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Introduction: Oncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells., Methods: In this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells., Results: We show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I -/- MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I -/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum., Conclusion: Our study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

In this article, we present a complete automated system for spotting a particular slice in a complete 3D Computed Tomography exam (CT scan). Our approach does not require any assumptions on which part of the patient's body is covered by the scan. It relies on an original machine learning regression approach. Our models are learned using the transfer learning trick by exploiting deep architectures that have been pre-trained on imageNet database, and therefore it requires very little annotation for its training. The whole pipeline consists of three steps: i) conversion of the CT scans into Maximum Intensity Projection (MIP) images, ii) prediction from a Convolutional Neural Network (CNN) applied in a sliding window fashion over the MIP image, and iii) robust analysis of the prediction sequence to predict the height of the desired slice within the whole CT scan. Our approach is applied to the detection of the third lumbar vertebra (L3) slice that has been found to be representative to the whole body composition. Our system is evaluated on a database collected in our clinical center, containing 642 CT scans from different patients. We obtained an average localization error of 1.91±2.69 slices (less than 5 mm) in an average time of less than 2.5 s/CT scan, allowing integration of the proposed system into daily clinical routines., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Current diagnostic methods for skin cancers are based on some morphological characteristics of the pigmented skin lesions, including the geometry of their contour. The aim of this article is to model the early growth of melanoma accounting for the biomechanical characteristics of the tumor micro-environment, and evaluating their influence on the tumor morphology and its evolution. The spatial distribution of tumor cells and diffusing molecules are explicitly described in a three-dimensional multiphase model, which incorporates general cell-to-cell mechanical interactions, a dependence of cell proliferation on contact inhibition, as well as a local diffusion of nutrients and inhibiting molecules. A two-dimensional model is derived in a lubrication limit accounting for the thin geometry of the epidermis. First, the dynamical and spatial properties of planar and circular tumor fronts are studied, with both numerical and analytical techniques. A WKB method is then developed in order to analyze the solution of the governing partial differential equations and to derive the threshold conditions for a contour instability of the growing tumor. A control parameter and a critical wavelength are identified, showing that high cell proliferation, high cell adhesion, large tumor radius and slow tumor growth correlate with the occurrence of a contour instability. Finally, comparing the theoretical results with a large amount of clinical data we show that our predictions describe accurately both the morphology of melanoma observed in vivo and its variations with the tumor growth rate. This study represents a fundamental step to understand more complex microstructural patterns observed during skin tumor growth. Its results have important implications for the improvement of the diagnostic methods for melanoma, possibly driving progress towards a personalized screening., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We reviewed the results of infiltrating bladder cancer treated by radical cystectomy to evaluate survival. Between January 1989 and December 1992, a total of 58 consecutive cystectomies or anterior pelvectomies performed on 48 men and 10 women (mean age 63.2 years) in our department were retrospectively evaluated. Four patients were lost to follow-up and the mean follow-up was 72 months. Pathologic staging was as follows: stage pT0,A,1: 13.5%, stage pT2: 17.5%, stage pT3a: 12%, stage pT3b: 36%, stage pT4: 21%. The year probability of the overall survival was 60% for p T2-p T3a patients, 15% for pT3b patients, and 9% for pT4 patients, respectively. Overall, 53.5% of patients died of cancer, 7.5% of intercurrent disease, and 39% were alive. The cancer related death rate was 12% for pT2-pT3a patients, and 82% for pT3b-pT4 patients. The 5- year probability of specific survival was 80% for pT2-pT3a patients, 15% for pT3b patients, and 9% for pT4 patients, respectively. Infiltrating bladder cancer still has a high mortality rate. Radical cystectomy may be considered to be a curative procedure for stages pT2 and pT3a. Adjuvant chemotherapy and/or radiotherapy seem necessary at stages pT3b and pT4. Preoperative criteria need to be better defined to reduce understaging.

All cases of superficial bladder tumor treated in 1991 at the urology department of La Pitié hospital were reviewed to study the course of superficial bladder tumors with regard to the risk of muscle infiltration and the value of endoscopic follow-up. In 1991, 73 patients (63 men and 10 women) with a mean age of 64 years had TUR for superficial bladder tumor. Patients had repeated cystoscopy at 3 and 6 months and then on a yearly basis for 5 years. Fourty-eight patients had TIS tumors, and 19 patients had T1 tumors. Five patients were lost to follow-up. Sixty-eight patients were followed for 5 years. Of 48 patients with stage TIS tumors, 39 (81.5%) did not show any deterioration at histological examination, eight patients (16.5%) had infiltration of the lamina propria by tumor (pT1) and the tumor invaded muscle in one patient (2%). Of the 19 patients with stage T1 tumors at the first TUR eight (47%) had no pathologic deterioration, but nine (53%) developed muscle invasion (pT2). Two patients were lost to follow-up. Invasion of the lamina propria present at diagnosis or during the subsequent course is considered to be an indicator of high risk of progression to muscle invasive disease (over 50% of cases). The prognostic accuracy of both the grade and stage needs to be enhanced using molecular markers.

The in vitro antibacterial activity of cefotaxime, cefepime and cefpirome was evaluated alone and in association with two beta-lactamase inhibitors: clavulanic acid and sulbactam against 65 extended broad spectrum beta-lactamase producing enterobacteriaceae strains [Klebsiella pneumoniae (35), Proteus mirabilis (9), Escherichia coli (11), Enterobacter aerogenes (10)]. The lowest MICs were observed for cefepime and cefpirome used alone. In association with inhibitors cefotaxime was less effective against E. aerogenes. Most isolates of K. pneumoniae, P. mirabilis, E. coli were susceptible to all the different tested associations.

Recombinant human interleukin-6 (IL-6) has previously been shown to increase platelet counts in normal and sublethally irradiated mice, dogs, and primates. To assess its tolerance and efficacy in clinical use, we performed a randomized phase Ib study in patients with ovarian carcinoma. IL-6 was administered during an initial 7-day cycle before any chemotherapy. Beginning 7 days later, six cycles of chemotherapy containing carboplatin were administered every 3 weeks. During chemotherapy cycles 2 to 6, IL-6 was administered from day 4 through day 17 at escalating dose levels from 0.5 to 10 micrograms/kg/d. At each level, three patients received IL-6 and one patient received a placebo. During the prechemotherapy cycle of IL-6, a dose-dependent increase in platelet count was observed from day 12 to 15 and was maximal on day 15 (r = .77; P < .01). The median ploidy of bone marrow megakaryocytes shifted from 16 N to 32 N after 7 days of the initial prechemotherapy IL-6 administration. Dose-dependent increases in C-reactive protein (CRP) and fibrinogen levels were observed on day 8 (P < .0001 for both). A significant decrease in hemoglobin level occured rapidly after initiation of IL-6 therapy and was maximal on day 8 (P < .001). When given after chemotherapy, IL-6 accelerated platelet recovery after chemotherapy cycles 2 to 6. Postponements of scheduled chemotherapy due to thrombocytopenia were less frequent in patients treated with IL-6. No difference in either neutrophils or peripheral blood progenitor assays was observed during or after IL-6 treatment. Toxicity of IL-6 appeared mild and was not dose-limiting up to 10 micrograms/kg/d. Systemic symptoms such as fever, headache, and myalgia were the main side effects and were easily relieved by acetaminophen administration. No biologic toxicity was observed. The data indicate that IL-6 is a well-tolerated cytokine and capable of accelerating platelet recovery in patients receiving chemotherapy.

A system for the accurate and rapid measurement of the ploidy of cultured megakaryocytes derived from megakaryocytic colony-forming cells (CFU-M) has been developed. Thirty thousand murine marrow cells per milliliter were cultured for varying time periods in agar in the presence of horse serum and pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM). To ensure the inclusion of all the megakaryocytic cells in the analysis, entire agar discs were transferred onto glass slides and dried. Cells of the megakaryocytic lineage were identified by staining for acetylcholinesterase (AchE) for two hours. Subsequently, the nuclei of the cells were stained using 1.7 X 10(-5) mol/L chromomycin A3, a specific DNA-binding fluorochrome. Megakaryocytic colonies (greater than or equal to 2 AchE+ cells) were located under transmission light. The fluorescence emission of each cell of the colony was then measured by a photometer interfaced with a computer. The mean fluorescence emission of about 20 random granulocytes per slide was used as a 2N standard. There was no significant cell loss, quenching of fluorescence by AchE staining, or overlapping of colonies or cells. Approximately 100 megakaryocytes per hour could be analyzed. Modal ploidy of cultured megakaryocytes increased from 2N to 32N between days 3 and 6 in culture. Varying concentrations of PWM-SCM from 5% to 20% did not affect the ploidy distribution when examined at day 5. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. Clonal analyses of mean ploidy and ploidy heterogeneity did not show distinct types or classes of colonies; rather, the data show that megakaryocytic colonies are structured as a continuum. An inverse correlation was found between the number of cells constituting the colonies and their mean DNA content. To determine if short-term in vivo exposure of CFU-M to a thrombocytopenic environment could affect the ploidy of their progeny, mice were given rabbit antimouse-platelet serum while control animals were given normal rabbit serum. Twenty-four hours after injection, marrow derived from these animals was cultured. At day 5, the ploidy distributions and ploidy heterogeneity were identical in both treated and control groups. Thus, factor(s) that promote CFU-M proliferation do not affect megakaryocytic endoreduplication, while stimuli that acutely influence megakaryocytic ploidy in vivo do not determine the ultimate ploidy potential of megakaryocytes derived from a CFU-M.

To evaluate the efficacy of cefuroxime, a second generation cephalosporin, in minimizing the risk of per and postoperative infection complications in patients with urinary tract infection undergoing transurethral surgery, 86 patients (ASA I, II) with persistent urinary tract infection despite antibiotic therapy were studied. A double blind protocol was followed. Patients were randomly assigned to receive 10 minutes before surgery either I.V. cefuroxime (1.5 g) (group C, n = 39) or placebo (group P, n = 47) the incidence of positive peroperative systematic blood cultures was lower in group C (9.7%) than in group P (25.2%) (p less than 0.001). The incidence of postoperative blood cultures taken when clinical septic signs were present, was significantly lower in group C (0%) than in group P (21.7%) (p less than 0.05). However neither the incidences of both postoperative urinary tract infection at the 48th postoperative hour and the clinical signs of bacteraemia including fever nor the average length of hospitalization were significantly different in the 2 groups. This lack of significant clinical benefit was not explained by the pharmacokinetic properties of this antibiotic. Thus, preoperative administration of a single dose of cefuroxime, reduces the incidence of per and postoperative bacteraemias in ASA I-II patients with persistent urinary tract infection.

To examine the effect of lithium (Li) on early megakaryocytopoiesis, murine marrow megakaryocytic (CFU-M) and granulocyte-macrophage (CFU-C) progenitors were assayed in vitro with and without addition of lithium chloride (LiCl) to culture. At 2 mM LiCl, the numbers of CFU-M- and CFU-C-derived colonies were increased to 146% +/- 8% and 128% +/- 6% of controls, respectively (p less than 0.005). Enumeration of megakaryocytes per colony showed a 78% increase of colonies (p less than 0.05) containing from 6 to 22 cells, suggesting an increased proliferative capacity of CFU-M in the presence of LiCl. Conditioned media from spleen cells cultured in the presence of both pokeweed mitogen (PWM-SCM) and 2 mM Li increased the numbers of CFU-M and CFU-C to 157% +/- 8% and 183% +/- 8%, respectively (p less than 0.025), compared to control cultures stimulated by PWM-SCM alone. Since the production of active colony-stimulating activities (CSA) from mitogen-stimulated conditioned media requires T lymphocytes, we hypothesized that the enhancement of the growth of early hematopoietic progenitors in marrow cultures was due to a Li-induced CSA production by accessory marrow cells, rather than a direct effect of Li on stem cells. To test this, cyclosporin-A (CyA), a T-lymphocyte function inhibitor known to suppress CSA production in PWM-SCM, was added to marrow cultures in the presence of 2 mM Li. CyA (3 micrograms/ml) abrogated the Li-induced enhancement of CFU-M and CFU-C growth, but had no effect on colony formation when added alone. The data suggest that the Li-induced enhancement of early megakaryocytopoiesis and granulocytopoiesis is due to local production of CSA(s) by an accessory cell population and requires the integrity of T-lymphocyte function.

Murine bone marrow cells were separated on discontinuous Percoll gradients and assayed for their ability to give rise to megakaryocyte colonies. Ninety-one percent of the megakaryocyte progenitors (CFU-M) sedimented at densities between 1.070 and 1.080 g/mL. Six percent of CFU-M were found at densities between 1.060 and 1.070 g/mL, 2% between 1.050 and 1.060 g/mL, whereas less than 1% had a density either lower than 1.050 g/mL or higher than 1.080 g/mL. The number of doublings and endomitoses achieved by progenitors of density classes higher than 1.050 g/mL were similar. However, colonies derived from CFU-M of densities less than 1.050 g/mL (LD-CFU-M) had a higher probability of polyploidization and a lower probability of cell division in vitro. The inverse correlation found between the number of cells per colony and their DNA content was invariate regardless of the density class of the progenitors. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. The study if a short-period exposure of LD-CFU-M to acute thrombocytopenia could modify the ploidy of their progeny, mice were given rabbit antimouse platelet serum while control animals received normal rabbit serum. Twenty-four hours after injection, marrow was cultured. After a five-day culture period, no change in the number of colonies, doublings, ploidy, and heterogeneity of ploidy were observed between control and thrombocytopenic animals. The data suggests that LD-CFU-M are a distinct category of CFU-M, perhaps more mature than the common CFU-M.