TG468: a text graph convolutional network for predicting clinical response to immune checkpoint inhibitor therapy.

Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468's prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model's predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data.

Siderophore-harboring gut bacteria and fecal siderophore genes for predicting the responsiveness of fecal microbiota transplantation for active ulcerative colitis.

BACKGROUND: Predictive markers for fecal microbiota transplantation (FMT) outcomes in patients with active ulcerative colitis (UC) are poorly defined. We aimed to investigate changes in gut microbiota pre- and post-FMT and to assess the potential value in determining the total copy number of fecal bacterial siderophore genes in predicting FMT responsiveness. METHODS: Patients with active UC (Mayo score ≥ 3) who had undergone two FMT procedures were enrolled. Fecal samples were collected before and 8 weeks after each FMT session. Patients were classified into clinical response and non-response groups, based on their Mayo scores. The fecal microbiota profile was accessed using metagenomic sequencing, and the total siderophore genes copy number via quantitative real-time polymerase chain reaction. Additionally, we examined the association between the total siderophore genes copy number and FMT efficacy. RESULTS: Seventy patients with UC had undergone FMT. The clinical response and remission rates were 50% and 10% after the first FMT procedure, increasing to 72.41% and 27.59% after the second FMT. The cumulative clinical response and clinical remission rates were 72.86% and 25.71%. Compared with baseline, the response group showed a significant increase in Faecalibacterium, and decrease in Enterobacteriaceae, consisted with the changes of the total bacterial siderophore genes copy number after the second FMT (1889.14 vs. 98.73 copies/ng, P < 0.01). Virulence factor analysis showed an enriched iron uptake system, especially bacterial siderophores, in the pre-FMT response group, with a greater contribution from Escherichia coli. The total baseline copy number was significantly higher in the response group than non-response group (1889.14 vs. 94.86 copies/ng, P < 0.01). A total baseline copy number cutoff value of 755.88 copies/ng showed 94.7% specificity and 72.5% sensitivity in predicting FMT responsiveness. CONCLUSIONS: A significant increase in Faecalibacterium, and decrease in Enterobacteriaceae and the total fecal siderophore genes copy number were observed in responders after FMT. The siderophore genes and its encoding bacteria may be of predictive value for the clinical responsiveness of FMT to active ulcerative colitis.

Economic Evaluation of 'Watch and Wait' Following Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review.

BACKGROUND: Owing to multimodal treatment and complex surgery, locally advanced rectal cancer (LARC) exerts a large healthcare burden. Watch and wait (W&W) may be cost saving by removing the need for surgery and inpatient care. This systematic review seeks to identify the economic impact of W&W, compared with standard care, in patients achieving a complete clinical response (cCR) following neoadjuvant therapy for LARC. METHODS: The PubMed, OVID Medline, OVID Embase, and Cochrane CENTRAL databases were systematically searched from inception to 26 April 2024. All economic evaluations (EEs) that compared W&W with standard care were included. Reporting and methodological quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), BMJ and Philips checklists. Narrative synthesis was performed. Primary and secondary outcomes were (incremental) cost-effectiveness ratios and the net financial cost. RESULTS: Of 1548 studies identified, 27 were assessed for full-text eligibility and 12 studies from eight countries (2016-2024) were included. Seven cost-effectiveness analyses (complete EEs) and five cost analyses (partial EEs) utilized model-based (n = 7) or trial-based (n = 5) analytics with significant variations in methodological design and reporting quality. W&W showed consistent cost effectiveness (n = 7) and cost saving (n = 12) compared with surgery from third-party payer and patient perspectives. Critical parameters identified by uncertainty analysis were rates of local and distant recurrence in W&W, salvage surgery, perioperative mortality and utilities assigned to W&W and surgery. CONCLUSION: Despite heterogenous methodological design and reporting quality, W&W is likely to be cost effective and cost saving compared with standard care following cCR in LARC. Clinical Trials Registration PROSPERO CRD42024513874.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Identifying the Best Initial Oral Antibiotics for Adults with Community-Acquired Pneumonia: A Network Meta-Analysis.

BACKGROUND: The objective of this network meta-analysis was to compare rates of clinical response and mortality for empiric oral antibiotic regimens in adults with mild-moderate community-acquired pneumonia (CAP). METHODS: We searched PubMed, Cochrane, and the reference lists of systematic reviews and clinical guidelines. We included randomized trials of adults with radiologically confirmed mild to moderate CAP initially treated orally and reporting clinical cure or mortality. Abstracts and studies were reviewed in parallel for inclusion in the analysis and for data abstraction. We performed separate analyses by antibiotic medications and antibiotic classes and present the results through network diagrams and forest plots sorted by p-scores. We assessed the quality of each study using the Cochrane Risk of Bias framework, as well as global and local inconsistency. RESULTS: We identified 24 studies with 9361 patients: six at low risk of bias, six at unclear risk, and 12 at high risk. Nemonoxacin, levofloxacin, and telithromycin were most likely to achieve clinical response (p-score 0.79, 0.71, and 0.69 respectively), while penicillin and amoxicillin were least likely to achieve clinical response. Levofloxacin, nemonoxacin, azithromycin, and amoxicillin-clavulanate were most likely to be associated with lower mortality (p-score 0.85, 0.75, 0.74, and 0.68 respectively). By antibiotic class, quinolones and macrolides were most effective for clinical response (0.71 and 0.70 respectively), with amoxicillin-clavulanate plus macrolides and beta-lactams being less effective (p-score 0.11 and 0.22). Quinolones were most likely to be associated with lower mortality (0.63). All confidence intervals were broad and partially overlapping. CONCLUSION: We observed trends toward a better clinical response and lower mortality for quinolones as empiric antibiotics for CAP, but found no conclusive evidence of any antibiotic being clearly more effective than another. More trials are needed to inform guideline recommendations on the most effective antibiotic regimens for outpatients with mild to moderate CAP.

CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types.

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

Prediction of Clinical Response to Dupilumab in Patients with Severe Asthma Using Fractional Exhaled Nitric Oxide Combined with Pulmonary Function Testing.

INTRODUCTION: This study aimed to assess the effectiveness of fractional exhaled nitric oxide (FeNO) combined with pulmonary function testing (PFT) for predicting the treatment outcome of patients with severe asthma receiving dupilumab. METHODS: A total of 31 patients with severe asthma visiting our hospital from January 2022 to June 2023 were included in this study, with 28 patients completing a 16-week course of dupilumab treatment. Baseline clinical data, including demographic information, blood eosinophil counts, serum IgE levels, FeNO, asthma control test (ACT), asthma control questionnaire (ACQ), and other parameters, were collected. A predictive model using a generalized linear model was established. RESULTS: Following the 16-week course of dupilumab treatment, 22 patients showed effective response based on GETE scores, while 6 patients were nonresponders. Notably, significant improvements were observed in clinical parameters such as blood eosinophil counts, serum IgE levels, FeNO, FEV1, FEV1%, ACT, and ACQ in both response groups (p < 0.05). FeNO and pulmonary function tests demonstrated AUC values of 0.530, 0.561, and 0.765, respectively, in predicting the clinical efficacy of dupilumab, which were lower than when FeNO was combined with FEV1%. The combination of FeNO and FEV1% had a sensitivity of 1.000 and specificity of 0.591 in predicting treatment response. CONCLUSION: The combined assessment of FeNO and FEV1% provides improved accuracy for predicting the clinical efficacy of dupilumab in managing severe asthma. However, further larger scale clinical studies with comprehensive follow-up data are needed to validate the therapeutic efficacy and applicability across diverse patient populations.

Thiamine deficiency-related neuropathy: A reversible entity from an endemic area.

BACKGROUND AND PURPOSE: Despite thiamine deficiency being a lesser-known entity in modern times, beriberi in various forms, including thiamine deficiency-related neuropathy, remains endemic in Kashmir due to the consumption of polished rice as a staple food. This observational study investigates cases of peripheral neuropathy of unknown etiology and their potential responsiveness to thiamine administration. METHODS: This prospective study enrolled adult patients presenting to the emergency department with weakness consistent with thiamine deficiency-related neuropathy and conducted a therapeutic challenge with thiamine on 41 patients. Response to thiamine therapy was monitored based on subjective and objective improvements in weakness and power. Patients were divided into thiamine responders (n = 25) and nonresponders (n = 16) based on their response to thiamine therapy and nerve conduction studies. RESULTS: Most of the baseline characteristics were similar between responders and nonresponders, except the responders exhibited lower thiamine levels and higher partial pressure of oxygen and lactate levels compared to nonresponders. All patients had a history of consuming polished rice and traditional salt tea. Although weakness in the lower limbs was present in both groups, nonresponders were more likely to exhibit weakness in all four limbs. Clinical improvement was observed within 24 h, but proximal muscle weakness persisted for an extended period of time. CONCLUSIONS: Thiamine deficiency-related neuropathy presents with predominant lower limb weakness, exacerbated by vomiting, poor food intake, psychiatric illness, and pregnancy. Thiamine challenge should be followed by observation of clinical and biochemical response.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Efficacy and safety of low-dose Interleukin-2 in the treatment of moderate to severe bullous pemphigoid: a single center perspective-controlled trial.

BACKGROUND: Regulatory T cells (Tregs) are reduced in the peripheral blood and skin lesions of bullous pemphigoid (BP) patients. Low-dose IL-2 therapy can stimulate Tregs specifically, suggesting potential for the treatment of BP. OBJECTIVE: To evaluate the response to low-dose IL-2 therapy in the treatment of moderate to severe BP. METHODS: 43 patients with moderate to severe BP were included. The therapy included systemic corticosteroids with initial dose of 0.5mg/kg/d for moderate and 1.0mg/kg/d for severe disease respectively, combined with allowed immunosuppressants for control group, while in addition to the same corticosteroids therapy, IL-2 (half million IU) was administered subcutaneously every other day for treatment group for 8 weeks. The primary outcome was the number of days required to achieve disease control. Secondary outcomes included other clinical responses. RESULTS: The number of days required to achieve disease control with treatment group was (7.60±3.00), which was shorter than in the control group (10.43±3.06) (p=0.008). The total amount of systemic corticosteroids was less and no serious infections were detected in the treatment group. LIMITATIONS: Single center, open-label study with short duration and small size. CONCLUSION: Our trial supports the potential of low-dose IL-2 therapy for patients with moderate to severe BP, which showed earlier treatment responses.

Daratumumab in Indian patients with relapsed and refractory multiple myeloma: a prospective, multicenter, phase IV study.

Aim: To assess the safety and effectiveness of daratumumab monotherapy in Indian patients with relapsed/refractory multiple myeloma. Methods: In this prospective, multicenter, phase IV study, patients (aged ≥18 years) received intravenous daratumumab (16 mg/kg) in six cycles. Safety was the primary end point. Results: Of the 139 patients included, 121 (87.1%) experienced ≥1 treatment-emergent adverse events (TEAEs; 53 [38.1%] drug-related), 32 (23%) had ≥1 serious TEAEs (five [3.6%] drug-related) and 16 (11.5%) deaths were reported (one death [0.7%] was drug-related). Overall response rate was 26.3%; 62.7% of patients had stable disease. Median time to first response and median progression-free survival were 5.2 and 5.9 months, respectively. Functional status and well-being were improved. Conclusion: Daratumumab showed an acceptable and expected safety profile with consistent efficacy, providing a novel therapeutic option for relapsed/refractory multiple myeloma management in India.

Daratumumab is a monoclonal antibody approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). This study evaluated the outcome of daratumumab single therapy in Indian patients who were not cured with other drugs used for the same disease. 139 adult patients were included in this study from 15 institutes across India. Daratumumab (16 mg/kg) was diluted with 500 or 1000 ml of saline solution and given slowly through the intravenous route 16-times within 6 months. The study examined whether the safety profile and benefits of daratumumab reported in Indian patients were similar to those reported in the RRMM populations of other countries. The study found that most of the adverse events were not severe and could be easily treated by the study physician. 16 patients died (one might have been due to daratumumab treatment). Daratumumab treatment provided life support and recovery benefits to many patients. Daratumumab single therapy provides an appropriate and acceptable safety profile with no new adverse events and consistent benefits in RRMM patients. Clinical Trial Registration: NCT03768960 (ClinicalTrials.gov), CTRI/2019/06/019546.

Nonoperative management protocol for locally advanced rectal cancer.

AIM: The standard treatment for low rectal cancer is preoperative chemoradiotherapy followed by surgery with low anterior resection with diverting ileostomy or abdominoperineal resection, both of which have significant long-term effects on bowel and sexual function. Due to the high morbidity of surgery, there has been increasing interest in nonoperative management for low rectal cancer. The aim of this work is to conduct a pan-Canadian Phase II trial assessing the safety of nonoperative management for low rectal cancer. METHOD: Patients with Stage II or III low rectal cancer completing chemoradiotherapy according to standard of care at participating centres will be assessed for complete clinical response 8-14 weeks following completion of chemoradiotherapy. Subjects achieving a clinical complete response will undergo active surveillance including endoscopy, imaging and bloodwork at regular intervals for 24 months. The primary outcome will be the rate of local regrowth 2 years after chemoradiotherapy. Nonoperative management will be considered safe (i.e. as effective as surgery to achieve local control) if the rate of local regrowth is ≤30% and surgical salvage is possible for all local regrowths. Secondary outcomes will include disease-free and overall survival. CONCLUSION: The results will be highly clinically relevant, as it is expected that nonoperative management will be safe and lead to widespread adoption of nonoperative management in Canada. This change in practice has the potential to decrease the number of patients requiring surgery and the costs associated with surgery and long-term surgical morbidity.

Low energy contact X-ray brachytherapy for treatment of rectal cancer: a health technology appraisal by Health Technology Wales.

AIM: Health Technology Wales sought to evaluate the clinical and cost-effectiveness of contact X-ray brachytherapy (CXB) for early-stage rectal cancer. METHODS: Relevant studies were identified through systematic searches of MEDLINE, Embase, Cochrane Library and Scopus. A cost-utility model was developed to estimate the cost-effectiveness of CXB in National Health Service Wales, using results of the Organ Preservation in Early Rectal Adenocarcinoma (OPERA) trial. Patient perspectives were obtained through the Papillon Patient Support group and All-Wales Cancer Network. RESULTS: The OPERA randomized controlled trial showed that CXB improved complete response and organ preservation rates compared with external-beam boost for people with T2-3b, N0-1, M0 rectal cancer who are fit for surgery. Managing more of this population non-operatively after CXB was estimated to provide 0.2 quality-adjusted life years at an additional cost of £887 per person. CXB was cost effective compared with external-beam boost at a cost of £4463 per quality-adjusted life year gained. This conclusion did not change in scenario analysis and CXB was cost effective in 91% of probabilistic sensitivity analyses. Patients valued receiving clear information on all available options to support their individual treatment choices. The detrimental impact of a stoma on quality of life led some patients to reject the idea that surgery was their only option. CONCLUSION: This evidence review and cost-utility analysis indicates that CXB is likely to be clinically and cost effective, as part of a watch and wait strategy for adults fit for surgery. Wider access to CXB is supported by patient testimonies.

Investigation of colistin utilization in the treatment of multidrug-resistant gram-negative nosocomial bloodstream infections in children and literature review.

This retrospective study aimed to assess the effectiveness and safety of colistin used in combination therapy for treating nosocomial bloodstream infections caused by multi-drug resistant gram-negative pathogens in pediatric patients. Patients aged between 1 month and 18 years consecutively hospitalized with healthcare-associated bloodstream infections necessitating the administration of intravenous colistin at Dr. Sami Ulus Training and Research Hospital between January 2015 and January 2020 were included in the study. Patient-specific detailed clinical information, prognoses, and laboratory findings on days 1, 3, and 7 of colistin treatment were obtained from medical records. The study included 45 pediatric patients receiving intravenous colistin; 26 (57.8%) were male and 19 (42.2%) were female, with a median age of 18 months. While the clinical response was observed at 82.2% and microbiological response at 91.1% with colistin treatment, two patients (4.4%) discontinued treatment due to side effects without assessing treatment response. The most common adverse effect associated with the use of colistin was nephrotoxicity, which occurred in eight patients (17.8%). Among these patients, only one had pre-existing chronic kidney failure.    Conclusion: Colistin used in combination therapy may be effective and safe for treating nosocomial infections caused by multi-drug resistant gram-negative bacteria in pediatric patients, who often have high mortality rates and limited treatment options. What is Known: • Colistin is an antibacterial agent used in the treatment of infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) and is associated with significant adverse effects such as nephrotoxicity. • The increasing prevalence of hospital-acquired infections has led to the expanded use of colistin in clinical practice. What is New: • The study demonstrates a high clinical and microbiological response rate to combination therapy with colistin in the treatment of infections caused by MDR-GNB. • The study highlights the importance of monitoring nephrotoxicity in pediatric patients receiving colistin, showing that these effects can be reversible after treatment cessation.

One-Anastomosis Gastric Bypass (OABG) vs. Single Anastomosis Duodeno-Ileal Bypass (SADI) as revisional procedure following Sleeve Gastrectomy: results of a multicenter study.

PURPOSE: Sleeve Gastrectomy (SG) is the most performed bariatric surgery, but a considerable number of patients may require revisional procedures for suboptimal clinical response/recurrence of weight (SCR/RoW). Conversion options include One-Anastomosis Gastric Bypass (OAGB) and Single Anastomosis Duodeno-Ileal Bypass (SADI). The study aims to compare SADI vs. OAGB as revisional procedures in terms of early and mid-term complications, operative time, postoperative hospital stay and clinical outcomes. METHODS: All patients who underwent OAGB or SADI as revisional procedures following SG for SCR/RoW at three high-volume bariatric centers between January 2014 and April 2021 were included. Propensity score matching (PSM) analysis was performed. Demographic, operative, and postoperative outcomes of the two groups were compared. RESULTS: One hundred and sixty-eight patients were identified. After PSM, the two groups included 42 OAGB and 42 SADI patients. Early (≤ 30 days) postoperative complications rate did not differ significantly between OAGB and SADI groups (3 bleedings vs. 0, p = 0.241). Mid-term (within 2 years) complications rate was significantly higher in the OAGB group (21.4% vs. 2.4%, p = 0.007), mainly anastomotic complications and reflux disease (12% of OAGBs). Seven OAGB patients required conversion to another procedure (Roux-en-Y Gastric Bypass-RYGB) vs. none among the SADI patients (p = 0.006). CONCLUSIONS: SADI and OAGB are both effective as revisional procedures for SCR/RoW after SG. OAGB is associated with a significantly higher rate of mid-term complications and a not negligible rate of conversion (RYGB). Larger studies are necessary to draw definitive conclusions.

Serum Cell Division Cycle 42 before and after Programmed Death-1 Inhibitor Therapy in Advanced Melanoma Patients: Correlation with Tumor Features, Clinical Response, and Survival.

Cell division cycle 42 (CDC42) mediates immune escape in cancers. This study aimed to investigate linkages of CDC42 with tumor features, treatment response, and survival in advanced melanoma patients receiving programmed death-1 (PD-1) inhibitors. Pre-treatment and post-treatment (after 2 cycles) serum CDC42 of 35 advanced melanoma patients receiving PD-1 inhibitor was assessed by enzyme-linked immunosorbent assay. Patients with tumor-node-metastasis (TNM) stage IV (vs. III) (P = 0.050) and abnormal (vs. normal) lactate dehydrogenase (LDH) (P = 0.022) had higher pre-treatment CDC42. After 2-cycle therapy, CDC42 was declined (P < 0.001). Objective response and disease control rates were 34.3% and 62.9%, respectively. Additionally, pre-treatment and post-treatment CDC42 was reduced in patients with objective response and disease control than those without (all P < 0.050). Concerning survival, pre-treatment with CDC42 > 700 pg/mL was associated with shorter progression-free survival (PFS) (P = 0.013), but not overall survival (OS) (P = 0.060). Specifically, the 12-month PFS rate was 26.7% and 66.2%, and the 12-month OS rate was 61.1% and 82.5% in patients with pre-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, respectively. Post-treatment with CDC42 > 700 pg/mL was correlated with shortened PFS (P = 0.010) and OS (P = 0.006). The 12-month PFS rate was 12.5% and 62.0%, and the 12-month OS rate was 42.3% and 88.0% in patients with post-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, accordingly. Furthermore, post-treatment with CDC42 > 700 pg/mL was independently related to PFS [hazard ratio (HR): 2.704, P = 0.029 and OS (HR: 7.749, P = 0.005)]. Elevated CDC42 correlates with advanced TNM, abnormal LDH, worse clinical response, and dismal survival in advanced melanoma patients receiving PD-1 inhibitors.

Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in patients with PNH and impaired bone marrow function in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. For patients with impaired bone marrow function, defined herein as haemoglobin <10 g/dL and absolute neutrophil count <1.5 × 109 cells/L, normalisation of the parameters may be difficult. Indeed, 20% and 43% had normalised haemoglobin in PEGASUS and PRINCE, respectively; 60% and 57% had normalised LDH, and 40% and 29% had normalised fatigue scores. A new set of parameters was applied using changes associated with clinically meaningful improvements, namely an increase in haemoglobin to ≥2 g/dL above baseline, decrease in LDH to ≤1.5× the upper limit of normal, and an increase in fatigue scores to ≥5 points above baseline. With these new parameters, 40% and 71% of PEGASUS and PRINCE patients had improved haemoglobin; 60% and 71% had an improvement in LDH, and 60% and 43% had an improvement in fatigue scores. Thus, even patients with impaired bone marrow function may achieve clinically meaningful improvements with pegcetacoplan.

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.

The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10-8; beta*15 = 0.03 mmol/L, p = 3 × 10-4), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.

[A unicenter real-world study of the correlation factors for complete clinical response in idiopathic inflammatory myopathies].

OBJECTIVE: To investigate the correlation factors of complete clinical response in idiopathic inflammatory myopathies (IIMs) patients receiving conventional treatment. METHODS: Patients diagnosed with IIMs hospitalized in Peking University People's Hospital from January 2000 to June 2023 were included. The correlation factors of complete clinical response to conventional treatment were identified by analyzing the clinical characteristics, laboratory features, peripheral blood lymphocytes, immunological indicators, and therapeutic drugs. RESULTS: Among the 635 patients included, 518 patients finished the follow-up, with an average time of 36.8 months. The total complete clinical response rate of IIMs was 50.0% (259/518). The complete clinical response rate of dermatomyositis (DM), anti-synthetase syndrome (ASS) and immune-mediated necrotizing myopathy (IMNM) were 53.5%, 48.9% and 39.0%, respectively. Fever (P=0.002) and rapid progressive interstitial lung disease (RP-ILD) (P=0.014) were observed much more frequently in non-complete clinical response group than in complete clinical response group. The aspartate transaminase (AST), lactate dehydrogenase (LDH), D-dimer, erythrocyte sedimentation rate (ESR), C-reaction protein (CRP) and serum ferritin were significantly higher in non-complete clinical response group as compared with complete clinical response group. As for the treatment, the percentage of glucocorticoid received and intravenous immunoglobin (IVIG) were significantly higher in non-complete clinical response group than in complete clinical response group. Risk factor analysis showed that IMNM subtype (P=0.007), interstitial lung disease (ILD) (P=0.001), eleva-ted AST (P=0.012), elevated serum ferritin (P=0.016) and decreased count of CD4+T cells in peripheral blood (P=0.004) might be the risk factors for IIMs non-complete clinical response. CONCLUSION: The total complete clinical response rate of IIMs is low, especially for IMNM subtype. More effective intervention should be administered to patients with ILD, elevated AST, elevated serum ferritin or decreased count of CD4+T cells at disease onset.

The Efficacy and Safety of Endoscopic Balloon Dilatation in the Treatment of Functional Post-Sleeve-Gastrectomy Stenosis.

Background and Objectives: Functional gastric stenosis, a consequence of sleeve gastrectomy, is defined as a rotation of the gastric tube along its longitudinal axis. It is brought on by gastric twisting without the anatomical constriction of the gastric lumen. During endoscopic examination, the staple line is deviated with a clockwise rotation, and the stenosis requires additional endoscopic manipulations for its transposition. Upper gastrointestinal series show the gastric twist with an upstream dilatation of the gastric tube in some patients. Data on its management have remained scarce. The objective was to assess the efficacy and safety of endoscopic balloon dilatation in the management of functional post-sleeve gastrectomy stenosis. Patients and Methods: Twenty-two patients with functional post-primary-sleeve-gastrectomy stenosis who had an endoscopic balloon dilatation between 2017 and 2023 were included in this retrospective study. Patients with alternative treatment plans and those undergoing endoscopic dilatation for other forms of gastric stenosis were excluded. The clinical outcomes were used to evaluate the efficacy and safety of balloon dilatation in the management of functional gastric stenosis. Results: A total of 45 dilatations were performed with a 30 mm balloon in 22 patients (100%), a 35 mm balloon in 18 patients (81.82%), and a 40 mm balloon in 5 patients (22.73%). The patients' clinical responses after the first balloon dilatation were a complete clinical response (4 patients, 18.18%), a partial clinical response (12 patients, 54.55%), and a non-response (6 patients, 27.27%). Nineteen patients (86.36%) had achieved clinical success at six months. Three patients (13.64%) who remained symptomatic even after achieving the maximal balloon dilation of 40 mm were considered failure of endoscopic dilatation, and they were referred for surgical intervention. No significant adverse events were found during or following the balloon dilatation. Conclusions: Endoscopic balloon dilatation is an effective and safe minimally invasive procedure in the management of functional post-sleeve-gastrectomy stenosis.