Exploring patient experiences of surveillance for pancreatic cystic neoplasms: a qualitative study.

BACKGROUND: Pancreatic cystic neoplasms (PCN) are considered premalignant conditions to pancreatic adenocarcinoma with varying degrees of cancerous potential. Management for individuals who do not require surgical treatment involves surveillance to assess for cancerous progression. Little is known about patients' experience and the impact of living with surveillance for these lesions. AIMS: To explore the experiences of patients living with surveillance for PCNs. METHODS: Semi-structured qualitative interviews were conducted with patients under surveillance for pancreatic cystic neoplasms in the UK. Age, gender, time from surveillance and surveillance method were used to purposively sample the patient group. Data were analysed using reflexive thematic analysis. RESULTS: A PCN diagnosis is incidental and unexpected and for some, the beginning of a disruptive experience. How patients make sense of their PCN diagnosis is influenced by their existing understanding of pancreatic cancer, explanations from clinicians and the presence of coexisting health concerns. A lack of understanding of the diagnosis and its meaning for their future led to an overarching theme of uncertainty for the PCN population. Surveillance for PCN could be seen as a reminder of fears of PCN and cancer, or as an opportunity for reassurance. CONCLUSIONS: Currently, individuals living with surveillance for PCNs experience uncertainty with a lack of support in making sense of a prognostically uncertain diagnosis with no immediate treatment. More research is needed to identify the needs of this population to make improvements to patient care and reduce negative experiences.

Unveiling myocardial microstructure shifts: exploring the impact of diabetes in stable CAD patients through CMR T1 mapping.

BACKGROUND: This study investigates myocardial structural changes in stable coronary artery disease (CAD) patients with type 2 diabetes (T2D) using cardiac magnetic resonance (CMR) strain and T1 mapping. METHODS: A total of 155 stable CAD patients underwent CMR examination, including left ventricular (LV) morphology and function assessment, late gadolinium enhancement (LGE), and feature tracking (CMR-FT) for LV global longitudinal, circumferential, and radial strain. T1 mapping with extracellular volume (ECV) evaluation was also performed. RESULTS: Among the enrolled patients, 67 had T2D. Diabetic patients exhibited impaired LV strain and higher ECV compared to non-diabetics. Multivariate analysis identified T2D as an independent predictor of increased ECV and decreased strain. CONCLUSIONS: CMR-based strain and T1 mapping highlighted impaired myocardial contractility, elevated ECV, and potential interstitial fibrosis in diabetic patients with stable CAD. This suggests a significant impact of diabetes on myocardial health beyond CAD, emphasizing the importance of a comprehensive assessment in these individuals. TRIAL REGISTRATION: http://www.controlled-trials.com/ISRCTN09454308.

Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis.

Background: Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. Methods: The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Results: Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Conclusions: Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. Trial registration: Registered number in PROSPERO: CRD42023405052.

A Multidisciplinary Curriculum to Standardize Chest Procedures Training for Trainees in General Surgery, Emergency Medicine, and Critical Care.

Introduction: Critical care, emergency medicine, and surgical trainees frequently perform surgical and Seldinger-technique tube thoracostomy, thoracentesis, and thoracic ultrasound. However, approaches to teaching these skills are highly heterogeneous. Over 10 years, we have developed a standardized, multidisciplinary curriculum to teach these procedures. Methods: Emergency medicine residents, surgical residents, and critical care fellows, all in the first year of their respective programs, underwent training in surgical and Seldinger chest tube placement and securement, thoracentesis, and thoracic ultrasound. The curriculum included preworkshop instructional videos and 45-minute in-person practice stations (3.5 hours total). Sessions were co-led by faculty from emergency medicine, thoracic surgery, and pulmonary/critical care who performed real-time formative assessment with standardized procedural steps. Postcourse surveys assessed learners' confidence before versus after the workshop in each procedure, learners' evaluations of faculty by station and specialty, and the workshop overall. Results: One hundred twenty-three trainees completed course evaluations, demonstrating stable and positive responses from learners of different backgrounds taught by a multidisciplinary group of instructors, as well as statistically significant improvement in learner confidence in each procedure. Over time, we have made incremental changes to our curriculum based on feedback from instructors and learners. Discussion: We have developed a unique curriculum designed, revised, and taught by a multidisciplinary faculty over many years to teach a unified approach to the performance of common chest procedures to surgical, emergency medicine, and critical care trainees. Our curriculum can be readily adapted to the needs of institutions that desire a standardized, multidisciplinary approach to thoracic procedural education.

Multi-tissue transcriptome-wide association study identifies novel candidate susceptibility genes for cataract.

Introduction: Cataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression. Methods: We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database. Results: Across tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data. Discussion: Our results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

Percutaneous triamcinolone injection for upper eyelid retraction in thyroid eye disease.

Purpose: To evaluate percutaneous triamcinolone (TA) injection efficacy in treating upper eyelid retraction (UER) for Australian thyroid eye disease (TED) patients. Methods: We conducted a retrospective analysis across 8 years and multiple diverse Australian centres identified UER patients who received TA injections. A single operator administered 40mg/1ml TA through upper eyelid skin. Assessments at 4-6 weeks and subsequent eyelid measurements gauged treatment response and complications. Results: 24 patients and 25 eyelids were included in the study. 91.6% were female, mean age 40.8 ± 10.3 years with mean follow-up of 17.5 months (± 18.5). Pre-treatment MRD1 was 6.2mm ± 1.4, and we observed a mean improvement of 2.2mm from pre-treatment to post-treatment (p<0.001). The mean UER measurement before treatment (defined as MRD1 - 4.0mm) was 3.0mm ± 1.3 (range, 0-6mm). After treatment, the mean UER measurement was -0.1mm. Quality of life (QOL) assessment improved significantly, from pre-treatment score of 4.13 ± 2.4 to post-treatment 8.0 ±1.7 (p<0.001). Conclusions: Percutaneous injection of TA is an effective and safe treatment option for UER in patients with TED. This technique can be performed without upper eyelid eversion, which makes it more tolerable for patients and less complex for the operator compared to the transconjunctival injection approach. Our results show a significant improvement in MRD1 and UER, as well as patient QOL. Moreover, we found a low rate of complications (4.2% induced ptosis) and no cases of raised intraocular pressure. Percutaneous TA injection can greatly reduce the need for eyelid lowering surgery in this patient population.

Case report: Nerve fiber regeneration in children with melanocortin 4 receptor gene mutation related obesity treated with semaglutide.

Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].

Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence.

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.

MEK-inhibitor treatment reduces the induction of regulatory T cells in mice after influenza A virus infection.

Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.

Phosphonium SF5- Salts Derived from Sulfur Hexafluoride as Deoxyfluorination Reagents.

Sulfur based deoxyfluorination reagents are usually derived from the corrosive gas SF4. Herein, we report the synthesis and properties of an easily accessible phosphonium salt [(tmg)3PF]+SF5- (1) which was obtained from the reaction of sulfur hexafluoride (SF6) with tris(tetramethylguanidinyl)phosphine. The performance of this crystalline SF5- salt as a reagent in deoxyfluorination reactions was investigated together with a second SF5- salt [(R1)3PF]+SF5- (2) containing bulky substituents (R1 = 1,3-di-tert-butylimidazolidin-2-ylidenamino). Both reagents proved to be effective for the deoxyfluorination of various functional groups including alcohols, anhydrides, and amides.

Are Pre-clerkship Remediation, Grading, and Reporting Practices Equitable in the U.S.? A National Survey.

Phenomenon: With the proliferation of pass/fail grading practices in the pre-clerkship phase of undergraduate medical education, questions arise about the transparency and variability of grading and grade reporting practices, raising issues of equity in assessment, particularly regarding residency matching. The purpose of this survey was to determine the remediation and academic performance reporting practices of United States (U.S.) allopathic medical schools in the pre-clerkship phase of their curricula. Approach: After an extensive literature search and feedback from curriculum deans and learning experts, we developed a survey that we sent in the Spring of 2022 to pre-clerkship curriculum officials at all 154 accredited U.S. allopathic medical schools. It addressed curriculum content and structure; pre-clerkship remediation (e.g., course retakes) and reporting (e.g., permanency of transcript notation) practices; documentation and reporting of nonacademic competencies; and participant opinions and recommendations regarding reporting, transparency, and equity. We generated descriptive statistics and did manifest coding of open-ended responses. Findings: We had a response rate of 40% (62/155), with over 71% indicating mainly organ systems-based curricula. Depending on the situation, there were a wide range of remediation approaches for single- and multiple-course failures, including tutoring or learning support, re-exams, and referrals to a promotion board. Professionalism concerns were a top priority to report to residency directors, with significant variability in respondent opinions and practices in reporting remedial activities. Respondents were concerned about equity, both in terms of flexible grading practices and transparency of reporting practices. Insights: The variability in reporting practices across schools, while allowing holistic and individualized approaches to academic support, also creates potential inequities. More work is needed to understand how different reporting practices across institutions may disadvantage marginalized and minoritized student groups at different points in their preparation.

Case-Based Specialty Training for Medical Students to Elicit Social Determinants of Health.

Introduction: Without explicit education and training on how social determinants of health (SDoH) impact patient care and health outcomes, medical schools are failing to effectively equip future physicians to serve their patients. We created this workshop on health equity with a focus on SDoH to help students more effectively communicate with diverse populations. Methods: Third-year medical students and faculty were provided with class guides, learning objectives, role-play vignettes containing clerkship-specific history and physical exams, schedules, and discussion questions during a 2-hour session centered on SDoH. The workshop's impact was measured through mixed-methods analysis of surveys. Results: Based on pre- and postsurvey results from 87 participants, medical students strongly agreed that (1) SDoH factor more into a patient's health outcomes than the clinical encounter (pre: 67%, post: 87%), (2) it is their duty to gather information about SDoH (pre: 86%, post: 97%), (3) neighborhood safety is one of the key SDoH (pre: 88%, post: 97%), (4) they understood the impact of upstream interventions (pre: 35%, post: 93%), (5) they could efficiently screen all patients for SDoH at every medical encounter (pre: 27%, post: 86%), and (6) they could find preliminary resources to quickly assist patients in need of help regarding particular SDoH (pre: 26%, post: 85%). Discussion: This was the first iteration of this workshop; challenges involved piloting the content, time restraints, and organizational structure of the workshop design. Future directions include making SDoH curricula an integral part of undergraduate medical education and diverse clinical environments.

Vascular Anastomoses and Dissection: A Six-Part Simulation Curriculum for Surgical Residents.

Introduction: As surgical technologies grow, so too do demands on surgical trainees to master increasing numbers of skill sets. With the rise of endovascular surgery, trainees have fewer opportunities to practice open vascular techniques in the operating room. Simulation can bridge this gap. However, existing published open vascular simulation curricula are basic or based on expensive models. Methods: We iteratively developed an open vascular skills curriculum for second-year surgery residents comprising six 2-hour sessions. We refined the curriculum based on feedback from learners and faculty. The curriculum required skilled facilitators, vascular instruments, and tissue models. We evaluated the latest iteration with a survey and by assessing participants' technical skills using the Objective Structured Assessment of Technical Skills (OSATS) form. Results: Over the past 10 years, 101 residents have participated in the curriculum. Nine of 13 residents who participated in the latest curricular iteration completed the survey. All respondents rated the sessions as excellent and strongly agreed that they had improved their abilities to perform anastomoses with tissue and prosthetic. Facilitators completed 18 OSATS forms for residents in the fifth and sixth sessions of the latest iteration. Residents scored well overall, with a median 26.5 (interquartile range: 24-29) out of a possible score of 35, with highest scores on knowledge of instruments. Discussion: This simulation-based curriculum facilitates open vascular surgical skill acquisition among surgery residents. The curriculum allows residents to acquire critical vascular skills that are challenging to learn in an increasingly demanding operative setting.

An At-Home Laparoscopic Curriculum for Junior Residents in Surgery, Obstetrics/Gynecology, and Urology.

Introduction: Laparoscopic surgery requires significant training, and prior studies have shown that surgical residents lack key laparoscopic skills. Many educators have implemented simulation curricula to improve laparoscopic training. Given limited time for dedicated, in-person simulation center practice, at-home training has emerged as a possible mechanism by which to expand training and promote practice. There remains a gap in published at-home laparoscopic curricula employing embedded feedback mechanisms. Methods: We developed a nine-task at-home laparoscopic curriculum and an end-of-curriculum assessment following Kern's six-step approach. We implemented the curriculum over 4 months with first- to third-year residents. Results: Of 47 invited residents from general surgery, obstetrics/gynecology, and urology, 37 (79%) participated in the at-home curriculum, and 25 (53%) participated in the end-of-curriculum assessment. Residents who participated in the at-home curriculum completed a median of six of nine tasks (interquartile range: 3-8). Twenty-two residents (47%) responded to a postcurriculum survey. Of these, 19 (86%) reported that their laparoscopic skills improved through completion of the curriculum, and the same 19 (86%) felt that the curriculum should be continued for future residents. Residents who completed more at-home curriculum tasks scored higher on the end-of-curriculum assessment (p = .009 with adjusted R 2 of .28) and performed assessment tasks in less time (p = .004 with adjusted R 2 of .28). Discussion: This learner-centered laparoscopic curriculum provides guiding examples, spaced practice, feedback, and graduated skill development to enable junior residents to improve their laparoscopic skills in a low-stakes, at-home environment.

miR-193b-3p/ PGC-1α pathway regulates an insulin dependent anti-inflammatory response in Parkinson's disease.

It has been shown that many miRNAs, including miR-193b-3p, are differentially expressed in Parkinson's disease (PD). Dysregulation of miR-193b-3p/PGC-1α axis may alter homeostasis in cells and can induce an inflammatory response commonly accompanied by metabolic disturbances. The aim of the present study is to investigate if dysregulation of the miR-193-3p/PGC-1α axis may contribute to the pathological changes observed in the PD brain. Brain tissue were obtained from middle frontal gyrus of non-demented controls and individuals with a PD diagnosis. RT-qPCR was used to determine the expression of miR-193b-3p and in situ hybridization (ISH) and immunological analysis were employed to establish the cellular distribution of miR-193b-3p. Functional assays were performed using SH-SY5Y cells, including transfection and knock-down of miR-193b-3p. We found significantly lower expression of miR-193b-3p in the early stages of PD (PD4) which increased throughout disease progression. Furthermore, altered expression of PGC-1α suggested a direct inhibitory effect of miR-193b-3p in the brain of individuals with PD. Moreover, we observed changes in expression of insulin after transfection of SH-SY5Y cells with miR-193b-3p, which led to dysregulation in the expression of several pro- or anti - inflammatory genes. Our findings indicate that the miR-193b-3p/PGC-1α axis is involved in the regulation of insulin signaling. This regulation is crucial, since insulin induced inflammatory response may serve as a protective mechanism during acute situations but potentially evolve into a pathological process in chronic conditions. This novel regulatory mechanism may represent an interesting therapeutic target with potential benefits for various neurodegenerative diseases.

Mapping the complexity and diversity of tertiary lymphoid structures in primary and peritoneal metastatic gastric cancer.

BACKGROUND: Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment. METHODS: Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45+ immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases. RESULTS: We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer. CONCLUSION: The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC.

Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer.

BACKGROUND: Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. METHODS: We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. RESULTS: Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). CONCLUSIONS: These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.

Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin-etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. EXPERIMENTAL DESIGN: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. RESULTS: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. CONCLUSIONS: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets.

BACKGROUND: Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved. METHODS: We performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials. RESULTS: Melanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended on B2M required for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A+ KIR- and partially to the NKG2A+ KIR+ NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A- KIR+, but not the NKG2A+ KIR+ NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins. CONCLUSION: Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.