Spatial Positioning of Immune Hotspots Reflects the Interplay between B and T Cells in Lung Squamous Cell Carcinoma

Beyond tertiary lymphoid structures, a significant number of immune-rich areas without germinal center-like structures are observed in non–small cell lung cancer. Here, we integrated transcriptomic data and digital pathology images to study the prognostic implications, spatial locations, and constitution of immune rich areas (immune hotspots) in a cohort of 935 patients with lung cancer from The Cancer Genome Atlas. A high intratumoral immune hotspot score, which measures the proportion of immune hotspots interfacing with tumor islands, was correlated with poor overall survival in lung squamous cell carcinoma but not in lung adenocarcinoma. Lung squamous cell carcinomas with high intratumoral immune hotspot scores were characterized by consistent upregulation of B-cell signatures. Spatial statistical analyses conducted on serial multiplex IHC slides further revealed that only 4.87% of peritumoral immune hotspots and 0.26% of intratumoral immune hotspots were tertiary lymphoid structures. Significantly lower densities of CD20+CXCR5+ and CD79b+ B cells and less diverse immune cell interactions were found in intratumoral immune hotspots compared with peritumoral immune hotspots. Furthermore, there was a negative correlation between the percentages of CD8+ T cells and T regulatory cells in intratumoral but not in peritumoral immune hotspots, with tertiary lymphoid structures excluded. These findings suggest that the intratumoral immune hotspots reflect an immunosuppressive niche compared with peritumoral immune hotspots, independent of the distribution of tertiary lymphoid structures. A balance toward increased intratumoral immune hotspots is indicative of a compromised antitumor immune response and poor outcome in lung squamous cell carcinoma

Adverse clinical sequelae after skin branding: a case series

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Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Neonatal tetanus in Turkey; what has changed in the last decade?

dikici, bunyamin/0000-0001-7572-6525WOS: 000259222800001PubMed: 18713452Background: Neonatal tetanus (NT) is still considered as one of the major causes of neonatal death in many developing countries. The aim of the present study was to assess the characteristics of sixty-seven infants with the diagnosis of neonatal tetanus followed-up in the Pediatric Infectious Diseases Ward of Dicle University Hospital, Diyarbakir, between 1991 and 2006, and to draw attention to factors that may contribute (or may have contributed) to the elimination of the disease in Diyarbakir. Methods: The data of sixty-seven infants whose epidemiological and clinical findings were compatible with neonatal tetanus were reviewed. Patients were stratified into two groups according to whether they survived or not to assess the effect of certain factors in the prognosis. Factors having a contribution to the higher rate of tetanus among newborn infants were discussed. Results: A total of 55 cases of NT had been hospitalized between 1991 and 1996 whereas only 12 patients admitted in the last decade. All of the infants had been delivered at home by untrained traditional birth attendants (TBA), and none of the mothers had been immunized with tetanus toxoid during her pregnancy. Twenty-eight (41.8%) of the infants died during their follow-up. Lower birth weight, younger age at onset of symptoms and at the time admission, the presence of opisthotonus, risus sardonicus and were associated with a higher mortality rate. Conclusion: Although the number of neonatal tetanus cases admitted to our clinic in recent years is lower than in the last decade efforts including appropriate health education of the masses, ensurement of access to antenatal sevices and increasing the rate of tetanus immunization among mothers still should be made in our region to achieve the goal of neonatal tetanus elimination

Diagnostic delay for giant cell arteritis – a systematic review and meta-analysis

Background Giant cell arteritis (GCA), if untreated, can lead to blindness and stroke. The study’s objectives were to (1) determine a new evidence-based benchmark of the extent of diagnostic delay for GCA and (2) examine the role of GCA-specific characteristics on diagnostic delay. Methods Medical literature databases were searched from inception to November 2015. Articles were included if reporting a time-period of diagnostic delay between onset of GCA symptoms and diagnosis. Two reviewers assessed the quality of the final articles and extracted data from these. Random-effects meta-analysis was used to pool the mean time-period (95% confidence interval (CI)) between GCA symptom onset and diagnosis, and the delay observed for GCA-specific characteristics. Heterogeneity was assessed by I 2 and by 95% prediction interval (PI). Results Of 4128 articles initially identified, 16 provided data for meta-analysis. Mean diagnostic delay was 9.0 weeks (95% CI, 6.5 to 11.4) between symptom onset and GCA diagnosis (I 2 = 96.0%; P < 0.001; 95% PI, 0 to 19.2 weeks). Patients with a cranial presentation of GCA received a diagnosis after 7.7 (95% CI, 2.7 to 12.8) weeks (I 2 = 98.4%; P < 0.001; 95% PI, 0 to 27.6 weeks) and those with non-cranial GCA after 17.6 (95% CI, 9.7 to 25.5) weeks (I 2 = 96.6%; P < 0.001; 95% PI, 0 to 46.1 weeks). Conclusions The mean delay from symptom onset to GCA diagnosis was 9 weeks, or longer when cranial symptoms were absent. Our research provides an evidence-based benchmark for diagnostic delay of GCA and supports the need for improved public awareness and fast-track diagnostic pathways

The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX-2 through an IKKγ/NF-κB-dependent pathway

The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells