Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland.

BACKGROUND In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype

Inheritance of gene density–related higher order chromatin arrangements in normal and tumor cell nuclei

A gene density–related difference in the radial arrangement of chromosome territories (CTs) was previously described for human lymphocyte nuclei with gene-poor CT #18 located toward the nuclear periphery and gene-dense CT #19 in the nuclear interior (Croft, J.A., J.M. Bridger, S. Boyle, P. Perry, P. Teague, and W.A. Bickmore. 1999. J. Cell Biol. 145:1119–1131). Here, we analyzed the radial distribution of chromosome 18 and 19 chromatin in six normal cell types and in eight tumor cell lines, some of them with imbalances and rearrangements of the two chromosomes. Our findings demonstrate that a significant difference in the radial distribution of #18 and #19 chromatin is a common feature of higher order chromatin architecture in both normal and malignant cell types. However, in seven of eight tumor cell lines, the difference was less pronounced compared with normal cell nuclei due to a higher fraction of nuclei showing an inverted CT position, i.e., a CT #18 located more internally than a CT #19. This observation emphasizes a partial loss of radial chromatin order in tumor cell nuclei

A Proposed Set of Metrics to Reduce Patient Safety Risk From Within the Anatomic Pathology Laboratory

Background: Anatomic pathology laboratory workflow consists of 3 major specimen handling processes. Among the workflow are preanalytic, analytic, and postanalytic phases that contain multistep subprocesses with great impact on patient care. A worldwide representation of experts came together to create a system of metrics, as a basis for laboratories worldwide, to help them evaluate and improve specimen handling to reduce patient safety risk. Method: Members of the Initiative for Anatomic Pathology Laboratory Patient Safety (IAPLPS) pooled their extensive expertise to generate a list of metrics highlighting processes with high and low risk for adverse patient outcomes. Results: Our group developed a universal, comprehensive list of 47 metrics for patient specimen handling in the anatomic pathology laboratory. Steps within the specimen workflow sequence are categorized as high or low risk. In general, steps associated with the potential for specimen misidentification correspond to the high-risk grouping and merit greater focus within quality management systems. Primarily workflow measures related to operational efficiency can be considered low risk. Conclusion: Our group intends to advance the widespread use of these metrics in anatomic pathology laboratories to reduce patient safety risk and improve patient care with development of best practices and interlaboratory error reporting programs

Relation of gallbladder function and Helicobacter pylori infection to gastric mucosa inflammation in patients with symptomatic cholecystolithiasis

Background. Inflammatory alterations of the gastric mucosa are commonly caused by Helicobacter pylori (Hp) infection in patients with symptomatic gallstone disease. However, the additional pathogenetic role of an impaired gallbladder function leading to an increased alkaline duodenogastric reflux is controversially discussed. Aim:To investigate the relation of gallbladder function and Hp infection to gastric mucosa inflammation in patients with symptomatic gallstones prior to cholecystectomy. Patients: Seventy-three patients with symptomatic gallstones were studied by endoscopy and Hp testing. Methods: Gastritis classification was performed according to the updated Sydney System and gallbladder function was determined by total lipid concentration of gallbladder bile collected during mainly laparoscopic cholecystectomy. Results: Fifteen patients revealed no, 39 patients mild, and 19 moderate to marked gastritis. No significant differences for bile salts, phospholipids, cholesterol, or total lipids in gallbladder bile were found between these three groups of patients. However, while only 1 out of 54 (< 2%) patients with mild or no gastritis was found histologically positive for Hp, this infection could be detected in 14 (74%) out of 19 patients with moderate to marked gastritis. Conclusion: Moderate to marked gastric mucosa inflammation in gallstone patients is mainly caused by Hp infection, whereas gallbladder function is not related to the degree of gastritis. Thus, an increased alkaline duodenogastric reflux in gallstone patients seems to be of limited pathophysiological relevance. Copyright (c) 2006 S. Karger AG, Basel

Human papillomavirus genotype distribution and socio-behavioural characteristics in women with cervical pre-cancer and cancer at the start of a human papillomavirus vaccination programme: the CIN3+ plus study.

The Swiss Federal Office of Public Health has recommended vaccination against human papillomavirus (HPV) to prevent cervical cancer since 2008. To establish monitoring of the future public health impact of vaccination, baseline population-based data are required. The objectives of this study were to examine the distribution of oncogenic HPV genotypes in biopsies with cervical intraepithelial neoplasia stage 3 or more severe lesions (CIN3+) at the beginning of HPV vaccination programmes and to compare sociodemographic and behavioural factors of women with CIN3+ with women in the Swiss general population. We conducted a retrospective and prospective cross-sectional study with women diagnosed with CIN3+ in Switzerland. Ten pathology institutes from six cantons and three language regions participated. We conducted HPV typing on formaldehyde fixed-paraffin embedded specimens from 2014 and 2015. Women enrolled in 2015 were asked to complete a questionnaire. We described frequencies of HPV types. We also compared demographic characteristics and socioeconomic status in the CIN3 + plus group with the Swiss National Cohort in 2014 and compared risk factors for HPV infection with the Swiss Health Survey in 2012. We included 768 biopsies from 767 women. Four hundred and seventy-five (61.8%) biopsies were positive for HPV 16 and/or 18, 687 (89.5%) were positive for oncogenic HPV genotypes 16, 18, 31, 33, 45, 52, and/or 58 and five (0.7%) were HPV negative. Twenty-eight (10.3%) of the 273 women who completed the patient questionnaire reported having received at least one dose of an HPV vaccine. When compared with Swiss women in the six study cantons, fewer women in the CIN3+ plus study group were of Swiss nationality, more were born abroad and more were single. The study group also had a higher proportion of women with ≥2 partners in the last year, current smokers and was younger at age of first sexual intercourse. Introduction of the nonavalent vaccine could cover approximately 90% of CIN3+ lesions in Swiss women compared with around 60% with the quadrivalent vaccine. Surveillance of HPV genotype distribution in CIN3+, together with information about vaccination and CIN3+ incidence will allow monitoring of the public health impact of vaccination programmes. ClinicalTrials.gov, NCT02323997 . Registered 24 December 2014

Diagnosing nodular regenerative hyperplasia of the liver is thwarted by low interobserver agreement

Background and Aims: Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (noncirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH. Methods: Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index. Results: After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45). Conclusions: The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone

Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors

How Reliable Is Ki-67 Immunohistochemistry in Grade 2 Breast Carcinomas? A QA Study of the Swiss Working Group of Breast- and Gynecopathologists

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. Methods Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. Results The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56–0.72). However, we found very high inter-observer variabilities (Kappa 0.04–0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01–0.04) and intra-observer agreement was likewise poor (Kappa 0.00–0.35). Conclusion Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas