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Introduction: RET rearrangements occur in 1% to 2% NSCLCs. Since no clinically validated RET antibody is currently available, fluorescence in situ hybridization (FISH) is often used as a screening tool to identify patients likely to benefit from RET-targeted therapy. In this study, we performed a comprehensive review of publications in which RET -rearrangement testing was performed by FISH and compared the methods and results with our data., Methods: The findings of an electronic search for publications using RET -FISH in lung cancer were compared with the results obtained at the Grenoble University Hospital where 784 EGFR - , KRAS - , ALK -, and ROS1 -negative NSCLCs were tested by RET break-apart FISH and confirmed by RNA-sequencing (RNA-seq)., Results: Out of the 85 publications using RET -FISH analysis, 52 pertained to patients with lung cancer. The most often used positivity threshold was 15%. Six publications compared RET -FISH with at least one other molecular technique on at least eight samples, and the concordance was variable, from 5.9% to 66.7% for FISH-positive cases. Regarding our data, out of the 784 analyzed samples, 32 (4%) were positive by RET -FISH. The concordance between RET -FISH and RNA-seq in RET -FISH positive samples was 69%., Conclusions: Overall, both existing literature and our data suggest that RET -FISH testing can be used for rapid screening of RET rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm RET -FISH-positive cases is essential for ensuring that only patients likely to benefit from RET -target therapy receive the treatment., Competing Interests: Dr. Mc Leer has declared consulting fees from 10.13039/100015756Janssen-Cilag, Eli Lilly, Takeda, JFR Access, Pfizer, payment for presentations from Amgen, AstraZeneca, Cancerodigest, Edimark, Janssen-Cilag and support for attending meetings from Amgen, AstraZeneca, Janssen-Cilag, Pfizer. Dr. Toffart has declared consulting fees from 10.13039/100004325AstraZeneca, 10.13039/100002491Bristol-Myers Squibb, 10.13039/100002429Amgen, 10.13039/501100014382Ipsen, Janssen, 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004319Pfizer, 10.13039/100004337Roche, Sanofi, Takeda, payment for presentations from AstraZeneca, Bristol-Myers Squibb, Amgen, Ipsen, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Takeda, payment for expert testimony from AstraZeneca, Bristol-Myers Squibb, Amgen, Ipsen, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Takeda and support for attending meetings from AstraZeneca, Pfizer, Roche, Takeda. Dr. Benito is a full-time employee at Eli Lilly Co. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Introduction: Stage III NSCLC comprises a heterogeneous population. Different treatment strategies are available, including surgery, radiotherapy, and chemotherapy. The PACIFIC trial results represented a significant change and improvement in the therapeutic strategy for these patients. We aimed to compare the different treatment strategies employed in Stage III NSCLC patients within our institution., Methods: All Stage III NSCLC patients discussed during the weekly thoracic oncology multidisciplinary team meetings at the University hospital Grenoble Alpes (France) between January 2010 and January 2017 were included. Patients' overall survival (OS) according to treatment strategies along with their respective changes were compared., Results: Overall, 476 patients were identified. Among patients initially scheduled to receive neoadjuvant chemotherapy followed by surgery (n = 60), only 37 (62%) actually underwent surgery. Median OS of the cohort was 21.3 months [IQR 25%-75%: 9.6-48.3]. Patients who received neoadjuvant chemotherapy followed by surgery displayed better survival than those treated by CT-RT: 53.2 months [IQR 25%-75%: 16.1-87.3] versus 23.9 [IQR 25%-75%, 13.3-48.1]. Survival was slightly superior for patients treated by upfront CT-RT than for those planned for neoadjuvant chemotherapy followed by surgery who eventually converted to CT-RT (concurrent or sequential): 23.9 months [IQR 25%-75%: 13.3-48.1] versus 20.4 [IQR 25%-75%:10.8-36], respectively., Conclusion: While patients who underwent neoadjuvant chemotherapy followed by surgery displayed a better survival than those treated using CT-RT, switch from surgery to CT-RT actually shortened survival. These results stress the relevance of the tumor board in deciding which is the best therapeutic strategy for Stage III disease patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In many centers, a protocol kidney biopsy (PKB) is performed at 3 months post-transplantation (M3), without a demonstrated benefit on death-censored graft survival (DCGS). In this study, we compared DCGS between kidney transplant recipients undergoing a PKB or without such biopsy while accounting for the obvious indication bias., Methods: In this retrospective, single-center study conducted between 2007 and 2013, we compared DCGS with respect to the availability and features of a PKB. We built a propensity score (PS) to account for PKB indication likelihood and adjusted the DCGS analysis on PKB availability and the PS., Results: A total of 615 patients were included: 333 had a PKB, 282 did not. In bivariate Kaplan-Meier survival analysis, adjusting for the availability of a PKB and for the PS, a PKB was associated with a better 5-year DCGS independently of the PS ( p < 0.001). Among the PKB+ patients, 87 recipients (26%) had IF/TA > 0. Patients with an IF/TA score of 3 had the worst survival. A total of 144 patients (44%) showed cv lesions. Patients with cv2 and cv3 lesions had the worst 5-year DCGS., Conclusions: A M3 PKB was associated with improved graft survival independently of potential confounders. These results could be explained by the early treatment of subclinical immunological events. It could be due to better management of the immunosuppressive regimen.

Antibody-mediated rejection (ABMR) at early or late post-transplantation remains challenging. We performed a single-center single-arm study where four cases of acute ABMR and nine cases of chronic active ABMR (defined by Banff classification) were treated with double-filtration plasmapheresis (two cycles of three consecutive daily sessions with a 4-day gap between). At the end of the third and sixth DFPP sessions, the patients received rituximab 375 mg/m 2 . After a median follow-up of 1078 (61-1676) days, kidney-allograft survival was 50%. Before DFPP/rituximab therapy, the median donor-specific alloantibody (DSA) mean fluorescence intensity (MFI) was 9160 (4000-15 400); 45 days (D45) later it had significantly decreased to 7375 (215-18 100) (P = .018). In addition, at one-year (Y1) post-therapy, MFI had decreased further, that is, 4060 (400-7850) (P = .001). In two patients, DSA MFIs decreased and remained below 2000. The slope of estimated glomerular-filtration rate within the 6 months preceding intervention was -1.18 mL/min/month and remained unchanged at -1.29 mL/min/month within the year after intervention. Proteinuria remained unchanged. Baseline Banff scores on repeat allograft biopsies (post-therapy D45, Y1) did not show any improvement. Side-effects were mild to moderate. We conclude that the combined DFPP/rituximab significantly decreased DSAs in ABMR kidney-transplant recipients but did not improve renal function or renal histology at 1-year follow-up., (© 2021 Wiley Periodicals LLC.)

NUT carcinoma (NC), formerly known as NUT midline carcinoma, is a rare and very aggressive cancer. It is genetically defined by the presence of acquired chromosomal rearrangement of the NUTM1 (NUclear protein in Testis Midline carcinoma family member 1) gene at chromosome 15q14 with a member of the bromodomain-containing protein (BRD) family gene, usually BRD4. Although primarily reported in the head and neck, and mediastinum locations of younger individuals, it is now established that NC arises in multiple sites in patients of all ages, with no gender predilection. NC is very likely to be underdiagnosed because of a lack of awareness of both clinicians and pathologists on the one hand, and of a nonspecific histological presentation on the other hand. As it is indistinguishable from other poorly differentiated carcinomas, pathologists should consider NC as a differential diagnosis of any poorly differentiated tumour. Diagnosis is now easily made by immunohistochemistry, using a highly sensitive and specific NUT monoclonal antibody. Despite chemo- or chemo-radiotherapy, the prognosis of this tumour remains very poor. We report here a series of 3 cases of NC with different clinical and pathological presentations in order to draw attention on some common morphological features that can help clinicians and pathologists to think about this rare entity., (Copyright © 2021. Published by Elsevier B.V.)

Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically engineered Pten (i)pe-/- mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analog with reported anticancer activities. We show that this analog induces apoptosis in senescent PINs, normalizes extracellular matrix remodeling by stromal fibroblasts, and reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal cells expressing Krt8, Krt4, and Tacstd2 (termed luminal-C cells) is lost by such a treatment, antiapoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of PINs and the microenvironment to Gemini-72, and shed light on mechanisms that limit treatment's efficacy., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Non-small-cell lung cancers (NSCLC) represent 85% of all lung cancers, with adenocarcinoma as the most common subtype. Since the 2000's, the discovery of molecular alterations including epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) rearrangements together with the development of specific tyrosine kinase inhibitors (TKIs) has facilitated the development of personalized medicine in the management of this disease. This review focuses on the biology of molecular alterations in NSCLC as well as the diagnostic tools and therapeutic alternatives available for each targetable alteration. Rapid and sensitive methods are essential to detect gene alterations, using tumor tissue biopsies or liquid biopsies. Massive parallel sequencing or Next Generation Sequencing (NGS) allows to simultaneously analyze numerous genes from relatively low amounts of DNA. The detection of oncogenic fusions can be conducted using fluorescence in situ hybridization, reverse-transcription polymerase chain reaction, immunohistochemistry, or NGS. EGFR mutations, ALK and ROS1 rearrangements, MET (MET proto-oncogenereceptor tyrosine kinase), BRAF (B-Raf proto-oncogen serine/threonine kinase), NTRK (neurotrophic tropomyosin receptor kinase ) , and RET (ret proto-oncogene) alterations are described with their respective TKIs, either already authorized or still in development. We have herein paid particular attention to the mechanisms of resistance to EGFR and ALK-TKI. As a wealth of diagnostic tools and personalized treatments are currently under development, a close collaboration between molecular biologists, pathologists, and oncologists is crucial., (Copyright © 2019 Pinsolle, McLeer-Florin, Giaj Levra, de Fraipont, Emprou, Gobbini and Toffart.)

Lymph node metastasis is an important prognosis factor in non-small cell lung cancer (NSCLC) patients. The aim of this study was to investigate the role of epithelial to mesenchymal transition (EMT) in lymph node progression in the early stages of NSCLC. We studied a retrospective cohort of 160 consecutive surgically treated NSCLC patients with available frozen tumor samples for expression of EMT markers (CDH1, CTNNB1, CDH2, and VIMENTIN), inducers (TGFB1, c-MET, and CAIX), and transcription factors (EMT-TF: SNAI1, SNAI2, ZEB1, TWIST1, and TWIST2). Partial EMT was more frequent in N1-2 (N+) vs N0 patients (P < .01). TGFB1 (P = .02) as well as SNAI2 (P < .01) and TWIST1 (P = .04) were the most differentially expressed genes in N+ tumors. In this group, ZEB1 was correlated with all EMT inducers and other EMT-TFs were overexpressed depending on the inducers. CAIX was an independent prognostic factor for overall survival (IC 95% HR: 1.10-5.14, P = .03). Partial EMT is involved in lymph node progression of NSCLC patients and depends on the TGFβ pathway. EMT-TFs are differentially expressed depending on EMT inducers. CAIX might be a relevant prognostic marker in early stage NSCLC., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The Epidermal Growth Factor Receptor (EGFR) is mutated in 15% of lung adenocarcinomas. Eight percent of instances with altered Anaplastic Lymphoma Kinase (ALK) are caused by lung adenocarcinomas. For tumours of Non-Small Cell Lung Cancer (NSCLC) that are EGFR mutant and ALK translocation positive, Tyrosine Kinase Inhibitor therapy (TKI therapy) has changed treatment and produced a remarkable preventive effect. Unfortunately, TKI resistance always appears to spread. To overcome the resistance, numerous innovative and promising medicines are being studied. Results: First-line, recognized opposition, and adjuvant treatment is being investigated for NSCLC with EGFR mutation and ALK positivity, along with the therapeutic implications of recent national meetings and beginning research. Conclusion: There is a signi icant therapeutic advantage to including EGFR TKIs in EGFR mutant NSCLC First Line (FL) therapy. In phase II and III studies, several possible third-generation EGFR TKIs are being examined in the context of acquired resistance. The medicine is better than chemotherapy as an FL treatment for NSCLC with ALK positivity. For NSCLC with established resistance and an ALK-positive test result, cetinib is approved and effective. More study is needed to develop new medications that can combat acquired resistance to TKIs. [ABSTRACT FROM AUTHOR]

Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D2 [ercalcitriol, 1,25(OH)2D2] and 1α,25-dihydroxyvitamin D3 [calcitriol, 1,25(OH)2D3], which act as classical steroid hormones. 1,25(OH)2D3 exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)2D3 cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)2D3 and 1,25(OH)2D2 have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies. [ABSTRACT FROM AUTHOR]

Lung cancer is a deeply malignant tumor with high incidence and mortality. Despite the rapid development of diagnosis and treatment technology, abundant patients with lung cancer are still inevitably faced with recurrence and metastasis, contributing to death. Lymphatic metastasis is the first step of distant metastasis and an important prognostic indicator of non-small cell lung cancer. Tumor-induced lymphangiogenesis is involved in the construction of the tumor microenvironment, except promoting malignant proliferation and metastasis of tumor cells, it also plays a crucial role in individual response to treatment, especially immunotherapy. Thus, this article reviews the current research status of lymphatic metastasis in non-small cell lung cancer, in order to provide some insights for the basic research and clinical and translational application in this field. [ABSTRACT FROM AUTHOR]

Background: Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear. Methods: We performed molecular profiling of 1045 PCa patients, leveraging genes linked to VD synthesis and VD receptors. We then identified highly variable gene modules with substantial associations with patient stratification. Subsequently, we intersected these modules with differentially expressed genes between PCa and adjacent paracancerous tissues. Following a meticulous process involving single-factor regression and LASSO regression to eliminate extraneous variables and construct a prognostic model. Within the high-risk subgroup defined by the calculated risk score, we analyzed their differences in cell infiltration, immune status, mutation landscape, and drug sensitivity. Finally, we selected Apolipoprotein E (APOE), which featured prominently in this model for further experimental exploration to evaluate its potential as a therapeutic target. Results: The prognostic model established in this study had commendable predictive efficacy. We observed diminished infiltration of various T-cell subtypes and reduced expression of co-stimulatory signals from antigen-presenting cells. Mutation analysis revealed that the high-risk cohort harbored a higher frequency of mutations in the TP53 and FOXA genes. Notably, drug sensitivity analysis suggested the heightened responsiveness of high-risk patients to molecular inhibitors targeting the Bcl-2 and MAPK pathways. Finally, our investigation also confirmed that APOE upregulates the proliferative and invasive capacity of PCa cells and concurrently enhances resistance to androgen receptor antagonist therapy. Conclusion: This comprehensive study elucidated the potential mechanisms through which this metabolic pathway orchestrates the biological behavior of PCa and findings hold promise in advancing the development of combination therapies in PCa. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Despite the well-known in vitro antitumoral effect of vitamin D3 (VD3), its impact on breast CAFs is almost unknown. In this study, we analyzed the ex vivo effects of calcitriol on CAFs isolated from breast cancer tissues. Methods: CAFs were cultured with 1 and 10 nM calcitriol and their phenotype; gene expression, protein expression, and secretion were assessed. Calcitriol-treated CAFs-conditioned media (CM) were used to analyze the effect of CAFs on the migration and protein expression of MCF-7 and MDA-MB-231 cells. Results: Tumor tissues from VD3-deficient patients exhibited lower levels of β-catenin and TGFβ1, along with higher levels of CYP24A1 compared to VD3-normal patients. In VD3-deficient patients, CAF infiltration was inversely associated with CYP24A1 levels and positively correlated with OPN levels. Calcitriol diminished CAFs' viability, but this effect was weaker in premenopausal and VD3-normal patients. Calcitriol reduced mRNA expression of CCL2, MMP9, TNC, and increased PDPN, SPP1, and TIMP1. It also decreased the secretion of CCL2, TNC, and the activity of MMP-2, while increasing cellular levels of TIMP1 in CAFs from all patient groups. In nonmetastatic and postmenopausal patients, PDPN surface expression increased, and CAFs CM from these groups decreased MCF-7 cell migration after ex vivo calcitriol treatment. In premenopausal and VD3-deficient patients, calcitriol reduced IDO1 expression in CAFs. Calcitriol-treated CAFs CM from these patients decreased OPN expression in MCF-7 and/or MDA-MB-231 cells. However, in premenopausal patients, calcitriol-treated CAFs CM also decreased E-cadherin expression in both cell lines. Conclusion: The effects of calcitriol on breast CAFs, both at the gene and protein levels, are complex, reflecting the immunosuppressive or procancer properties of CAFs. The anticancer polarization of CAFs following ex vivo calcitriol treatment may result from decreased CCL2, TNC (gene and protein), MMP9, and MMP-2, while the opposite effect may result from increased PDPN, TIMP1 (gene and protein), and SPP1. Despite these multifaceted effects of calcitriol on molecule expression, CAFs' CMs from nonmetastatic and postmenopausal patients treated ex vivo with calcitriol decreased the migration of MCF-7 cells. [ABSTRACT FROM AUTHOR]

Nuclear protein of the testis (NUT) midline carcinoma (NMC) is a rare tumor, with particularly low incidence in the lungs, and a correspondingly poor prognosis. To determine the clinicopathological characteristics, outcomes, and prognostic factors of primary pulmonary NMC, a case was reported and a systematic review was performed. Twenty-nine records, including ours, involving 62 cases, were finally included. The median age at diagnosis was 29.5 years. At presentation, the most common symptoms at presentation were cough (47.50%) and chest/back pain (37.50%). In terms of diagnosis, 32.14% of NMC cases were identified through immunohistochemistry (IHC); However, a greater number of cases may be misdiagnosed initially, and ultimately, the diagnosis of NMC was confirmed through a combination of IHC and fluorescence in situ hybridization (FISH). Despite the clinical application of various chemotherapy-based treatments, the actual effectiveness remains unsatisfactory. Furthermore, Cox regression analysis of multiple factors identified male gender and concurrent presence of pleural effusion as indicators of shorter survival time in patients. These results emphasize the importance of increased diagnostic awareness among clinical and pathology practitioners concerning NMC. While there is currently no established standard for treating NMC, a treatment approach combining multiple methods shows promise for future research. Concurrently, clinical and foundational investigations addressing variables such as gender and the presence of pleural effusion may yield valuable insights into the diagnosis and treatment of NMC. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma of the gingivo‐buccal region (OSCC‐GB) is the most common cancer among men in India, and is associated with poor prognosis and frequent recurrence. Cellular heterogeneity in OSCC‐GB was investigated by single‐cell RNA sequencing of tumors derived from the oral cavity of 12 OSCC‐GB patients, 3 of whom had concomitant presence of a precancerous lesion (oral submucous fibrosis [OSMF]). Unique malignant cell types, features, and phenotypic shifts in the stromal cell population were identified in oral tumors with associated submucous fibrosis. Expression levels of FOS, ATP1A, and DUSP1 provided robust discrimination between tumors with or without the concomitant presence of OSMF. Malignant cell populations shared between tumors with and without OSMF were enriched with the expression of partial epithelial–mesenchymal transition (pEMT) or fetal cell type signatures indicative of two dominant cellular programs in OSCC‐GB—pEMT and fetal cellular reprogramming. Malignant cells exhibiting fetal cellular and pEMT programs were enriched with the expression of immune‐related pathway genes known to be involved in antitumor immune response. In the tumor microenvironment, higher infiltration of immune cells than the stromal cells was observed. The T cell population was large in tumors and diverse subtypes of T cells with varying levels of infiltration were found. We also detected double‐negative PLCG2+ T cells and cells with intermediate M1–M2 macrophage polarization. Our findings shed light on unique aspects of cellular heterogeneity and cell states in OSCC‐GB. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) is a cutting-edge technology that provides insights at the individual cell level. In contrast to traditional bulk RNAseq, which captures gene expression at an average level and may overlook important details, scRNA-seq examines each individual cell as a fundamental unit and is particularly well-suited for identifying rare cell populations. Analogous to a microscope that distinguishes various cell types within a tissue sample, scRNAseq unravels the heterogeneity and diversity within a single cell species, offering great potential as a leading sequencing method in the future. In the context of prostate cancer (PCa), a disease characterized by significant heterogeneity and multiple stages of progression, scRNA-seq emerges as a powerful tool for uncovering its intricate secrets. [ABSTRACT FROM AUTHOR]

Antibody mediated rejection (ABMR) is the leading cause of immune-related allograft failure following kidney transplantation. Chronic active ABMR (CABMR) typically occurs after one-year post-transplant andis themost common causeof late allograft failure. This studywas designed to assess common practices in Europe for post-transplant surveillance 1year after kidney transplant, as well as the diagnosis and management of CABMR. A 15-minute online survey with 58 multiple choice or open-ended questions was completed by EU transplant nephrologists, transplant surgeons and nephrologists. Survey topics included patient caseloads, post-transplant routine screening and treatment of CABMR. The results indicated that observing clinical measures of graft function form the cornerstone of posttransplant surveillance. This may be suboptimal, leading to late diagnoses and untreatable disease. Indeed, less than half of patients who develop CABMR receive treatment beyond optimization of immune suppression. This is attributable to not only late diagnoses, but also a lack of proven efficacious therapies. Intravenous Immunoglobulin (IVIG), steroid pulse and apheresis are prescribed by the majority to treat CABMR. While biologics can feature as part of treatment, there is no single agent that is being used by more than half of physicians. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten(i)pe−/− mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten(i)pe−/− mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis: Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background: IgA nephropathy (IgAN) is a major cause of chronic kidney disease (CKD). Renal interstitial fibrosis is a hallmark of CKD progression. Non-invasive biomarkers are needed to dynamically evaluate renal fibrosis. Data independent acquisition (DIA)-based liquid chromatography-mass spectrometry (DIA-MS) was used to identify candidate urinary biomarkers in IgAN patients with different renal interstitial fibrosis degrees. Methods: Eighteen biopsy-proven IgAN patients and six healthy controls were recruited in a discovery cohort. Interstitial fibrosis changes were evaluated according to Oxford MEST-C scores. Urinary samples were analyzed with DIA-MS to identify hub proteins. Hub proteins were then confirmed by enzyme-linked immunosorbent assay (ELISA) in a validation cohort and the associated gene mRNA expression was analyzed using public gene expression omnibus (GEO) datasets. Results: Complement and coagulation cascades pathway was the main KEGG pathway related to the over-expressed proteins. Fibrinogen γ-Chain (FGG) was selected as the potential urinary marker for further validation. Urinary FGG to creatinine ratio (uFGG/Cr) levels were higher in both disease controls and IgAN group than in healthy controls, but were not significantly different between IgAN and disease groups. uFGG/Cr was confirmed to be increased with the extent of renal fibrosis and presented moderate correlations with T score (r = 0.614, p < 0.01) and eGFR (r = -0.682, p < 0.01), and a mild correlation with UTP (r = 0.497, p < 0.01) in IgAN group. In disease control group, uFGG/Cr was higher in patients with T1 + 2 compared to those with T0. uFGG/Cr had a good discriminatory power to distinguish different fibrosis stages in IgAN: interstitial fibrosis ≤ 5% (minimal fibrosis) vs. interstitial fibrosis (mild fibrosis) > 5%, AUC 0.743; T0 vs. T1 + 2, AUC 0.839; T0 + 1 vs. T2, AUC 0.854. In disease control group, uFGG/Cr showed better performance of AUC than UTP between minimal and mild fibrosis (p = 0.038 for Delong's test). Moreover, GSE104954 dataset showed that FGG mRNA expression was up-regulated (fold change 1.20, p = 0.009) in tubulointerstitium of IgAN patients when compared to healthy living kidney donors. Conclusion: Urinary FGG is associated with renal interstitial fibrosis and could be used as a noninvasive biomarker for renal fibrosis in IgAN. [ABSTRACT FROM AUTHOR]

With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease–like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed. [ABSTRACT FROM AUTHOR]

The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Stage III non-small cell lung cancer (NSCLC) is a highly heterogeneous group of diseases with wide differences in tumor size and in nodal involvement and, although the intent of treatments is potentially curative, survival data still remain disappointing in some cases. The treatment of locally advanced NSCLC involves a multidisciplinary approach to determine which patients might benefit from a trimodality treatment that includes tumour resection and to identify patients with unresectable stage III NSCLC who are candidates for definitive chemo-radiation therapy (CRT). The main aim of this work was to provide a real-world description of treatment evolution and survival outcomes of stage III NSCLC patients referred to the Veneto Institute of Oncology—IRCCS and University Hospital of Padova for about 10 years. Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment. Methods: This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS). Results: A total of 301 patients were included. The majority of patients received surgical multimodality treatment (n = 223, 74.1%), while the remaining patients (n = 78, 25.9%) underwent definitive CRT followed or not by durvalumab as consolidation therapy. At data cut-off, 188 patients (62.5%) relapsed and the median RFS (mRFS) of the entire population was 18.2 months (95% CI: 15.83–20.57). At the time of analyses 140 patients (46.5%) were alive and the median OS (mOS) was 44.7 months (95% CI: 38.4–51.0). A statistically significant difference both in mRFS (p = 0.002) and in mOS (p < 0.001) was observed according to the therapeutic pathway in the entire population, and selecting patients treated after 2018, a significant difference in mRFS (p = 0.006) and mOS (p < 0.001) was observed according to treatment modality. Furthermore, considering only patients diagnosed with stage IIIB-C (N = 131, 43.5%), there were significant differences both in mRFS (p = 0.047) and in mOS (p = 0.022) as per the treatment algorithm. The mRFS of the unresectable population was 16.3 months (95% CI: 11.48–21.12), with a significant difference among subgroups (p = 0.030) in favour of patients who underwent the PACIFIC-regimen; while the mOS was 46.5 months (95% CI: 26.46–66.65), with a significant difference between two subgroups (p = 0.003) in favour of consolidation immunotherapy. Conclusions: Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients. [ABSTRACT FROM AUTHOR]

TPE in the treatment of limbic encephalitis Four studies describe TPE treatment for limbic encephalitis.70-73 The largest case series includes 19 patients in which TPE was used in only one patient.73 In this study, no TPE detail was provided. Patients with pre-existing autoantibodies appear to be more susceptible.25 TREATMENT OF ICI-ASSOCIATED IRAES AND THE ROLE OF TPE Treatment of ICI-associated irAEs Treatment of ICI-associated irAEs, as outlined in the American Society of Clinical Oncology (ASCO) guidelines,3,30 involves both general principles and organ-specific interventions. TPE in the treatment of endocrine irAEs There are three case reports of TPE use for endocrine irAEs, including thyroiditis and hypertriglyceridemia.102-104 The case with hypertriglyceridemia did not provide additional TPE detail, stating only that two apheresis sessions were performed with successful lowering of triglyceride levels.103 In the two case reports of thyroiditis, there was no improvement with steroids alone and TPE was added. Keywords: immune checkpoint inhibitors; immune-related adverse events; plasma exchange EN immune checkpoint inhibitors immune-related adverse events plasma exchange 2370 2390 21 11/10/22 20221101 NES 221101 INTRODUCTION With the FDA approval of ipilimumab in 2011, immune checkpoint inhibitors (ICIs) have become a cornerstone of cancer immunotherapy.1 Despite their contribution to improved cancer immunotherapy outcomes, ICIs are associated with immune-related adverse events (irAE), which range from mild (Grade 1) to severe (Grade 4) and sometimes lead to death (Grade 5).2,3 A number of these adverse events have been treated with therapeutic plasma exchange (TPE). [Extracted from the article]

NUT carcinoma is a rare, highly lethal cancer characterized with the rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, which primarily occurs in the midline organs. Primary pulmonary NUT carcinoma (NC) lacks characteristic clinical manifestations, which leads to the high rate of misdiagnose and nonstandard treatment. To date, fewer than one hundred cases have been reported worldwide. Here, a comprehensive literature search involving a total of 35 articles with 55 patients was conducted in this paper. We reviewed and analyzed the associated clinical and pathological characteristics, the efficacy of various treatment options and the prognosis. Pulmonary NC mainly occurred in middle young-aged men (median age, 36) with no smoking history (2:1) and would present with symptoms of cough (63.6%), dyspnea (29.5%), chest pain (18.2%) and hemoptysis (18.2%). The initial imaging frequently revealed large and irregular lesions in the lower lobe (46.5%) of the left or right lungs; lymph node metastasis was also prevalent (91.9%). A focal squamous differentiation with abrupt keratinization often occurred in the undifferentiated or poorly differentiated (93.75%) tumor cells, with abundant necrosis and numerous neutrophils infiltrated. The mean overall survival (OS) in patients of this malignant disease was 6.21 months, and the median OS was 4.4 months. According to our results, this disease is sensitive to radiotherapy, and chemoradiotherapy (either concurrent chemoradiotherapy or sequential chemoradiotherapy) was the most efficient therapeutic regimen to prolong the OS of patients with pulmonary NC. [ABSTRACT FROM AUTHOR]

NUT carcinoma and thoracic SMARCA4-deficient undifferentiated tumour are unique entities in the 5th edition of the World Health Organisation (WHO) Classification of Thoracic Tumours, whose definitions include molecular genetic abnormalities. These aggressive tumours require rapid work-ups on biopsies, but a broad list of differential diagnoses poses challenges for practising pathologists. This review provides an update on their key clinicopathological and molecular characteristics, as well as controversies regarding tumour classification and diagnostic strategy. Phenotypical assessment plays a substantial role in diagnosis because recurrent and predictable clinicopathological findings exist, including robust immunohistochemical phenotypes. Accurate diagnosis is crucial for appropriate management and a clearer understanding of the disease., (© 2023 John Wiley & Sons Ltd.)

Simple Summary: The shift from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC) has been hypothesized to be driven by prostatic luminal cells exhibiting castration tolerance, progenitor and tumor-initiating capacity. LSCmed cells that we recently isolated in a relevant mouse model of CRPC fulfil these three criteria. Using various bioinformatic pipelines, we here demonstrate that LSCmed cells match Club/Hillock cells recently identified in human prostate and prostate cancer. We identified EGFR/ERBB4, IGF-1 and MET pathways as key regulators of LSCmed cell progenitor and growth properties. We also demonstrate, for the first time in primary cultures of castration-tolerant prostatic progenitor cells, that the functional redundancy of these growth factor pathways confers to these cells the ability to bypass receptor-targeted pharmacological inhibition. Given the failure of EGFR- and MET-targeted monotherapies in CRPC patients, our data further support LSCmed cells as a relevant preclinical model to study the cellular and molecular mechanisms driving CRPC. Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression. [ABSTRACT FROM AUTHOR]

The activities of 1α,25-dihydroxyvitamin D3, 1,25D3, are mediated via its binding to the vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Numerous studies have demonstrated the important role of 1,25D3 and VDR signaling in various biological processes and associated pathologies. A wealth of information about ligand recognition and mechanism of action by structural analysis of the VDR complexes is also available. The methods used in these structural studies were mainly X-ray crystallography complemented by NMR, cryo-electron microscopy and structural mass spectrometry. This review aims to provide an overview of the current knowledge of VDR structures and also to explore the recent progress in understanding the complex mechanism of action of 1,25D3 from a structural perspective. [ABSTRACT FROM AUTHOR]

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects. [ABSTRACT FROM AUTHOR]

p40 immunohistochemistry is a cornerstone of histopathological examination for non-small cell lung carcinoma. p40 is an isoform of p63 and is reported to be highly specific for the diagnosis of squamous cell carcinoma. Very rare pitfalls are reported for this antibody, and p40 is typically negative in melanoma. A 66-year-old patient was admitted for multiple hemorrhagic brain tumors evocative of secondary tumors. On imaging, a 26 mm lung tumor was detected, and a biopsy of the lung tumor was performed. The tumor was stained by melanic markers and diffusely stained by p40 and p63. Molecular analysis found a somatic p.Asn581Ser (c.1742A>G) point mutation in exon 15 of BRAF and a p.Arg80Ter (c.238C>T) germline variant of CDKN2A , a predisposing mutation to melanoma. This case report highlights the importance of clinical, pathologic, and molecular correlation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Approximately 75% of all breast cancers express the nuclear hormone receptor estrogen receptor α (ERα). However, the majority of mammary tumors from genetically engineered mouse models (GEMMs) are ERα-negative. To model ERα-positive breast cancer in mice, we exogenously introduced expression of mouse and human ERα in an existing GEMM of p53-deficient breast cancer. After initial ERα expression during mammary gland development, expression was reduced or lost in adult glands and p53-deficient mammary tumors. Chromatin immunoprecipitation (ChIP)-sequencing analysis of primary mouse mammary epithelial cells (MMECs) derived from these models, in which expression of the ERα constructs was induced in vitro, confirmed interaction of ERα with the DNA. In human breast and endometrial cancer, and also in healthy breast tissue, DNA binding of ERα is facilitated by the pioneer factor FOXA1. Surprisingly, the ERα binding sites identified in primary MMECs, but also in mouse mammary gland and uterus, showed an high enrichment of ERE motifs, but were devoid of Forkhead motifs. Furthermore, exogenous introduction of FOXA1 and GATA3 in ERα-expressing MMECs was not sufficient to promote ERα-responsiveness of these cells. Together, this suggests that species-specific differences in pioneer factor usage between mouse and human are dictated by the DNA sequence, resulting in ERα-dependencies in mice that are not FOXA1 driven. These species-specific differences in ERα-biology may limit the utility of mice for in vivo modeling of ERα-positive breast cancer. [ABSTRACT FROM AUTHOR]

Ceramide synthase 6 (CerS6) is an enzyme that preferentially generates pro-apoptotic C16-ceramide in the sphingolipid metabolic pathway. Reduced expression of CerS6 has been associated with apoptosis resistance and recent studies point to a role for CerS6 in epithelial mesenchymal transition (EMT). Because cells that undergo EMT are also more resistant to apoptosis, we hypothesized that reduced expression of CerS6 could induce changes that are associated with EMT. We found that shRNA-mediated knockdown of CerS6 increases expression of the EMT transcription factor SNAI2 but not SNAI1 or TWIST. Treatment with C6-ceramide nanoliposomes (CNL) resulted in a preferential increase in C16-ceramide and suppressed SNAI2 transcriptional activation and protein expression. The increase in C16-ceramide following CNL treatment was dependent on CerS activity and occurred even when CerS6 shRNA was expressed. shRNA against CerS5, which like CerS6 preferentially generates C16-ceramide, also decreased transcriptional activation of SNAI2, suggesting a role for C16-ceramide rather than a specific enzyme in the regulation of this transcription factor. While loss of CerS6 has been associated with apoptosis resistance, we found that cells lacking this protein are more susceptible to the effects CNL. In summary, our study identifies SNAI2 as a novel target whose expression can be influenced by C16-ceramide levels. The potential of CNL to suppress SNAI2 expression has important clinical implications, since elevated expression of this transcription factor has been associated with an aggressive phenotype or poor outcomes in several types of solid tumors. [ABSTRACT FROM AUTHOR]

Estrogen receptor-positive (ER+) tumors account for 70-80% of all breast cancer (BC) cases and are characterized by estrogen dependency for their growth. Endocrine therapies using estrogen receptor antagonists or aromatase inhibitors represent a key component of the standard of care for these tumors. The occurrence of de novo or acquired resistance to estrogen withdrawal represents an important clinical problem, impacting on patient survival. In addition, despite an initially favorable outcome, a part of ER+ BC patients present with disease recurrence locally or at distant sites years or even decades after apparent remission. In vivo models that closely mimic human disease are urgently needed to study the biology of these tumors, investigate the molecular mechanisms underlying endocrine resistance and identify patients at risk of recurrence. Despite the similarities in the overall hormonal regulation of mammary gland development between mice and humans, the majority of the mammary carcinomas occurring in genetically engineered mouse models (GEMMs) are ER negative and most xenograft models are based on few ER+ cancer cell lines. We recently showed that the microenvironment is critical for ER+ cancer cells and discuss in this review the potential of intraductal xenograft model for basic and preclinical research. [ABSTRACT FROM AUTHOR]