BET inhibitors as a therapeutic intervention in gastrointestinal gene signature-positive castration-resistant prostate cancer.

A subgroup of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi. SIGNIFICANCE: GI transcriptome expression in CRPC is regulated by the HNF1A-HNF4G-BRD4 axis and correlates with worse clinical outcomes. Accordingly, BET inhibitors significantly reduce tumor cell growth in multiple GI-transcriptome-positive preclinical models of CRPC. Our studies point that expression of GI transcriptome could serve as a predictive biomarker to BETi therapy response.

Hemophagocytic syndrome in A patient of upper urinary tract urothelial cancer after Bacillus Calmette-Guérin instillation: A case report.

Bacillus Calmette-Guérin (BCG) therapy is an adjuvant treatment for urothelial carcinomas of the upper urinary tract (UTUC). BCG therapy can result in various side effects. We present a case of a 67-year-old female with a history of UTUC who developed disseminated tuberculosis following BCG instillation into the upper urinary tract after conservative management. This complex clinical scenario required a multidisciplinary approach, including antibiotic therapy, immunoglobulin infusion, and tailored tuberculosis treatment. The case underscores the importance of vigilance, early detection, and tailored interventions in managing disseminated tuberculosis arising from BCG therapy and rare complications like hemophagocytic syndrome.

Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads.

Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Diet Pattern Analysis in Alzheimer's Disease Implicates Gender Differences in Folate-B12-Homocysteine Axis on Cognitive Outcomes.

BACKGROUND & AIMS: Low plasma B12 and folate levels or hyperhomocysteinemia are related to cognitive impairment. This study explores the relationships among diet pattern, blood folate-B12-homocysteine levels, and cognition measurement in Alzheimer's disease (AD) while exploring whether a gender effect may exist. METHODS: This cross-sectional study enrolled 592 AD patients (246 males, 346 females) and the demographic data, blood biochemical profiles, Mini-Mental State Examination (MMSE), and a Food Frequency Questionnaire (FFQ) for quantitative assessment of dietary frequency were collected. Structural Equation Modeling (SEM) was employed to explore the associations among dietary patterns, blood profiles, and cognition. A least absolute shrinkage and selection operator regression model, stratified by gender, was constructed to analyze the weighting of possible confounders. RESULTS: Higher MMSE scores were related to higher frequencies of coffee/tea and higher educational levels, body mass index, and younger age. The SEM model revealed a direct influence of dietary frequencies (skimmed milk, thin pork, coffee/tea) and blood profiles (homocysteine, B12, and folate) on cognitive outcomes. At the same time, the influence of dietary pattern on cognition was not mediated by folate-B12-homocysteine levels. In males, a direct influence on the MMSE is attributed to B12, while in females, homocysteine is considered a more critical factor. CONCLUSIONS: Dietary patterns and blood profiles are both associated with cognitive domains in AD, and there are gender differences in the associations of dietary patterns and the levels of B12 and homocysteine. To enhance the quality of dietary care and nutritional status for individuals with dementia, our study results still require future validations with multi-center and longitudinal studies.

Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling.

SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors. IMPORTANCE: Cyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.

SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction.

Members of the serine-arginine protein kinase (SRPK) family, SRPK1 and SRPK2, phosphorylate the hepatitis B core protein (Cp) and are crucial for pregenomic RNA encapsidation during viral nucleocapsid assembly. Among them, SRPK2 exhibits higher kinase activity toward Cp. In this study, we identified Cp sites that are phosphorylated by SRPK2 and demonstrated that the kinase utilizes an SRPK-specific docking groove to interact with and regulate the phosphorylation of the C-terminal arginine rich domain of Cp. We determined that direct interaction between the docking groove of SRPK2 and unphosphorylated Cp inhibited premature viral capsid assembly in vitro, whereas the phosphorylation of the viral protein reactivated the process. Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle.

Non-mitotic proliferation of malignant cancer cells revealed through live-cell imaging of primary and cell-line cultures.

INTRODUCTION: Anti-mitosis has been a key strategy of anti-cancer therapies, targeting at a fundamental property of cancer cells, their non-controllable proliferation due to overactive mitotic divisions. For improved anti-cancer therapies, it is important to find out whether cancer cells can proliferate independent of mitosis and become resistant to anti-mitotic agents. RESULTS: In this study, live-cell imaging was applied to both primary-cultures of tumor cells, and immortalized cancer cell lines, to detect aberrant proliferations. Cells isolated from various malignant tumors, such as Grade-III hemangiopericytoma, atypical meningioma, and metastatic brain tumor exhibit distinct cellular behaviors, including amoeboid sequestration, tailing, tunneling, nucleic DNA leakage, as well as prokaryote-like division such as binary fission and budding-shedding, which are collectively referred to and reported as 'non-mitotic proliferation' in this study. In contrast, benign tumors including Grade-I hemangiopericytoma and meningioma were not obvious in such behaviors. Moreover, when cultured in medium free of any anti-cancer drugs, cells from a recurrent Grade-III hemangiopericytoma that had been subjected to pre-operation adjuvant chemotherapy gradually shifted from non-mitotic proliferation to abnormal mitosis in the form of daughter number variation (DNV) and endomitosis, and eventually regular mitosis. Similarly, when treated with the anti-cancer drugs Epirubicin or Cisplatin, the cancer cell lines HeLa and A549 showed a shift from regular mitosis to abnormal mitosis, and further to non-mitosis as the dominant mode of proliferation with increasing drug concentrations. Upon removal of the drugs, the cells reversed back to regular mitosis with only minor occurrences of abnormal mitosis, accompanied by increased expression of the stem cell markers ALDH1, Sox, Oct4 and Nanog. CONCLUSIONS: The present study revealed that various types of malignant, but not benign, cancer cells exhibited cellular behaviors indicative of non-mitotic proliferation such as binary fission, which was typical of prokaryotic cell division, suggesting cell level atavism. Moreover, reversible transitions through the three modes of proliferation, i.e., mitosis, abnormal mitosis and non-mitosis, were observed when anticancer drug concentrations were grossly increased inducing non-mitosis or decreased favoring mitosis. Potential clinical significance of non-mitotic proliferation in cancer drug resistance and recurrence, and its relationship with cancer stem cells are worthy of further studies.

The phosphorylation of the movement protein TGBp1 regulates the accumulation of the Bamboo mosaic virus.

Phosphorylation and dephosphorylation of viral movement proteins plays a crucial role in regulating virus movement. Our study focused on investigating the movement protein TGBp1 of Bamboo mosaic virus (BaMV), which is a single-stranded positive-sense RNA virus. Specifically, we examined four potential phosphorylation sites (S15, S18, T58, and S247) within the TGBp1 protein. To study the impact of phosphorylation, we introduced amino acid substitutions at the selected sites. Alanine substitutions were used to prevent phosphorylation, while aspartate substitutions were employed to mimic phosphorylation. Our findings suggest that mimicking phosphorylation at S15, S18 and T58 of TGBp1 might be linked to silencing suppressor activities. The phosphorylated form at these sites exhibits a loss of silencing suppressor activity, leading to reduced viral accumulation in the inoculated leaves. Furthermore, mimicking phosphorylation at residues S15 and S18 could diminish viral accumulation at the single-cell level, while doing so at residue T58 could influence virus movement. However, mimicking phosphorylation at residue S247 does not appear to be relevant to both functions of TGBp1. Overall, our study provides insights into the functional significance of specific phosphorylation sites in BaMV TGBp1, illuminating the regulatory mechanisms involved in virus movement and silencing suppression.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

Activating neutrophils by co-administration of immunogenic recombinant modified vaccinia virus Ankara and granulocyte colony-stimulating factor for the treatment of malignant peripheral nerve sheath tumor.

Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft-tissue sarcoma with a poor prognosis and is insensitive to immune checkpoint blockade (ICB) therapy. Loss-of-function of the histone modifying polycomb repressive complex 2 (PRC2) components, EED or SUZ12, is one of the main mechanisms of malignant transformation. In a murine model of MPNST, PRC2-loss tumors have an "immune desert" phenotype and intratumoral (IT) delivery immunogenic modified vaccinia virus Ankara (MVA) sensitized the PRC2-loss tumors to ICB. Here we show that IT MQ833, a second-generation recombinant modified vaccinia virus Ankara virus, results in neutrophil recruitment and activation and neutrophil-dependent tumor killing in the MPNST model. MQ833 was engineered by deleting three viral immune evasion genes, E5R, E3L, and WR199, and expressing three transgenes, including the two membrane-bound Flt3L and OX40L, and IL-12 with an extracellular matrix anchoring signal. Furthermore, we explored strategies to enhance anti-tumor effects of MQ833 by co-administration of granulocyte colony-stimulating factor (G-CSF).

Machine Learning and Radiomics of Bone Scintigraphy: Their Role in Predicting Recurrence of Localized or Locally Advanced Prostate Cancer.

BACKGROUND: Machine-learning (ML) and radiomics features have been utilized for survival outcome analysis in various cancers. This study aims to investigate the application of ML based on patients' clinical features and radiomics features derived from bone scintigraphy (BS) and to evaluate recurrence-free survival in local or locally advanced prostate cancer (PCa) patients after the initial treatment. METHODS: A total of 354 patients who met the eligibility criteria were analyzed and used to train the model. Clinical information and radiomics features of BS were obtained. Survival-related clinical features and radiomics features were included in the ML model training. Using the pyradiomics software, 128 radiomics features from each BS image's region of interest, validated by experts, were extracted. Four textural matrices were also calculated: GLCM, NGLDM, GLRLM, and GLSZM. Five training models (Logistic Regression, Naive Bayes, Random Forest, Support Vector Classification, and XGBoost) were applied using K-fold cross-validation. Recurrence was defined as either a rise in PSA levels, radiographic progression, or death. To assess the classifier's effectiveness, the ROC curve area and confusion matrix were employed. RESULTS: Of the 354 patients, 101 patients were categorized into the recurrence group with more advanced disease status compared to the non-recurrence group. Key clinical features including tumor stage, radical prostatectomy, initial PSA, Gleason Score primary pattern, and radiotherapy were used for model training. Random Forest (RF) was the best-performing model, with a sensitivity of 0.81, specificity of 0.87, and accuracy of 0.85. The ROC curve analysis showed that predictions from RF outperformed predictions from other ML models with a final AUC of 0.94 and a p-value of <0.001. The other models had accuracy ranges from 0.52 to 0.78 and AUC ranges from 0.67 to 0.84. CONCLUSIONS: The study showed that ML based on clinical features and radiomics features of BS improves the prediction of PCa recurrence after initial treatment. These findings highlight the added value of ML techniques for risk classification in PCa based on clinical features and radiomics features of BS.

Immunotherapeutic Agents for Intratumoral Immunotherapy.

Immunotherapy using systemic immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cells has revolutionized cancer treatment, but it only benefits a subset of patients. Systemic immunotherapies cause severe autoimmune toxicities and cytokine storms. Immune-related adverse events (irAEs) plus the immunosuppressive tumor microenvironment (TME) have been linked to the inefficacy of systemic immunotherapy. Intratumoral immunotherapy that increases immunotherapeutic agent bioavailability inside tumors could enhance the efficacy of immunotherapies and reduce systemic toxicities. In preclinical and clinical studies, intratumoral administration of immunostimulatory agents from small molecules to xenogeneic cells has demonstrated antitumor effects not only on the injected tumors but also against noninjected lesions. Herein, we review and discuss the results of these approaches in preclinical models and clinical trials to build the landscape of intratumoral immunotherapeutic agents and we describe how they stimulate the body's immune system to trigger antitumor immunity as well as the challenges in clinical practice. Systemic and intratumoral combination immunotherapy would make the best use of the body's immune system to treat cancers. Combining precision medicine and immunotherapy in cancer treatment would treat both the mutated targets in tumors and the weakened body's immune system simultaneously, exerting maximum effects of the medical intervention.

Synthesis and Capacitive Properties of Mesoporous Tungsten Oxide Films Prepared by Ultrasonic Spray Deposition.

Mesoporous tungsten trioxide (WO3) films are prepared by the combination of the template-assisted sol-gel method and ultrasonic spraying deposition (USD) for supercapacitors, and then the surface morphology and electrochemical performance of the films are studied. Compared to WO3 prepared by the traditional hydrothermal synthesis and spin coating method, the films obtained by USD exhibit advantages such as low cost, minimal material usage, and suitability for large-area in-line manufacturing. Additionally, the mesoporous structure of USD-produced films is also supportive of ion transportation. Due to the high specific surface area of WO3 films deposited by USD, it is a material capable of use in a high-performance energy storage device. Through the control of spray coats, the film thickness and specific capacitance can be effectively controlled. Electrochemical measurements show that the mesoporous WO3 films possess excellent electrochemical performance with a maximum specific capacitance of 109.15 F/g at 0.5 A/g. The cycling performance up to 5000 cycles of mesoporous WO3 films is due to the stable nature of nanocrystalline produced by the combination of USD and sol-gel chemistry.

Immune-related Adverse Events after Immune Checkpoint Blockade-based Therapy Are Associated with Improved Survival in Advanced Sarcomas.

The association between immune-related AEs (irAE) and outcome in patients with sarcoma is not known. We retrospectively reviewed a cohort of patients with advanced sarcoma treated with immune checkpoint blockade (ICB)-based therapy. Association of irAEs with survival was assessed using a Cox regression model that incorporated irAE occurrence as a time-dependent covariate. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one grade ≥ 3 irAE. The most common irAEs were hypothyroidism (8.3%), arthralgias (5.3%), pneumonitis (4.6%), allergic reaction (3.8%), and elevated transaminases (3.8%). Median progression-free survival (PFS) and overall survival (OS) from the time of study entry were 11.4 [95% confidence interval (CI), 10.7-15.0) and 74.6 weeks (CI, 44.9-89.7), respectively. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the HR for an irAE (HR, 0.662; CI, 0.421-1.041) approached, but did not reach statistical significance for PFS (P = 0.074). Patients had a significantly lower HR for OS (HR, 0.443; CI, 0.246-0.798; P = 0.007) compared with those without or before an irAE. Gene expression profiling on baseline tumor samples found that patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways. SIGNIFICANCE: irAE after ICB therapy was associated with an improved OS; it also approached statistical significance for improved PFS. Patients who had an irAE were more likely to have an inflamed tumor microenvironment at baseline.

Oncological and functional outcome of robotic-assisted radical cystectomy with total intracorporeal stentless J-pouch neobladder reconstruction.

BACKGROUND: Robotic-assisted radical cystectomy (RARC) with neobladder reconstruction has gained popularity in recent years. METHODS: We conducted a retrospective study of 17 consecutive patients who underwent RARC with totally intracorporeal J-pouch neobladder reconstruction without ureteral stent by a single experienced surgeon to evaluate perioperative, oncological and functional outcomes. RESULTS: The median follow-up duration was 32.8 months (range: 17.4-59.0 months), and the 2-year disease-free survival rate was 88.2%. Five out of 12 patients were totally continent, and none required more than one pad per day. The overall complication rate was 41.2%, and hydronephrosis was the most common adverse event. The renal function remained stable, and no long-term renal function impairment was detected. CONCLUSION: Our study suggests that RARC with totally intracorporeal J-pouch neobladder reconstruction without ureteral stent is a safe and feasible option for the treatment of muscle-invasive bladder cancer, with good oncological and functional outcomes.

Increased intraoperative vein ligation in microsurgical varicocelectomy is associated with pain improvement.

Varicocele is a major cause of male infertility. However, few studies have discussed the potential associations between the pain caused by varicocele and preoperative and intraoperative factors. The aim of this study was to evaluate factors potentially associated with changes in pain score after microsurgical varicocelectomy. This retrospective study was conducted between August 2020 and August 2022 at China Medical University Hospital in Taichung, Taiwan. Patient characteristics including age, body mass index, semen analysis, testicular volume, and the number of veins ligated were collected. Preoperative and intraoperative factors were analyzed to determine if they were correlated with changes in numeric rating scale (NRS) after microsurgical varicocelectomy. A total of 44 patients with clinical varicocele underwent subinguinal microsurgical varicocelectomy and were analyzed. The overall pain resolution rate was 91%, and the average satisfaction score after surgery was 9.2 according to their subjective feelings. Multivariate analysis revealed that severe varicocele grade (odds ratio [OR] 16.5, 95% confidence interval [CI] 3.01-90.47; P = .018) and the number of veins ligated (OR 6, 95% CI 1.6-22.48; P = .013), were significantly associated with changes in NRS after surgery. In addition, the area under the receiver operating characteristic curve for changes in NRS and the total number of veins ligated was 0.869. Microsurgical varicocelectomy had a high success rate for scrotal pain and satisfaction. Severe varicocele grade and the number of veins ligated in microsurgical varicocelectomy were associated with postoperative pain improvement.

Exploring tumor-normal cross-talk with TranNet: Role of the environment in tumor progression.

There is a growing awareness that tumor-adjacent normal tissues used as control samples in cancer studies do not represent fully healthy tissues. Instead, they are intermediates between healthy tissues and tumors. The factors that contribute to the deviation of such control samples from healthy state include exposure to the tumor-promoting factors, tumor-related immune response, and other aspects of tumor microenvironment. Characterizing the relation between gene expression of tumor-adjacent control samples and tumors is fundamental for understanding roles of microenvironment in tumor initiation and progression, as well as for identification of diagnostic and prognostic biomarkers for cancers. To address the demand, we developed and validated TranNet, a computational approach that utilizes gene expression in matched control and tumor samples to study the relation between their gene expression profiles. TranNet infers a sparse weighted bipartite graph from gene expression profiles of matched control samples to tumors. The results allow us to identify predictors (potential regulators) of this transition. To our knowledge, TranNet is the first computational method to infer such dependencies. We applied TranNet to the data of several cancer types and their matched control samples from The Cancer Genome Atlas (TCGA). Many predictors identified by TranNet are genes associated with regulation by the tumor microenvironment as they are enriched in G-protein coupled receptor signaling, cell-to-cell communication, immune processes, and cell adhesion. Correspondingly, targets of inferred predictors are enriched in pathways related to tissue remodelling (including the epithelial-mesenchymal Transition (EMT)), immune response, and cell proliferation. This implies that the predictors are markers and potential stromal facilitators of tumor progression. Our results provide new insights into the relationships between tumor adjacent control sample, tumor and the tumor environment. Moreover, the set of predictors identified by TranNet will provide a valuable resource for future investigations.

An interpretable AI model for recurrence prediction after surgery in gastrointestinal stromal tumour: an observational cohort study.

Background: There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. Methods: In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982-2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987-2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981-2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). Findings: The internal cohort included 395 patients (median [IQR] age, 63 [54-71] years; 214 men [54.2%]) and the external cohort included 556 patients (median [IQR] age, 60 [52-68] years; 308 men [55.4%]). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803-0.808) vs 0.788 (95% CI: 0.786-0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25-50% recurrence risk as well as those with >50% risk of recurrence. Interpretation: We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. Funding: The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.