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PurposeMen with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of atezolizumab (anti-PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC.Patients and methodsThis phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety-efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS).ResultsAs of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% [95% confidence interval (CI), 1.4-18.7], median rPFS was 3.0 months (95% CI, 2.8-4.6), median PSA progression was 3.0 months (95% CI, 2.8-3.3), and median OS was 16.3 months (95% CI, 10.9-22.3).ConclusionsThis phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.

IntroductionThe catecholaminergic component of the brain-pituitary-gonadal axis, which mediates the influence of external and internal stimuli on the central nervous system and gonad development in vertebrates, is largely unexplored in Chondrichthyes. We considered Scyliorhinus canicula (L., 1758) females as a model for this vertebrate's class, to assess the involvement of the catecholaminergic system of the brain in its reproduction. Along the S. canicula reproductive cycle, we characterized and evaluated differences in somata morphometry and the number of putative catecholaminergic neurons in two brain nuclei: the periventricular preoptic nucleus, hypothesized to be a positive control for ovarian development, and the suprachiasmatic nucleus, examined as a negative control.Materials and methods16 S. canicula wild females were sampled and grouped in maturity stages (immature, maturing, mature, and mature egg-laying). The ovary was histologically processed for the qualitative description of maturity stages. Anti-tyrosine hydroxylase immunofluorescence was performed on the diencephalic brain sections. The immunoreactive somata were investigated for morphometry and counted using the optical fractionator method, throughout the confocal microscopy.Results and discussionsQualitative and quantitative research confirmed two separate populations of immunoreactive neurons. The modifications detected in the preoptic nucleus revealed that somata were more numerous, significantly smaller in size, and more excitable during the maturing phase but decreased, becoming slightly bigger and less excitable in the egg-laying stage. This may indicate that the catecholaminergic preoptic nucleus is involved in the control of reproduction, regulating both the onset of puberty and the imminent spawning. In contrast, somata in the suprachiasmatic nucleus grew in size and underwent turnover in morphometry, increasing the total number from the immature-virgin to maturing stage, with similar values in the more advanced maturity stages. These changes were not linked to a reproductive role. These findings provide new valuable information on Chondrichthyes, suggesting the existence of an additional brain system implicated in the integration of internal and environmental cues for reproduction.

Fluorescent lighting and optical techniques have been widely utilized to enhance the detection of latent fingerprints. However, the development of new techniques is imperative to expand the range of surfaces from which latent fingerprints can be detected. When relying on traditional methods, fingerprint evidence can remain undetected or even disregarded due to insufficient detection and limited detail, especially when dealing with a luminescent background.In this study, we propose the utilization of optically stimulated luminescence (OSL) applied to a Ba2SiO4 matrix, co-doped with Eu2+ and Dy3+, as a powerful method for visualizing latent fingerprints on various surfaces, including thin plastic bags, rigid duct tape, thin aluminum foil, and glass slices. This technique effectively eliminates any luminescent background and significantly enhances optical imaging.This represents the first successful application of OSL in the development of latent fingerprints, thus paving the way for more efficient and effective forensic techniques in the future.

Cutaneous adverse events of both topical and systemic drugs in patients with mycosis fungoides (MF) present a diagnostic challenge as it is often difficult to distinguish drug associated rash from disease progression in the skin. Mogamulizumab and mechlorethamine gel are approved treatments for MF, both of which can cause treatment related cutaneous adverse events. It can often be challenging to distinguish mogamulizumab associated rash (MAR) and mechlorethamine gel associated hypersensitivity dermatitis from MF progression both clinically and histologically. High-throughput sequencing (HTS) of the T-cell receptor (TCR), also known as immunosequencing, can be used to assess T-cell clonality to support a diagnosis of MF. After identification of the malignant TCR clone at baseline, immunosequencing can track the established malignant TCR sequence and its frequency over time with high sensitivity. As a result, immunosequencing clone tracking can aid in distinguishing disease progression from treatment side effects. Here, we present a case series to demonstrate how monitoring of the malignant T-cell frequency by immunosequencing can aid in diagnosis of mogamulizumab and mechlorethamine gel cutaneous adverse events.

Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner’s syndrome is characterized by highly variable genetic anomalies that consist in a partial or complete deletion of the X sexual chromosome; it can be present as a monosomy or as a mosaicism with two o three different cellular lines. 50% of the patients with Turner’s syndrome has a 45 XO karyotype while the remaining cases have karyotypes with mosaicism or X isochromosome or with partial or whole Y chromosome. This pathology is characterized by multiple anomalies that involve physical and cognitive development and in particular endocrine, cardiovascular, reproductive, auditive and visual systems. Integrity of the X chromosome in essential for fertility. In TS is accelerated germ cells apoptosis. About 30% of TS girls have some pubertal development, 10-20% undergo menarche and 2-8% go through spontaneous pregnancy. Women with TS should be informed about the risk of premature menopause and should be referred, if possible, to a specialist evaluation with a doctor expert in assisted reproductive techniques. In adolescents and in adults, Premature Ovarian Insufficiency (POI) can be evaluated clinically and biochemically with the classic combination of amenorrhea and elevated FSH concentrations (hypergonadotropic hypogonadism). However, in postpubertal adolescents and adult women, reproductive hormones may remain within the normal range before POI is clinically evident, despite significant depletion of the ovarian reserve. Today, reproductive medicine offers the opportunity of fertility preservation in women with premature ovarian insufficiency (POI). Two techniques have been suggested such as ovarian cortex cryopreservation and oocytes cryopreservation.

Objectives To explore the effects of anti-ribosomal P protein (anti-P) and anti-N-methyl-D-aspartic acid receptor subunit 2 (anti-NR2) autoantibodies on depression and cognitive dysfunction and their relationships with functional brain connectivity in SLE.Methods This cross-sectional study included adult patients who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 SLE criteria. Anti-P and anti-NR2 were quantified using ELISA. A 1-hour battery of neuropsychological testing interpreted by a neuropsychologist explored depressive symptoms (Center for Epidemiologic Studies Depression Scale, CES-D), cognitive domains and quality of life (SF-12). Resting-state functional connectivity (rs-fc) MRI analysis was performed within 1 month, and region-of-interest to region-of-interest (ROI-to-ROI) analyses with the graph theory were performed.Results Thirty-three patients with SLE (9% male) were enrolled, mean age (SD) of 43.5 (14) years and median disease duration of 10.4 years (2.9–25.4). Anti-P was positive in 6 (18.2%) and anti-NR2 in 14 (42.4%) patients. Depressive symptoms were found in 14 (42.4%) patients using the CES-D (range 0–51). After correction for age, disease duration, disease activity and white matter lesion load, the CES-D score was independently associated with anti-P serum level (β=0.32; p=0.049) and prednisone daily dose (β=0.38; p=0.023). Nineteen patients (57.6%) showed at least a cognitive test alteration, but no significant association with autoantibodies was found. The rs-fc MRI analysis revealed an independent association between the anti-P serum levels and many altered brain ROI properties but no anti-NR2 and prednisone effects on the cerebral network.Conclusions Anti-P was associated with brain network perturbation, which may be responsible for depressive symptoms in patients with SLE.

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy. Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used. Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P

Comparing deaths averted by vaccination campaigns is a crucial public health endeavour. Excess all-cause deaths better reflect the impact of the pandemic than COVID-19 deaths. We used a seasonal autoregressive integrated moving average with exogenous factors model to regress daily all-cause deaths on annual trend, seasonality, and environmental temperature in three Italian regions (Lombardy, Marche and Sicily) from 2015 to 2019. The model was used to forecast excess deaths during the vaccinal period (December 2020–October 2022). We used the prevented fraction to estimate excess deaths observed during the vaccinal campaigns, those which would have occurred without vaccination, and those averted by the campaigns. At the end of the vaccinal period, the Lombardy region proceeded with a more intensive COVID-19 vaccination campaign than other regions (on average, 1.82 doses per resident, versus 1.67 and 1.56 in Marche and Sicily, respectively). A higher prevented fraction of all-cause deaths was consistently found in Lombardy (65% avoided deaths, as opposed to 60% and 58% in Marche and Sicily). Nevertheless, because of a lower excess mortality rate found in Lombardy compared to Marche and Sicily (12, 24 and 23 per 10,000 person-years, respectively), a lower rate of averted deaths was observed (22 avoided deaths per 10,000 person-years, versus 36 and 32 in Marche and Sicily). In Lombardy, early and full implementation of adult COVID-19 vaccination was associated with the largest reduction in all-cause deaths compared to Marche and Sicily.

Numerous studies have shown the multiple benefits of plant biodiversity and the crucial role of residents’ awareness of conservation and land management. Plant biodiversity was investigated in an analytical monitoring report conducted jointly with the local population engaged in livestock activities and young residents who were shifting toward hospitality and tourism. The study area, covering over 800 km2 in Sardinia, is half forested and attracts interest in its landscape. During our research, genotypes of Quercus ilex L., with sweet acorns rich in polyphenols, as the oldest ecosystem services in these rural communities, were discovered. Collaborative monitoring focused attention on the benefits of plants in different habitats as follows: 53% were known to livestock farmers as food for local breeds of goats and pigs, 15% were official, and 13% were endemic. They had also been used for human nutrition within the Mediterranean diet and attracted interest for their use in landscapes and gardens. This study analyzes numerical data from critical and educational perspectives. These data serve as indicators of ecosystem health for the purpose of sustainable management policies and attest to collaborative monitoring as a tool for analyzing human activities and the necessary balance between profit and biodiversity conservation, given the current challenging climate change conditions.

A series of typhoons and tropical storms have produced extreme precipitation events in Vietnam during the first part of the 2020 monsoon season: events of this magnitude pose significant challenges to remote sensing Quantitative Precipitation Estimation (QPE) techniques. The weather-monitoring needs of modern human activities require that these challenges be overcome. In order to address this issue, in this work, seven precipitation products were validated with high spatial and temporal detail against over 1200 rain gauges in Vietnam during six case studies tailored around the most intense events of 2020. The data sources included the Vietnamese weather radar network, IMERG Early run and Final run, the South Korean GEO-KOMPSAT-2A and Chinese FengYun-4A geostationary satellites, DPR on board the GPM-Core Observatory, and European ERA5-Land reanalysis. All products were resampled to a standardized 0.02° grid and compared at hourly scale with ground stations measurements. The results indicated that the radars product was the most capable of reproducing the information collected by the rain gauges during the selected extreme events, with a correlation coefficient of 0.70 and a coefficient of variation of 1.38. However, it exhibited some underestimation, approximately 30%, in both occurrence and intensity. Conversely, geostationary products tended to overestimate moderate rain rates (FY-4A) and areas with low precipitation (GK-2A). More complex products such as ERA5-Land and IMERG failed to capture the highest intensities typical of extreme events, while GPM-DPR showed promising results in detecting the highest rain rates, but its capability to observe isolated events was limited by its intermittent coverage.

Introduction:. Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to systemic disease. Cutaneous mastocytosis is managed symptomatically, but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT, the pathogenic driver of mastocytosis. However, there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic management. We herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous mastocytosis. Case presentation:. We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous mastocytosis. The analysis revealed a aspartic acid to valine substitution at codon 816 (D816V) mutation in the protein c-KIT. Based on these results, we initiated treatment with the multi-kinase/KIT inhibitor midostaurin, a treatment effective against the D816V c-KIT mutation. After 3 months of treatment, the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related symptoms. Discussion:. The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or systemic. However, there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic management. In the present report describing a patient with recalcitrant cutaneous mastocytosis, we describe a strategy in which skin mutational analysis is used to guide the selection of targeted therapy. Conclusion:. Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.

Background: Diffuse large B-cell lymphoma (DLBCL) is one of several lymphoid malignancies in which Epstein-Barr virus (EBV) can play a significant role in pathogenesis. An estimated 5–14% of DLBCL cases are linked to EBV, which is associated with poor prognosis and 5-year survival rates as low as 25%. EBV is an attractive and druggable, but largely untapped, non-host tumor target, partly due to its latency. Most EBV genes, including those of the lytic cycle, are epigenetically silenced, preventing effective viral targeting. However, reactivation of viral gene expression with a histone deacetylase inhibitor (HDACi), combined with a DNA synthesis inhibitor, such as ganciclovir and its oral prodrug valganciclovir (VGCV), is an effective strategy to induce EBV+ tumor cell apoptosis. The safety and efficacy of this novel therapeutic strategy was investigated here using the HDACi nanatinostat (Nstat) and VGCV in patients (pts) with EBV-positive (EBV+) DLBCL. Methods: This Phase 1b/2 study (NCT03397706) assessed Nstat+VGCV in pts aged ≥18 years with EBV+ relapsed/refractory lymphoid malignancies. For inclusion, pts must have had ≥1 prior systemic therapies and no viable curative treatment options. Phase 1b evaluated safety and defined the recommended Phase 2 dose of Nstat+VGCV. Safety was assessed from first drug administration until 28 days post-last dose or until the start of a new anticancer therapy. Phase 2 assessed efficacy (overall response rate [ORR]). Here, subgroup analysis data of pts with DLBCL are reported. Results: Ten pts with DLBCL were included in the Safety Analysis Set. The median age was 76 years, 70% of pts were male and 80% had stage 3–4 disease. At the data cut-off (May 4, 2023), all pts had reported ≥1 treatment-emergent adverse event (TEAE). The most common any-grade TEAEs were fatigue (n = 8, 80%), neutropenia (n = 6, 60%), anemia, and decreased platelet count/thrombocytopenia (both n = 5, 50%). The most common grade ≥3 TEAEs were neutropenia (n = 5, 50%), anemia (n = 3, 30%), and decreased white blood cell/lymphocyte count (n = 2, 20%). The most common any-grade TEAEs related to the study drugs were fatigue, neutropenia (both n = 6, 60%), anemia, and decreased platelet count/thrombocytopenia (both n = 4, 40%). Five pts (50%) reported ≥1 serious TEAE. Four pts (40%) experienced study drug-related serious adverse reactions, namely atrial fibrillation (n = 2, 20%), febrile neutropenia, and myelodysplastic syndrome (both n = 1, 10%). No deaths due to events related to the study drugs were reported. Nine pts were evaluable for efficacy (1 excluded due to an unrelated serious adverse event). Three pts (33.3%) had a complete response (CR) and 3 (33.3%) had a partial response (PR); 1 pt (11%) had stable disease (SD). The ORR was 66.7%, with a 77.8% disease control rate (CR+PR+SD). At data cut-off, the duration of response (DoR) was not evaluable, as 3 pts remained on study treatment with DoR values of 11.2 (CR), 42.5 (PR) and 49.7 (CR) months. Conclusions: Encouraging safety and efficacy findings were observed with Nstat+VGCV in DLBCL, with durable disease control in responders. Hematologic toxicities were consistent with the VGCV safety profile. An ongoing confirmatory Phase 2 study (NCT05011058) will provide further data on this novel treatment combination for EBV+ lymphomas. Editorial support for this abstract was funded by Viracta.

Background: Around 40% of peripheral T-cell lymphomas (PTCL) are linked to Epstein-Barr virus (EBV), which is associated with poor prognosis and 5-year overall survival rates as low as 20%. EBV is latent in tumors: most viral genes, bar those driving host cell growth and apoptosis blockade, are silenced. However, novel therapeutics aim to target EBV-positive (EBV+) tumors by reinstating viral gene expression to activate the nucleoside analogue ganciclovir (GCV) that inhibits viral and tumor DNA synthesis and prompts cell death. The safety and efficacy of this strategy was evaluated here with the histone deacetylase inhibitor nanatinostat (Nstat) and the oral pro-drug of GCV, valganciclovir (VGCV), in patients (pts) with EBV+ PTCL. Methods: This Phase 1b/2 study (NCT03397706) assessed Nstat+VGCV in pts aged ≥18 years with EBV+ relapsed/refractory lymphoid malignancies who had ≥1 prior systemic therapy and no viable curative treatment options. EBV status was determined by the site or central laboratory on a specimen representative of the current disease. Phase 1b evaluated safety (from first drug administration until 28 days post-last dose or until the start of a new anticancer therapy) and established the recommended Phase 2 dose. Phase 2 assessed efficacy (overall response rate [ORR]). Here, subgroup analysis data from pts with PTCL (angioimmunoblastic T-cell lymphoma [AITL] and PTCL not otherwise specified [PTCL-NOS]), are reported. Results: Thirteen patients with nodal PTCL (8 AITL, 5 PTCL-NOS) were enrolled. The median age was 68.4 years, 69% were male, and 92% had stage 3–4 disease. At data cut-off (May 4, 2023), all pts had ≥1 treatment-emergent adverse event (TEAE). The most common (reported in ≥10% of pts) any-grade TEAEs were decreased white blood cell (WBC)/lymphocyte count (n = 6, 46%), fatigue and diarrhea (both n = 5, 38%) (Table 1). Grade ≥3 TEAEs included decreased WBC/lymphocyte count (n = 4, 31%) and decreased neutrophil count (n = 3, 23%). The most common any-grade, study drug-related TEAEs were nausea and increased blood creatine (both n = 4, 31%); anemia, fatigue, diarrhea, decreased neutrophil count, decreased appetite and decreased WBC/lymphocyte count were the next most common (all n = 3, 23%). Of the most common study drug-related TEAEs, most (76%) were grade 1/2. Three pts had ≥1 serious TEAE, including infection, gastrointestinal disorders and new neoplasm. No serious adverse reactions or deaths due to events related to the study drugs were reported. Eight pts were evaluable for efficacy (5 pts non-evaluable due to TEAEs [ n = 3], investigator decision [ n = 1] and EBV− status [ n = 1]). Three pts (37.5%) had complete responses (CR), 1 (12.5%) had a partial response (PR), 1 had stable disease (SD) and 3 had progressive disease. The ORR was 50%, with a 62.5% disease control rate (DCR [CR+PR+SD]). The median duration of response (DoR) was 17.3 months (mos). ORR and DCR were similar in AITL and PTCL-NOS, but DoR was longer in pts with AITL (n = 2, 38.3 mos) compared with PTCL-NOS (n = 2, 6.1 mos). Conclusions: Encouraging safety and efficacy findings were observed with Nstat+VGCV in PTCL. Hematologic toxicities were consistent with the VGCV safety profile. An ongoing Phase 2 study (NCT05011058) will provide further data on this novel therapy for EBV+ lymphomas. Editorial support for this abstract was funded by Viracta.

Nearly a billion people worldwide are infected with the hepatitis B Virus (HBV) and about a third of them have chronic infection. HBV is an important cause of morbidity and mortality, including acute and chronic hepatitis and hepatocellular carcinoma (HCC). Screening and control of primary HBV infection through vaccination represent a major advance in global public health, but large sections of the world population, in both developed and underdeveloped countries, remain unscreened and unvaccinated. In addition to being a global cause of liver disease, an important role of HBV in lymphoma has also emerged. First, the high risk of HBV reactivation in previously infected patients receiving chemo-immunotherapy necessitates the systematic evaluation of HBV serological status in all non-Hodgkin’s lymphoma (NHL) cases and preemptive antiviral therapy for those who may have chronic or occult HBV infection. Second, HBV has been shown to infect lymphocytes, namely B-cells, and has been associated with a higher risk of developing B-cell lymphoma, most clearly in countries where HBV is endemic. While the risk of HBV reactivation with chemoimmunotherapy in NHL is well known, the role and the impact of HBV as a global lymphoma risk factor and potential oncogenic driver in B-cells are very poorly understood. Here, we review the clinical and scientific evidence supporting an association between HBV and B-cell lymphoma, with a particular focus on diffuse large B-cell lymphoma (DLBCL) and provide an overview of the estimated impact of HBV infection on the biology and clinical course of DLBCL. We also discuss ways to gain a better insight into the unmet need posed by HBV in lymphoma and whether assessing immune responses to HBV, measuring viral loads, and detecting the presence of HBV-encoded proteins in tumor tissue could be integrated into the molecular and clinical risk stratification of patients with DLBCL.

IntroductionEarly social isolation (ESI) disrupts neurodevelopmental processes, potentially leading to long-lasting emotional and cognitive changes in adulthood. Communal nesting (CN), i.e., the sharing of parental responsibilities between multiple individuals in a nest, creates a socially enriching environment known to impact social and anxiety-related behaviors.MethodsThis study examines the effects of (i) the CN condition and of (ii) ESI during the 3rd week of life (i.e., pre-weaning ESI) on motor, cognitive, and emotional domains during adolescence and adulthood in male and female rats reared in the two different housing conditions, as well as (iii) the potential of CN to mitigate the impact of ESI on offspring.ResultsWe found that in a spontaneous locomotor activity test, females exhibited higher activity levels compared to males. In female groups, adolescents reared in standard housing (SH) condition spent less time in the center of the arena, suggestive of increased anxiety levels, while the CN condition increased the time spent in the center during adolescence, but not adulthood, independently from ESI. The prepulse inhibition (PPI) test showed a reduced PPI in ESI adolescent animals of both sexes and in adult males (but not in adult females), with CN restoring PPI in males, but not in adolescent females. Further, in the marble burying test SH-ESI adolescent males exhibited higher marble burying behavior than all other groups, suggestive of obsessive-compulsive traits. CN completely reversed this stress-induced effect. Interestingly, ESI and CN did not have a significant impact on burying behavior in adult animals of both sexes.DiscussionOverall, our findings (i) assess the effects of ESI on locomotion, sensorimotor gating, and compulsive-like behaviors, (ii) reveal distinct vulnerabilities of males and females within these domains, and (iii) show how early-life social enrichment may successfully counteract some of the behavioral alterations induced by early-life social stress in a sex-dependent manner. This study strengthens the notion that social experiences during early-life can shape emotional and cognitive outcomes in adulthood, and points to the importance of social enrichment interventions for mitigating the negative effects of early social stress on neurodevelopment.

Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.

Purpose: To identify novel susceptibility loci for retinal vascular tortuosity, to better understand the molecular mechanisms modulating this trait, and reveal causal relationships with diseases and their risk factors. Design: Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR). Participants: We analyzed 116 639 fundus images of suitable quality from 63 662 participants from 3 cohorts, namely the UK Biobank (n = 62 751), the Swiss Kidney Project on Genes in Hypertension (n = 397), and OphtalmoLaus (n = 512). Methods: Using a fully automated retina image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, we computed the median arterial, venous and combined vessel tortuosity measured by the distance factor (the length of a vessel segment over its chord length), as well as by 6 alternative measures that integrate over vessel curvature. We then performed the largest GWAS of these traits to date and assessed gene set enrichment using the novel high-precision statistical method PascalX. Main Outcome Measure: We evaluated the genetic association of retinal tortuosity, measured by the distance factor. Results: Higher retinal tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, metacohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 116 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that retinal tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, MR revealed causal effects between tortuosity, body mass index, and low-density lipoprotein. Conclusions: Several alleles associated with retinal vessel tortuosity suggest a common genetic architecture of this trait with ocular diseases (glaucoma, myopia), cardiovascular diseases, and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.