Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Application of artificial intelligence in the diagnosis, treatment, and recurrence prediction of peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) is a type of secondary cancer which is not sensitive to conventional intravenous chemotherapy. Treatment strategies for PC are usually palliative rather than curative. Recently, artificial intelligence (AI) has been widely used in the medical field, making the early diagnosis, individualized treatment, and accurate prognostic evaluation of various cancers, including mediastinal malignancies, colorectal cancer, lung cancer more feasible. As a branch of computer science, AI specializes in image recognition, speech recognition, automatic large-scale data extraction and output. AI technologies have also made breakthrough progress in the field of peritoneal carcinomatosis (PC) based on its powerful learning capacity and efficient computational power. AI has been successfully applied in various approaches in PC diagnosis, including imaging, blood tests, proteomics, and pathological diagnosis. Due to the automatic extraction function of the convolutional neural network and the learning model based on machine learning algorithms, AI-assisted diagnosis types are associated with a higher accuracy rate compared to conventional diagnosis methods. In addition, AI is also used in the treatment of peritoneal cancer, including surgical resection, intraperitoneal chemotherapy, systemic chemotherapy, which significantly improves the survival of patients with PC. In particular, the recurrence prediction and emotion evaluation of PC patients are also combined with AI technology, further improving the quality of life of patients. Here we have comprehensively reviewed and summarized the latest developments in the application of AI in PC, helping oncologists to comprehensively diagnose PC and provide more precise treatment strategies for patients with PC.

Photocatalytic Sulfonyl Peroxidation of Alkenes via Deamination of N-Sulfonyl Ketimines.

A photocatalytic three-component sulfonyl peroxidation of alkenes with N-sulfonyl ketimines and tert-butyl hydroperoxide is reported. The reaction takes place via the photoinduced EnT process, which allows the efficient synthesis of a variety of ß-peroxyl sulfones under mild reaction conditions in the absence of a transition metal catalyst. The downstream derivatizations of the peroxides were also performed. Furthermore, the utility of this protocol was manifested by the synthesis of 11ß-HSD1 inhibitor and the antiprostate cancer drug bicalutamide.

A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription.

The essential G1-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G1-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2BS14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2BS14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.

Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). METHOD AND MATERIALS: All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. RESULTS: ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. CONCLUSION: The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Toxicity Spectrum of Anti-GD2 Immunotherapy: A Real-World Study Leveraging the US Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Anti-disialoganglioside (anti-GD2) monoclonal antibodies are effective immunotherapeutic drugs for treating neuroblastoma, yet their toxicity spectrum is unclear. OBJECTIVE: This study aimed to assess the toxicity profiles of three anti-GD2 monoclonal antibodies (dinutuximab, dinutuximab ß, and naxitamab) in clinical applications by mining and evaluating the adverse drug reaction (ADR) signals from the US Food and Drug Administration Adverse Event Reporting System. METHODS: Data in the US Food and Drug Administration Adverse Event Reporting System from the time anti-GD2 monoclonal antibodies became available in the market to the first quarter of 2023 were searched. The signals of anti-GD2 monoclonal antibody-associated ADRs were quantified using four types of algorithms, including the reporting odds ratio, the proportional reporting ratio, the combination of the proportional reporting ratio and χ2 statistic method used by the UK Medicines and Healthcare Products Regulatory Agency, and the Bayesian confidence propagation neural network. The ADRs were categorized by System Organ Class based on the Medical Dictionary for Regulatory Activities, and were sorted according to the frequency and signal strength of ADRs. RESULTS: A total of 370 adverse drug event reports with anti-GD2 monoclonal antibodies listed as the 'primary suspected drugs' were identified, with 116 ADR signals detected, of which 22 were not in the drug labels. Among the adverse drug event reports, 276 reports concerned dinutuximab/dinutuximab ß as primary suspected drugs with 90 ADR signals, involving 19 System Organ Classes, of which 21 signals were not in the label; 94 adverse drug event reports concerned naxitamab as the primary suspected drug with 26 ADR signals, involving 11 System Organ Classes, of which one was not in the label. For dinutuximab/dinutuximab ß-related ADRs, the top five most frequent were "fever", "abdominal pain", "elevated aspartate aminotransferase (AST)", "elevated alanine aminotransferase (ALT)" and "hypotension"; the top five most intensive signals were "hypoalbuminemia", "elevated AST", "capillary leakage syndrome", "hypoxia" and "elevated ALT". For naxitamab-related ADRs, the top five most frequent were "hypotension", "pain", "urticarial", "hypertension" and "rash"; the top five most intensive signals were "hypotension", "urticaria", "hypoxemia", "bronchospasm" and "hypertension". Involved System Organ Classes included "investigations" and "respiratory, thoracic and mediastinal disorders" containing the most types of ADR signals in dinutuximab/dintuximab ß-related ADRs and naxitamab-related ADRs, respectively. CONCLUSIONS: Our study comprehensively analyzed the toxicity profiles of anti-GD2 monoclonal antibodies and provides an important reference for clinical monitoring and ADR identification of these drugs.

A radiomics approach based on MR imaging for classification of deficiency and excess syndrome of traditional Chinese medicine in prostate cancer.

Objective: To explore the potential imaging biomarkers for predicting Traditional Chinese medicine (TCM) deficiency and excess syndrome in prostate cancer (PCa) patients by radiomics approach based on MR imaging. Methods: A total of 121 PCa patients from 2 centers were divided into 1 training cohort with 84 PCa patients and 1 validation cohort with 37 PCa patients. The PCa patients were divided into deficiency and excess syndrome group according to TCM syndrome differentiation. Radiomic features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging and apparent diffusion coefficient images originated from diffusion-weighted imaging. A radiomic signature was constructed after reduction of dimension in training group by the minimum redundancy maximum relevance and the least absolute shrinkage and selection operator. The performance of the model was evaluated by receiver operating characteristic (ROC) curve and calibration curve. Results: The radiomic scores of PCa with TCM excess syndrome group were statistically higher than those of PCa with TCM deficiency syndrome group among T2WI, diffusion-weighted imaging and apparent diffusion coefficient imaging models. The area under ROC curves for T2WI, diffusion-weighted imaging and apparent diffusion coefficient imaging models were 0.824, 0.824, 0.847 in the training cohort and 0.759, 0.750, 0.809 in the validation cohort, respectively. The apparent diffusion coefficient imaging model had the best discrimination in separating patients with TCM excess syndrome and deficiency syndrome, and its accuracy was 0.788, 0.778 in the training and validation cohort, respectively. The calibration curve demonstrated that there was a high consistency between the prediction of radiomic scores and the actual classification of TCM's deficiency and excess syndrome in PCa. Conclusion: The radiomic signature based on MR imaging can be performed as a non-invasive, potential approach to discriminate TCM deficiency syndrome from excess syndrome in PCa, in which apparent diffusion coefficient imaging model has the best diagnostic efficiency.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Disitamab Vedotin plus anti-PD-1 antibody show good efficacy in refractory primary urethral cancer with low HER2 expression: a case report.

Primary urethral carcinoma (PUC) has a low incidence, but with high aggressiveness. Most of the patients are found in late stage, with poor prognosis. At present, chemotherapy is still the main treatment for metastatic PUC, but it has limited effect. Here, we report a case of metastatic PUC with low HER2 expression that developed disease progression after multiline therapy including chemotherapy, programmed death-1 (PD-1) inhibitors and multi-targeted receptor tyrosine kinase (RTK) inhibitor. After receiving Disitamab Vedotin(a novel antibody drug conjugate, ADC) and toripalimab (a PD-1 inhibitor), the patient achieved persistent PR, and the PFS exceeded 12 months up to now. Our report indicates that, despite the patient of metastatic PUC has low expression of HER2, it is still possible to benefit from Disitamab Vedotin combined with PD-1 inhibitor, which may reverse the drug resistance of PD-1 inhibitor and chemotherapy to a certain extent. But larger sample studies are needed to determine the efficacy of this treatment strategy and its impact on survival.

Favorable response to PD-1 inhibitor plus chemotherapy as first-line treatment for metastatic follicular dendritic cell sarcoma of the spleen: a case report.

Follicular dendritic cell sarcoma (FDCS) is an uncommon low-grade malignant sarcoma. For localized FDCS, surgery is the most commonly recommended therapy option. However, there is no standard treatment protocol for metastatic FDCS. Here, we present a 68-year-old female with primary spleen FDCS who had multiple peritoneal metastases. She was treated with sintilimab (PD-1 inhibitor) plus chemotherapy (epirubicin plus ifosfamide) as first-line treatment achieving partial response (PR) and a relatively long progression-free survival (PFS) of 17 months. This case suggests that PD-1 inhibitor plus chemotherapy as first-line therapy seem to be a promising treatment option for metastatic FDCS.

[Application of 3D printing modified tooth-supported cyst plug in decompression of mandibular cystic lesions].

PURPOSE: To evaluate the application value of 3D printing modified dental support cyst plug in fenestration of large jaw cystic lesions. METHODS: Forty patients with mandibular cystic disease in Xuzhou Central Hospital from October 2019 to April 2021 were selected. They were randomly divided into experimental group(3D printing group) and control group (traditional plug group), with 20 cases in each group. All enrolled patients underwent preoperative digital modeling of cystic lesions of the jaw, obtained the cystic cavity volume data of preoperative lesions, designed the windowing site according to the plan and performed decompression for jaw cysts. Three days after surgery, the patient's postoperative CBCT and Oral-scan data in the experimental group was obtained, and a digitally modified tooth-supported cyst plug with porous column channel was designed, and titanium alloy material for 3D printing was selected. In the control group, the plug was manually molded by experienced physicians. The visual analogue scale(VAS) score of pain, retention, mechanical properties of the plug and its effect on the adjacent teeth were compared between the two groups during the process of model preparation, and the changes of the cyst volume 1, 3 and 6 months after operation were compared between the two groups. SPSS 25.0 software package was used for data analysis. RESULTS: Compared with the control group, the patients in the experimental group who made titanium alloy as printing material by digital impression complained more comfortable, and the mechanical strength and stability of the cyst plug were better than those in the control group(P＜0.05). There was no significant difference in retention between the two groups(P＞0.05). The reduction rate of cyst volume in the experimental group was significantly higher than that in the traditional plug group 3 and 6 months after operation(P＜0.05). CONCLUSIONS: The modified tooth-supported titanium alloy cyst plug with digital 3D printing has good mechanical properties and stability. It has little damage to the abutment and no lateral force, and has the advantages of precision, individualization and comfort. The improved irrigation and injection channel can fully flush the cavity and speed up the narrowing of the cyst and reduce the waiting time before the second operation, which is worth promoting in clinical practice.

Delineation of clinical target volume and organs at risk in cervical cancer radiotherapy by deep learning networks.

PURPOSE: Delineation of the clinical target volume (CTV) and organs-at-risk (OARs) is important in cervical cancer radiotherapy. But it is generally labor-intensive, time-consuming, and subjective. This paper proposes a parallel-path attention fusion network (PPAF-net) to overcome these disadvantages in the delineation task. METHODS: The PPAF-net utilizes both the texture and structure information of CTV and OARs by employing a U-Net network to capture the high-level texture information, and an up-sampling and down-sampling (USDS) network to capture the low-level structure information to accentuate the boundaries of CTV and OARs. Multi-level features extracted from both networks are then fused together through an attention module to generate the delineation result. RESULTS: The dataset contains 276 computed tomography (CT) scans of patients with cervical cancer of staging IB-IIA. The images are provided by the West China Hospital of Sichuan University. Simulation results demonstrate that PPAF-net performs favorably on the delineation of the CTV and OARs (e.g., rectum, bladder and etc.) and achieves the state-of-the-art delineation accuracy, respectively, for the CTV and OARs. In terms of the Dice Similarity Coefficient (DSC) and the Hausdorff Distance (HD), 88.61% and 2.25 cm for the CTV, 92.27% and 0.73 cm for the rectum, 96.74% and 0.68 cm for the bladder, 96.38% and 0.65 cm for the left kidney, 96.79% and 0.63 cm for the right kidney, 93.42% and 0.52 cm for the left femoral head, 93.69% and 0.51 cm for the right femoral head, 87.53% and 1.07 cm for the small intestine, and 91.50% and 0.84 cm for the spinal cord. CONCLUSIONS: The proposed automatic delineation network PPAF-net performs well on CTV and OARs segmentation tasks, which has great potential for reducing the burden of radiation oncologists and increasing the accuracy of delineation. In future, radiation oncologists from the West China Hospital of Sichuan University will further evaluate the results of network delineation, making this method helpful in clinical practice.

Distribution, enrichment mechanisms, and health risk assessment of high-fluorine groundwater in the Yudong Plain, Henan Province, China.

The Yudong Plain is in the eastern part of Henan Province, China, where there is little rain and high evaporation. Compared to other areas in Henan Province, the groundwater fluorine content is generally high, which affects the health of residents. Based on the systematic analysis of water chemistry data of shallow and mid-depth groundwater samples in the Yudong Plain, the causes of shallow and mid-depth high-fluorine groundwater in the Yudong Plain were explored using mathematical statistics, spatial interpolation, and ion ratios. The results show that the fluorine contents of both shallow and mid-depth groundwater in the study area are high. The shallow samples had fluorine contents ranging from 0.1 to 4.89 mg/L, with an exceedance rate of 48% and an average content of 1.15 mg/L. The fluorine content of mid-depth samples ranged from 0.14 to 3.32 mg/L, with an exceedance rate of 68% and an average content of 1.33 mg/L. The shallow high-fluorine groundwater is mainly distributed in the central low-lying area, and its main hydrochemical type is HCO3-Na·Mg; the mid-depth high-fluorine groundwater is mainly distributed in strips in the north and east of the study area, and its main water chemistry type is HCO3-Na. Fluorine enrichment in shallow groundwater in the study area is controlled by rock weathering, evaporation concentration, and competitive adsorption, while leaching and dissolution of fluorine-containing minerals in sedimentary strata are the main factors influencing fluorine enrichment in mid-depth groundwater. The results of the human health risk assessment (HRA) showed that the mean non-carcinogenic hazard quotients (HQs) in shallow groundwater were 0.95, 0.64, 0.57, and 0.55 for infants, children, teenagers, and adults, respectively, while the mean non-carcinogenic HQs in mid-depth groundwater were 1.11, 0.74, 0.66, and 0.63, respectively. The study provides a scientific basis for the rational development and use of groundwater in the area and offers theoretical support for the prevention and control of groundwater pollution.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFß activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFß kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

Stuttering as a signal of encephalopathy associated with toripalimab in a pancreatic ductal adenocarcinoma patient: a case report.

BACKGROUND: Immune checkpoint inhibitor (ICI) combined with chemotherapy has exhibited promising results in small sample studies of pancreatic cancer patients. The efficacy of toripalimab, a programmed cell death protein 1 (PD-1) monoclonal antibody has been explored in the previous studies and it was established that immune-related adverse events (irAEs) associated with administration of this drug deserve proper attention and adequate management. CASE PRESENTATION: A 43-year-old female patient with advanced pancreatic ductal adenocarcinoma (PDAC) was treated with toripalimab in combination with gemcitabine and nab-paclitaxel (T-GA) as the first-line treatment. She developed immune-related encephalopathy with stuttering as the main clinical symptom and Magnetic resonance imaging (MRI) showed multiple cerebral white matter demyelination changes, concomitant with asymptomatic cardiac enzyme elevation and hypothyroidism. The symptoms resolved after the discontinuation of toripalimab and corticosteroid treatment. CONCLUSIONS: Stuttering might be an early sign of neurotoxicity which can be easily neglected during the treatment. These findings provide guidance for the identification of these rare and occult neurological irAEs (n-irAEs) in the clinical practice.

Multidisciplinary Team (MDT) Discussion Improves Overall Survival Outcomes for Metastatic Renal Cell Carcinoma Patients.

Purpose: Multidisciplinary team (MDT) discussion is a widely used model to manage patients diagnosed with cancer. However, there has been no direct evidence to prove its effect on the prognosis of metastatic renal cell carcinoma (mRCC) patients, so this study explored the impact of MDT discussion on mRCC patient survival. Methods: The clinical data of 269 mRCC patients were retrospectively collected from 2012 to 2021. The cases were grouped into the MDT and non-MDT groups, then subgroup analysis was performed according to different histology types, as well as exploring the role of MDT in patients who have undergone multiple-line therapy. Overall survival (OS) and progression free survival (PFS) were set as the study endpoint. Results: Approximately half (48.0%, 129/269) of the patients were in the MDT group, with univariable survival analyses showing these patients had remarkably longer median OS (MDT group: 73.7 months; non-MDT group: 33.2 months, hazard ratio (HR): 0.423 (0.288, 0.622), p<0.001) and longer median PFS (MDT group: 16.9 months, non-MDT group: 12.7 months, HR: 0.722 (0.542, 0.962), p=0.026). Furthermore, MDT management resulted in longer survival for both ccRCC and non-ccRCC subgroups. Patients in the MDT group were more likely to receive multi-line therapy (MDT group: 79/129, 61.2% vs non-MDT group: 56/140, 40.0%, p<0.001), and within this patient group, MDT management still resulted in longer OS (MDT group: 94.0 months; non-MDT group: 43.5 months, p=0.009). Conclusion: MDT is associated with prolonged overall survival in mRCC independent of histology, ensuring that patients receive better management and precise treatment.

A lifetime economic research of universal HLA-B*58:01 genotyping or febuxostat initiation therapy in Chinese gout patients with mild to moderate chronic kidney disease.

OBJECTIVE: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system. METHODS: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed. RESULTS: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results. CONCLUSION: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFb activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFb kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.