Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

Reverse Osmosis Membrane Zero Liquid Discharge for Agriculture Drainage Water Desalination: Technical, Economic, and Environmental Assessment.

Agricultural drainage water (ADW) represents a potential source for fresh water after receiving appropriate treatments to satisfy the water quality requirements. Desalination of ADW with medium salinity and moderate contamination with organic and inorganic chemical pollutants could provide a techno-economically feasible approach for facing water scarcity in arid areas. The current work presents a conceptual zero liquid discharge ADW desalination system proposed to treat 300,000 m3/d. The system is based on pretreatment to remove impurities harmful to desalination by staged reverse osmosis (RO) membrane. The brine from the last RO stage is treated via thermal vapor compression followed by evaporation in solar ponds to recover more fresh water and salts of economic value. The essential technical features of the proposed system components are formulated. The proposed system components and its technical and economic indicators are deduced using available software for water pretreatment, RO membrane, desalination, thermal desalination, and solar evaporation ponds. The system provides total distilled water recovery of about 98% viz. 294,000 m3/d in addition to recovered salts of 245,000 t/y. The net cost of water production amounts to USD 0.46 /m3. The environmental considerations of the system are addressed and advantages of applying zero liquid discharge system are elucidated.

Can lifetime exposure to intimate partner violence predict suicidality in a sample of Egyptian pregnant women: a cross-sectional study?

Background and objectives: Research on suicidal behaviors during pregnancy in Egypt is limited; being apparently rationalized by pregnancy is a protective period. This study aimed to address the current suicide risk (CSR), and evaluate its correlates of among pregnant women in Egypt.MethodsIt is a cross-sectional study which included 835 of Egyptian pregnant women who were receiving their antenatal care at Zagazig University Obstetrics and Gynecology Outpatient clinics, during the period from 1 October 2017 to 30 September 2018. The sociodemographic and clinical data were collected by a simple semi-structured questionnaire. The psychometric assessment included Beck Suicidal Ideation Scale (BSS), Zagazig Depression Scale (ZDS), Hamilton Anxiety Rating Scale (HAM-A), and Structured Clinical Interview for DSM-IV-TR Axis II Personality Disorders (SCID-II) for assessment of CSR, and comorbid depression, anxiety and personality disorders, respectively.ResultsAmong pregnant women, 23.4% reported CSR. This included suicidal ideation of 21.6% and suicidal attempt of 1.8%. Predictors of CSR were history of intimate partner violence (IPV) exposure (OR 8.8, 95% CI: 2.8, 27.7), identification of their current pregnancy as a female baby (OR 6.9, 95% CI: 2.0, 23.5), previous history of fetal loss (OR 3.9, 95% CI: 1.5, 10.6), and moderate-to-severe depression (OR 3.0, 95% CI: 1.0, 8.7).ConclusionsOur findings suggest that CSR, including suicidal ideation and attempts, is not rare during pregnancy. Exposure to IPV is the most robust predictor of CSR. Pregnant women should be routinely screened for suicidal behaviors, violence exposure and depressive symptoms, as part of their antenatal assessments. (AU)

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Assessment of left ventricular ejection fraction with late-systolic and mid-diastolic cardiac phases using multi-slice computed tomography.

INTRODUCTION: Multi-slice computed tomography (MSCT) is an accurate tool for the assessment of left ventricular ejection fraction (LVEF). However, in order to reduce radiation dose, prospective acquisition protocols are currently used, in which the end-systole and end-diastole are not scanned. Our aim was to study the accuracy of the assessment of LVEF using fixed late-systolic and mid-diastolic cardiac phases compared with echocardiography. METHODS: MSCT-derived LVEF was measured with off-line commercially available software packages, and compared with echocardiography-derived LVEF using the Simpson's method. LVEF was categorized as normal vs. abnormal (50% cut-off) and was also analyzed as a quantitative parameter. Bland-Altman plots and Pearson correlations were used for inter-technique comparisons. RESULTS: 58 patients were included. The sensitivity and specificity of fixed-phase MSCT when compared with echocardiography for detection of LVEF ≤50% was 79% (95% CI = 65-89%) and 43% (10-82%). Misclassification was associated with older age (68 ± 12 vs. 54 ± 13 years, p < 0.01), faster heart rate (79 ± 14 vs. 68 ± 10 bpm, p = 0.01), and LV hypertrophy (86% vs. 52%, p = 0.03). The quantitative comparison revealed no correlation (r = 0.095, p = 0.478) and a significantly different LVEF (median[IQR], 57.0[50.5-63.1]% vs. 61.0[57.3-64.3]%, p = 0.03). The observed bias between the two methods was -3.7% with broad limits of agreement (±25.5%). CONCLUSIONS: Fixed-phase MSCT assessment using late-systole and mid-diastole agreed in defining normal and abnormal LVEF in 76% of patients when compared with echocardiography. Quantitation of LVEF by this method yielded significantly lower values of LVEF and showed no correlation. Thus, accurate quantitation of LVEF by MSCT requires the acquisition of end-systolic and end-diastolic phases.

Laparoscopic Interrupted Muscular Arch Repair in Recurrent Unilateral Inguinal Hernia Among Children.

PURPOSE: We present a procedure of suturing the transversus abdominis muscular arch to the ileopubic tract laparoscopically in order to repair recurrent unilateral pediatric inguinal hernia (PIH). PATIENTS AND METHODS: Twenty-five children with recurrent unilateral PIH were treated during a 5-year period in a tertiary academic center. All cases were subjected to laparoscopic hernia repair and discharged the next morning. Sutures were placed from the muscular arch to the ileopubic tract, avoiding the spermatic vessels and duct, in an interrupted manner using 2/0-3/0 polypropylene (Prolene®; Ethicon, Somerville, NJ) or polyglactin 910 (Vicryl®; Ethicon) sutures. In 4 cases, a rectangular purse-string-like suture was added to narrow the internal ring defect. Operative findings and postoperative results and complications were assessed. The patients were followed up for a period that ranged between 6 and 60 months. RESULTS: There were 23 boys and 2 girls. Operative age ranged between 18 months and 15 years. Three or four sutures were placed in each case. In 4 cases, an additional rectangular purse-string-like suture was added. Operative time ranged between 35 and 70 minutes, and there was no conversion. Mild scrotal edema was reported in 4 cases and port-site infection in 2 cases; all cases were treated conservatively. One case of recurrence among boys was reported, but there was no case of testicular atrophy. Cosmetic outcomes were excellent. CONCLUSIONS: Laparoscopic interrupted muscular arch repair is a feasible and safe technique in the reconstruction of the inguinal canal in recurrent unilateral PIH. Larger studies and long-term follow-up are needed to support our encouraging results.

Baseline nutritional status is prognostic factor after definitive radiochemotherapy for esophageal cancer.

Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42-81). Median radiation dose was 62.5 Gy (38-72) with 1.8-2 Gy fraction. Median follow-up was 20.8 months (2.8-92.4). Three and 5-year local recurrence-free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5-year locoregional recurrence-free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5-year disease-free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) ≥ 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5-year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI ≥ 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials.

[Definitive chemoradiotherapy for esophageal cancer: 66Gy versus 50Gy, a retrospective study]. / Chimioradiothérapie exclusive pour cancer de l'œsophage : comparaison entre 66Gy et 50Gy, une étude rétrospective.

PURPOSE: To compare the influence of radiation dose, high dose versus standard dose, on survival for patients with esophageal carcinomas treated with definitive radiochemotherapy. PATIENTS AND METHODS: Between 2003 and 2006, 143 consecutive patients with squamous-cell carcinoma and adenocarcinoma, clinical stage I to IVA, treated in two different institutions were retrospectively reviewed, 83 patients had received more than 50.4Gy, median dose 66Gy (50.7-72Gy) and 60 less than or equal to 50.4Gy, median dose 50Gy (38-50.4Gy). RESULTS: Median age was higher in high dose group (67.6 versus 61.7 years). Nutritional status and stage were better in high dose group with a lower weight loss (5.1 versus 7.9%), a higher body mass index (25.7 versus 22.9), more N0 patients (60.2 versus 31.7%) and less stage III (27.7 versus 63.3%). Median follow up was 20.8 months (2.8-92.4 months), and 64.9 months (4.2-92.4 months) for the 33 surviving patients. No statistically significant difference was shown for local/locoregional control, disease-free survival. Overall survival at 2-, 3- and 5-year and median survival was respectively 44.7%, 36.8%, 19.1% and 21.2 months in high dose group and 50.8%, 31.6%, 20.7% and 24.6 months in standard dose group (P=0.9). CONCLUSION: No difference was found between the two groups in terms of local/distant control and overall survival. A prospective randomised study is needed.

Sensitivity derivatives for flexible sensorimotor learning.

To learn effectively, an adaptive controller needs to know its sensitivity derivatives--the variables that quantify how system performance depends on the commands from the controller. In the case of biological sensorimotor control, no one has explained how those derivatives themselves might be learned, and some authors suggest they are not learned at all but are known innately. Here we show that this knowledge cannot be solely innate, given the adaptive flexibility of neural systems. And we show how it could be learned using forms of information transport that are available in the brain. The mechanism, which we call implicit supervision, helps explain the flexibility and speed of sensorimotor learning and our ability to cope with high-dimensional work spaces and tools.

Multiple and time-scheduled in situ DNA delivery mediated by beta-cyclodextrin embedded in a polyelectrolyte multilayer.

The basic premise of gene therapy is that genes can be used to produce in situ therapeutic proteins. The controlled delivery of DNA complexes from biomaterials offers the potential to enhance gene transfer by maintaining an elevated concentration of DNA within the cellular microenvironment. Immobilization of the DNA to the substrate to which cells adhere maintains the DNA in the cell microenvironment for subsequent cellular internalization. Here, layer-by-layer (LBL) films made from poly(L-glutamic acid) (PLGA) and poly(L-lysine) (PLL) containing DNA were built in the presence of charged cyclodextrins. The biological activities of these polyelectrolyte films were tested by means of induced production of a specific protein in the nucleus or in the cytoplasm by cells in contact with the films. This type of coating offers the possibility for either simultaneous or sequential interfacial delivery of different DNA molecules aimed at cell transfection. These results open the route to numerous potential applications in patch vaccination, for example.

[A urachus cyst revealing a torpid Crohn's disease in a young adult with chronic fever]. / Kyste de l'ouraque révélateur d'une maladie de Crohn torpide chez un adulte jeune atteint d'une fievre nue chronique.

INTRODUCTION: This case report describes a rare situation in which a superinfected cyst of the urachus complicated initially unknown and inactive Crohn's disease. CASE: A 21-year-old man presented a chronic fever finally attributed to a superinfected urachal cyst. Six months after ablation of the cyst, progressive Crohn's disease was diagnosed. DISCUSSION: The association of Crohn's disease and a superinfected urachal cyst is extremely rare. The case reported here is original in two aspects: the slowly progressive Crohn's disease was diagnosed after its complication; the superinfection developed through local bacterial translocation (ileal loop adjacent to the urachal cyst).

UV-damaged DNA-binding protein in the TFTC complex links DNA damage recognition to nucleosome acetylation.

Initiation of transcription of protein-encoding genes by RNA polymerase II (Pol II) was thought to require transcription factor TFIID, a complex comprised of the TATA box-binding protein (TBP) and TBP-associated factors (TAF(II)s). In the presence of TBP-free TAF(II) complex (TFTC), initiation of Pol II transcription can occur in the absence of TFIID. TFTC containing the GCN5 acetyltransferase acetylates histone H3 in a nucleosomal context. We have identified a 130 kDa subunit of TFTC (SAP130) that shares homology with the large subunit of UV-damaged DNA-binding factor. TFTC preferentially binds UV-irradiated DNA, UV-damaged DNA inhibits TFTC-mediated Pol II transcription and TFTC is recruited in parallel with the nucleotide excision repair protein XP-A to UV-damaged DNA. TFTC preferentially acetylates histone H3 in nucleosomes assembled on UV-damaged DNA. In agreement with this, strong histone H3 acetylation occurs in intact cells after UV irradiation. These results suggest that the access of DNA repair machinery to lesions within chromatin may be facilitated by TFTC via covalent modification of chromatin. Thus, our experiments reveal a molecular link between DNA damage recognition and chromatin modification.

Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins.

Members of the heterochromatin protein 1 (HP1) family are silencing nonhistone proteins. Here, we show that in P19 embryonal carcinoma (EC) nuclei, HP1 alpha, beta, and gamma form homo- and heteromers associated with nucleosomal core histones. In vitro, all three HP1s bind to tailed and tailless nucleosomes and specifically interact with the histone-fold of histone H3. Furthermore, HP1alpha interacts with the linker histone H1. HP1alpha binds to H3 and H1 through its chromodomain (CD) and hinge region, respectively. Interestingly, the Polycomb (Pc1/M33) CD also interacts with H3, and HP1alpha and Pc1/M33 binding to H3 is severely impaired by CD mutations known to abrogate HP1 and Polycomb silencing in Drosophila. These results define a novel function for the conserved CD and suggest that HP1 self-association and histone binding may play a crucial role in HP1-mediated heterochromatin assembly.

Differential expression of retinoic acid-inducible (Stra) genes during mouse placentation.

Several retinoid binding proteins and nuclear receptors are specifically expressed in murine placenta. However, little is known about molecular events and target genes regulated by retinoids during placentation. Here, we report that several retinoic acid-inducible (Stra) genes, originally isolated by a differential screening procedure, exhibit specific expression patterns in mouse placental tissues. Three Stra genes, including the ephrinB1 receptor tyrosine kinase ligand, are prominently expressed in the regions of exchanges between maternal and embryonic circulations, i.e. the yolk sac and/or the labyrinthine zone of the mature placenta. The Meis2 homeobox gene appears to be specifically expressed in maternally-derived cell populations. Three other Stra genes, including the AP-2-related gene AP-2gamma, are differentially expressed in the trophoblastic cell lineage. Thus, retinoids may regulate various signaling pathways in specific placental cell-types.

Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family.

Mammalian TIF1alpha and TIF1beta (KAP-1/KRIP-1) are related transcriptional intermediary factors that possess intrinsic silencing activity. TIF1alpha is believed to be a euchromatic target for liganded nuclear receptors, while TIF1beta may serve as a co-repressor for the large family of KRAB domain-containing zinc finger proteins. Here, we report an association of TIF1beta with both heterochromatin and euchromatin in interphase nuclei. Co-immunoprecipitation of nuclear extracts shows that endogenous TIF1beta, but not TIF1alpha, is associated with members of the heterochromatin protein 1 (HP1) family. However, in vitro, both TIF1alpha and TIF1beta interact with and phosphorylate the HP1 proteins. This interaction involves a conserved amino acid motif, which is critical for the silencing activity of TIF1beta but not TIF1alpha. We further show that trichostatin A, an inhibitor of histone deacetylases, can interfere with both TIF1 and HP1 silencing. The silencing activity of TIF1alpha appears to result chiefly from histone deacetylation, whereas that of TIF1beta may be mediated via both HP1 binding and histone deacetylation.

Stra3/lefty, a retinoic acid-inducible novel member of the transforming growth factor-beta superfamily.

We report the structure, chromosomal localization and expression features of Stra3, a novel mouse gene whose expression is upregulated by retinoic acid in P19 embryonal carcinoma cells. The Stra3 cDNA sequence, which encodes a novel member of the TGF-beta superfamily, corresponds to, but extends more 3' than the recently published lefty sequence (Meno et al., 1996, Nature 381:151-155). The Stra3/lefty protein, which exhibits characteristics of secreted proteins, is synthesized as a precursor of 42 kDa and secreted after cleavage, suggesting that it may function as an intercellular signaling molecule. There are four exons in the Stra3/lefty gene and its 5' flanking region contains, among other putative regulatory elements, an unusual retinoid response element consisting of two half sites arranged as a palindrome, with an 8 base pairs spacer. We also show that Stra3/lefty is ectopically induced in the endodermal and ectodermal layers following in vivo administration of retinoic acid to gastrulating mouse embryos.

Meis2, a novel mouse Pbx-related homeobox gene induced by retinoic acid during differentiation of P19 embryonal carcinoma cells.

We report the cDNA cloning, partial genomic organization, and expression pattern of Stra10, a novel retinoic acid-inducible gene in P19 embryonal carcinoma cells. Four murine cDNA isoforms have been isolated, which are likely to result from alternative splicing. The predicted protein sequences exhibit approximately 85% identity with the Pbx-related Meis1 homeobox gene products, which are involved in myeloid leukemia in BXH-2 mice, and one of the Stra10 isoforms corresponds to the recently published Meis2 sequence (Nakamura et al. [1996] Oncogene 13:2235-2242). The Meis2 homeodomain is identical to that of Meis1, and is most closely related to those of the Pbx/TGIF homeobox gene products. By in situ hybridization analysis, we show that the Meis2 gene displays spatially restricted expression patterns in the developing nervous system, limbs, face, and in various viscera. In adult mice, Meis2 is mainly expressed in the brain and female genital tract, with a different distribution of the alternative splice forms in these organs.

Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene.

The full-length cDNA corresponding to Stra8, a novel gene inducible by retinoic acid (RA) in P19 embryonal carcinoma cells, has been isolated and shown to encode a 45-kD protein. Both Stra8 mRNA and protein were induced in cells treated by all-trans and 9-cis retinoic acids. Two-dimensional gel analysis and dephosphorylation experiments revealed that the two stereoisomers of RA differentially regulate the phosphorylation status of the Stra8 protein, which was shown to exist in differently phosphorylated forms. Subcellular fractionation and immunocytochemistry studies showed that the Stra8 protein is cytoplasmic. During mouse embryogenesis, Stra8 expression was restricted to the male developing gonads, and in adult mice, the expression of Stra8 was restricted to the premeiotic germ cells. Thus, Stra8 protein may play a role in the premeiotic phase of spermatogenesis.

A new mouse member of the Wnt gene family, mWnt-8, is expressed during early embryogenesis and is ectopically induced by retinoic acid.

We have identified a novel mouse Wnt genc using a cDNA differential screening procedure for retinoic-acid-induced transcripts in P19 embryonal carcinoma cells. Sequence analysis showed that this gene represents the first murine Wnt-8 (mWnt-8) gene reported to date. The expression of the mWnt-8 gene, which is rapidly induced by retinoic acid in P19 and embryonic stem cells, appears to be restricted to early stages of mouse embryogenesis. mWnt-8 transcripts are first detected in the posterior region of the epiblast of early primitive streak-stage embryos. As gastrulation proceeds, mWnt-8 expression spreads into the embryonic ectoderm up to a sharp rostral boundary at the base of the developing headfolds. mWnt-8 is also transiently expressed in the newly formed mesoderm. mWnt-8 expression is rapidly down-regulated during early somitogenesis, the latest detectable expression domains corresponding to the presumptive fourth rhombomere and the caudal region of the neural plate. The expression pattern of mWnt-8 is clearly distinct from those of other murine Wnt genes expressed during gastrulation, but shows striking similarities with that of the chicken Cwnt-8C gene. We also show that mWnt-8 expression is ectopically induced in the rostral neural plate in response to RA exposure of presumitic (7-7.5 days post coitum) cultured mouse embryos.