding has never been demonstrated. In the future, this should be a very promising technique for the diagnosis of ocular toxoplasmosis.