Organ and function preservation in gastrointestinal cancer: Current and future perspectives on endoscopic ablation.

The escalating prevalence of gastrointestinal cancers underscores the urgency for transformative approaches. Current treatment costs amount to billions of dollars annually, combined with the risks and comorbidities associated with invasive surgery. This highlights the importance of less invasive alternatives with organ preservation being a central aspect of the treatment paradigm. The current standard of care typically involves neoadjuvant systemic therapy followed by surgical resection. There is a growing interest in organ preservation approaches by way of minimizing extensive surgical resections. Endoscopic ablation has proven to be useful in precursor lesions, as well as in palliative cases of unresectable disease. More recently, there has been an increase in reports on the utility of adjunct endoscopic ablative techniques for downstaging disease as well as contributing to non-surgical complete clinical response. This expansive field within endoscopic oncology holds great potential for advancing patient care. By addressing challenges, fostering collaboration, and embracing technological advancements, the gastrointestinal cancer treatment paradigm can shift towards a more sustainable and patient-centric future emphasizing organ and function preservation. This editorial examines the evolving landscape of endoscopic ablation strategies, emphasizing their potential to improve patient outcomes. We briefly review current applications of endoscopic ablation in the esophagus, stomach, duodenum, pancreas, bile ducts, and colon.

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.

Complete clinical response to chemoradiation in adenoid cystic carcinoma of the base of tongue: Case report of a rare tumor in a rare location.

Key Clinical Message: Adenoid cystic carcinoma (ACC) is an uncommon malignancy of head and neck. Although the cornerstone of treatment is surgery, concurrent chemoradiotherapy (CRT) might be used as an effective treatment for unresectable tumors. Herein we report a case of massive ACC of base of tongue with durable complete response to definitive CRT. Abstract: Adenoid cystic carcinoma (ACC) is a rare tumor accounting for 1% of all head and neck cancers. The best treatment option is complete surgical resection with or without adjuvant radiotherapy. When surgical resection is not feasible, definitive radiotherapy with or without concurrent chemotherapy can be considered. Herein we report a non-smoker 72-year-old woman presented with throat discomfort and sensation of a lump. Evaluation revealed an unresectable adenoid cystic carcinoma of the base of tongue in whom complete clinical response was achieved after definitive concurrent chemoradiation. Although the cornerstone of treatment is complete surgical resection, this case report indicates that concurrent chemoradiotherapy might result in complete clinical response and could be used as a definitive treatment in selected ACC tumors.

Clinical Predictors of Bacteremia Outcome After Initial Empirical Antimicrobial Therapy in Patients with Hematological Malignancies: A Retrospective Analysis.

Objective: We performed a retrospective analysis to investigate the clinical predictors of bacteremia outcome involving Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) after initial empirical antimicrobial therapy among hematological malignancy cases. Methods: This retrospective study was conducted between April 2018 and April 2023. All bloodstream infections (BSIs) caused by E. coli and K. pneumoniae in hospitalized hematological malignancy (HM) patients were identified. Data on patient demographics, clinical characteristics, empirical antimicrobial treatment, outcomes and the antimicrobial susceptibility were collected from medical records. Multivariate analyses were utilized to assess the risk factors for all-cause mortality within 28 days and carbapenem resistance. Optimal cutoffs for continuous predictive variables were evaluated by receiver operating characteristic (ROC) curve analysis. Results: Among 61 individuals diagnosed with bacteremia, 39 cases were caused by E. coli bacteremia, while the remaining 22 were identified as K. pneumoniae bacteremia. Out of these, there were 10 cases of carbapenem-resistant Enterobacteriaceae (CRE) and 12 cases resulted in all-cause mortality within 28 days. Analysis indicated that Pitt score was an independent risk factor for mortality and a cut-off of 2.5 was a reliable predictor with 83.3% sensitivity and 85.7% specificity, respectively. Impaired mental status and elevated body temperature exceeding 38.6°C as well as a procalcitonin (PCT) level over 8.24 ng/mL on the third day (d3) after antimicrobial treatment were identified as independent risk factors for predicting carbapenem resistance. Conclusion: We found that Pitt score with a cut-off of 2.5 was a reliable predictor for mortality within 28 days in HM bacteremia cases. Impaired mental status and elevated temperature exceeding 38.6°C as well as a procalcitonin (PCT) level over 8.24 ng/mL on d3 after antimicrobial treatment were identified as predictive risk factors to carbapenem resistance.

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.

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.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

BACKGROUND: Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. OBJECTIVE: The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. METHOD: Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. RESULTS: During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. CONCLUSIONS: The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

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.

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.

Personalized medicine for locally advanced rectal cancer: five years of complete clinical response after neoadjuvant radiochemotherapy-a case report with a literature review.

We present a case report of a 73-year-old male patient with a complete clinical response following neoadjuvant radiochemotherapy of mid-rectal adenocarcinoma. The patient was initially diagnosed with stage IIIB microsatellite stable mid-rectal adenocarcinoma in February 2017. During restaging in June 2017, which included rectoscopy, endosonography, computed tomography and magnetic resonance imaging, a complete clinical response was observed. After appropriate consultation, a watch-and-wait strategy was chosen. During stringent follow-up every 3 months for the first 3 years and thereafter every 6 months, no recurrence or regrowth was observed. After the fifth year of complete clinical response, we recommended an annual follow-up. As of November 2023, the patient has no signs of recurrence or late toxicity after radiochemotherapy. The omission of resection in patients with locally advanced rectal cancer and the establishment of a watch-and-wait strategy are currently under discussion as possible treatment courses in patients with complete clinical response. Long-term data on watch-and-wait strategies for patients with a complete clinical response in locally advanced rectal cancer are rare. A clear national and international accepted standardization of follow-up programs for patients managed by a watch-and-wait strategy in the long-term is missing. Here, we report the case of a patient who had undergone a follow-up program for more than five years and discuss the current literature. Our case report and literature review highlights that a watch-and-wait strategy does not seem to increase the risk of systemic disease or compromise survival outcomes in selected locally advanced rectal cancer patients. Thus, our case contributes to the growing body of knowledge on personalized and precision medicine for rectal cancer.

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.

[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.

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.

Patients with complete clinical response after neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: A Markov decision analysis of esophagectomy versus active surveillance.

OBJECTIVE: Chemoradiation followed by esophagectomy is a standard treatment option for patients with locally advanced esophageal cancer (LAEC). Esophagectomy is a high-risk procedure, and recent evidence suggests select patients may benefit from omitting or delaying surgery. This study aims to compare surgery versus active surveillance for LAEC patients with complete clinical response (cCR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: Decision analysis with Markov modeling was used. The base case was a 60-year-old man with T3N0M0 esophageal cancer with cCR after nCRT. The decision was modeled for a 5-year time horizon. Primary outcomes were life-years and quality-adjusted life-years (QALY). Probabilities and utilities were derived through the literature. Deterministic sensitivity analyses were performed using ranges from the literature with consideration for clinical plausibility. RESULTS: Surgery was favored for survival with an expected life-years of 2.89 versus 2.64. After incorporating quality of life, active surveillance was favored, with an expected QALY of 1.70 versus 1.56. The model was sensitive to probability of recurrence on active surveillance (threshold value 0.598), probability of recurrence being resectable (0.318), and disutility of previous esophagectomy (-0.091). The model was not sensitive to perioperative morbidity and mortality. CONCLUSIONS: Our study finds that surgery increases life expectancy but decreases QALY. Although the incremental change in QALY for either modality is insufficient to make broad clinical recommendations, our study demonstrates that either approach is acceptable. As probabilities of key factors are further defined in the literature, treatment decisions for patients with LAEC and a cCR after nCRT should consider histology, patient values, and quality of life.

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.

When to Stop Antibiotics in the Critically Ill?

Over the past century, antibiotic usage has skyrocketed in the treatment of critically ill patients. There have been increasing calls to establish guidelines for appropriate treatment and durations of antibiosis. Antibiotic treatment, even when appropriately tailored to the patient and infection, is not without cost. Short term risks-hepatic/renal dysfunction, intermediate effects-concomitant superinfections, and long-term risks-potentiating antimicrobial resistance (AMR), are all possible consequences of antimicrobial administration. These risks are increased by longer periods of treatment and unnecessarily broad treatment courses. Recently, the literature has focused on multiple strategies to determine the appropriate duration of antimicrobial therapy. Further, there is a clinical shift to multi-modal approaches to determine the most suitable timepoint at which to end an antibiotic course. An approach utilising biomarker assays and an inter-disciplinary team of pharmacists, nurses, physicians, and microbiologists appears to be the way forward to develop sound clinical decision-making surrounding antibiotic treatment.

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.

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.

Association between olanzapine plasma concentrations and treatment response: A systematic review, meta-analysis and individual participant data meta-analysis.

AIMS: By meta-analysing pooled studies and available individual participant data, we aim to provide new insight on olanzapine therapeutic drug monitoring in schizophrenia. METHOD: We conducted a computerized search of bibliographic databases (Pubmed, Cochrane library, Web of Science and PsycINFO) to identify studies that assessed the relationship between olanzapine plasma concentration and the change in patients' clinical scores. We investigated this relationship with olanzapine plasma level 12h00 post-intake using a random-effects model. RESULTS: 7 studies were included in the pooled data analysis (781 patients). We found no difference in oral dose between responders and non-responders but a significantly higher concentration of 4.50 µg/L in responders (p < 0.01). Olanzapine concentration above the thresholds identified in each study was associated with response (odd ratio = 3.50, p = 0.0007). We identified that non-responder patients showed greater inter-individual variability than responders. In the individual data analysis (159 patients), we found no relationship between dose and clinical response but an association between plasma level and response in the shape of a parabolic curve. The Receiver Operating Characteristic curve found a threshold of 22.07 µg/L to identify responders (96% sensitivity, 86% specificity) and a threshold of 56.47 µg/L to identify a decreased probability of response. CONCLUSION: In contrast to oral dose, our work confirmed that plasma olanzapine levels are associated with clinical response and should therefore be used to optimise treatment. We determined a treatment response threshold of 22.07 µg/L and suggest that a concentration above the therapeutic window may result in a decreased response.

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.