Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study.

PURPOSE: Refractory cancer-induced bone pain (CIBP) affects a patient's functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort. METHODS: Adults with CIBP and worst pain intensity ≥ 4/10 and/or opioid toxicity graded ≥ 2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to 14 days. RESULTS: Of 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow-up post-opioid rotation. Both groups displayed significant reduction in average (MR: d = - 1.2, p = 0.003, OOR: d = - 0.8, p = 0.015) and worst pain (MR: d = - 0.9, p = 0.042, OOR: d = - 0.6, p = 0.048) and total pain interference score (MR: d = - 1.1, p = 0.042, OOR: d = - 0.7, p = 0.007). Oral morphine equivalent daily dose was reduced significantly in MR compared to the OOR group (d = - 0.8, p = 0.05). The incidence of opioid-related adverse events following MR was unchanged but lower in the OOR group (d = 0.9, 95% CI 0.1,1.7, p = 0.022). There were no within-group or between-group differences in satisfaction with analgesia at the end of the study. CONCLUSION: This pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort. TRIAL REGISTRATION: ACTRN12621000141842 registered 11 February 2021.

Comparison of the therapeutic effects of lens capsular flap transplantation and autologous retinal transplantation in the management of refractory macular holes.

PURPOSE: To report the comparison of the therapeutic effects of lens capsular flap transplantation (LCT) and autologous retinal transplantation (ART) in refractory macular hole (MH) treatment. METHODS: Thirty-one patients (31 eyes) with refractory MH were retrospectively reviewed. The patients were divided into two groups based on the surgical procedures: the LCT group (13 eyes) and the ART group (18 eyes). Patients were monitored for a minimum of 6 months. Best corrected visual acuity (BCVA), hole closure rate, postoperative central foveolar thickness (CFT), and some complications (e.g. graft loss or dislocation, postoperative retinal detachment, or postoperatively elevated intraocular pressure) were the primary outcome measures. RESULTS: The mean preoperative MH diameter was 1104 ± 287 µm in the LCT group and 1066 ± 297 µm in the ART group (t = 0.353, P = 0.727). The MH was closed in 12 patients (92.3%) of the LCT group and 17 patients (94.4%) of the ART group (χ2 = 0.057, P = 0.811); the MHs of 10 patients (76.9%) in the LCT group and 11 patients (61.1%) in the ART group were completely closed (χ2 = 0.864, P = 0.353). The BCVA improved from 2.3 ± 1.0 logMAR preoperatively to 1.3 ± 0.9 logMAR postoperatively in the LCT group and 2.3 ± 0.9 logMAR preoperatively to 1.0 ± 0.6 logMAR postoperatively in the ART group (postoperative BCVA vs preoperative BCVA in the LCT group: t = 4.374, P = 0.001; postoperative BCVA vs preoperative BCVA in the ART group: t = 5.899, P = 0.000018). The visual improvement was 1.3 ± 0.9 logMAR in the ART group and 1.0 ± 0.8 logMAR in the LCT group (t = - 1.033, P = 0.310). The postoperative CFT was 139.7 ± 48.3 µm in the LCT and 199.2 ± 25.1 µm in the ART group (t = - 4.062, P = 0.001). Graft dislocation emerged in 2 patients (15.4%) in the LCT group and 1 patient (5.6%) in the ART group. CONCLUSIONS: Applications of LCT and ART may both enhance anatomical and visual outcomes in refractory MH cases. The ART group exhibited a more optimal postoperative CFT than the LCT group one.

Drug-Resistant Epilepsy: Experience From a Tertiary Care Center in Saudi Arabia.

Objectives This study aimed to describe the clinical characteristics, investigational results, and management strategies in patients with drug-resistant epilepsy (DRE). Methods This retrospective cohort study included all adult and adolescent patients (aged 14 years or older) diagnosed with DRE who visited the adult neurology clinic at King Abdulaziz Medical City, Jeddah, Saudi Arabia from January 2019 to December 2021. DRE was defined as failure to achieve seizure freedom despite undergoing adequate trials of two well-tolerated and appropriately selected antiseizure medications. Results This study included 299 patients with DRE. Most patients were in their second to fourth decade, with a mean age of 37 ± 17 years. Focal onset epilepsy was diagnosed in 52.5% of the patients, and an etiology for epilepsy was determined in 44.1% of the patients. Findings in brain magnetic resonance imaging were abnormal in 49% of the patients, whereas abnormal findings in electroencephalograms were found in 27.5%. The most common antiseizure medication was levetiracetam (67.6% of cases). Conclusion The findings of this study confirm the challenges in diagnosing and managing patients with DRE and emphasize the necessity for careful and comprehensive patient evaluation. Further research is needed to investigate the effectiveness, safety, and accessibility of diagnostic and therapeutic resources for patients with DRE.

An Interesting Case of Refractory Kawasaki Disease With Co-infection.

Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the common vasculitides of childhood. KD most commonly occurs in children over six months up to five years of age, although it can occur in young infants, older children, and adults. Early diagnosis is critical to achieving optimal treatment. We present a case of a three-year-old female child who was admitted with a fever for five days and fulfilled the diagnostic clinical criteria for KD. She was given intravenous immunoglobulin (IVIG) and aspirin. However, the fever persisted, and a urine culture showed the growth of Klebsiella pneumoniae. We started an antibiotic based on her sensitivity. Since fever spikes were not subsiding, she was given a repeat dose of IVIG along with an oral corticosteroid for refractory KD, after which she showed clinical improvement. This case highlighted that refractory KD can coexist with infection.

Human gastric microbiota analysis of refractory H. pylori infection.

H. pylori infection is gaining increasing attention, but detailed investigations into its impact on gastric microbiota remain limited. We collected gastric mucosa samples from 47 individuals divided into three groups: 1. Group HP: patients with initial positive H. pylori infection (25 cases); 2. Group ck: H. pylori-negative patients (14 cases); 3. Group DiffHP: patients with refractory H. pylori infection (8 cases). The samples were analyzed using 16S rDNA sequencing and functional prediction with PICRUSt. Group HP showed differences in flora distribution and function compared to Group ck, while Group DiffHP overlapped with Group HP. The abundances of Aeromonas piscicola, Shewanella algae, Vibrio plantisponsor, Aeromonas caviae, Serratia marcescens, Vibrio parahaemolyticus, Microbacterium lacticum, and Prevotella nigrescens were significantly reduced in both Group DiffHP and Group HP compared to Group ck. Vibrio shilonii was reduced only in Group DiffHP compared to Group ck, while Clostridium perfringens and Paracoccus marinus were increased only in Group DiffHP. LEfSe analysis revealed that Clostridium perfringens and Paracoccus marinus were enriched, whereas Vibrio shilonii was reduced in Group DiffHP compared to Group ck at the species level. In individuals with refractory H. pylori infection, the gastric microbiota exhibited enrichment in various human diseases, organic systems, and metabolic pathways (amino acid metabolism, carbohydrate metabolism, transcription, replication and repair, cell cycle pathways, and apoptosis). Patients with multiple failed H. pylori eradication exhibited significant changes in the gastric microbiota. An increase in Clostridium perfringens and Paracoccus marinus and a decrease in Vibrio shilonii appears to be characteristic of refractory H. pylori infection.

New investigational drugs for steroid-refractory acute graft-versus-host disease: a review of the literature.

INTRODUCTION: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a formidable obstacle in the field of allogeneic hematopoietic cell transplantation (allo-HCT), significantly contributing to patient morbidity and mortality. The current therapeutic landscape for SR-aGVHD is limited, often yielding suboptimal results, thereby emphasizing the urgent need for innovative and effective treatments. AREAS COVERED: In light of the pivotal REACH2 trial, ruxolitinib phosphate, a Janus kinase inhibitor, has gained prominence as the standard treatment for SR-aGVHD. Nevertheless, a considerable number of patients either do not respond to or cannot tolerate this therapy. This review delves into emerging treatments for SR-aGVHD, including mesenchymal stromal cells (MSCs), fecal microbiota transplantation (FMT), CD3/CD7 blockade, neihulizumab, begelomab, tocilizumab, and vedolizumab. While some of these agents have shown encouraging results in early-phase trials, issues such as treatment-related toxicities and inconsistent responses in larger studies highlight the necessity for ongoing research. EXPERT OPINION: Current trials exploring new agents and combination therapies offer hope for fulfilling the unmet clinical needs in SR-aGVHD, potentially leading to more effective and precise treatment strategies.

Plain language summary of SUNLIGHT: trifluridine/tipiracil and bevacizumab for refractory metastatic colorectal cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results from a phase 3 clinical trial called SUNLIGHT. The study looked at treatment with orally administered trifluridine/tipiracil plus intravenously administered bevacizumab in people with metastatic colorectal cancer (mCRC) that is refractory to treatment.This study included people whose cancer had grown or spread beyond its original location after no more than two previous treatments. People in the study received either the combination of trifluridine/tipiracil plus bevacizumab or they received trifluridine/tipiracil alone. The aims of the study were to see how long people lived after treatment with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil alone and to find out how well the combination of trifluridine/tipiracil plus bevacizumab worked at slowing down the spread of the cancer. Researchers also looked at side effects from taking the medicines and at how treatment affected people's physical functioning. WHAT ARE THE KEY TAKEAWAYS?: People in the combination group lived longer (a median of 10.8 months) than people who received trifluridine/tipiracil alone (7.5 months). In addition, the time it took for the cancer to worsen was longer for those who received the combination treatment (a median of 5.6 months) compared with those who received trifluridine/tipiracil alone (2.4 months). People's physical functioning took longer to worsen with combination therapy (a median of 9.3 months) than it did with trifluridine/tipiracil alone (6.3 months), as measured by the impact of treatment on people's ability to carry out daily living activities. The most common side effects in both treatment groups were low levels of white blood cells, known as neutrophils (neutropenia), nausea, and low levels of healthy red blood cells (anemia). WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The results from the study suggest that treatment with oral trifluridine/tipiracil plus intravenous (IV) bevacizumab could help people with refractory mCRC live longer and maintain good physical functioning, and it could slow the worsening of their cancer.Clinical Trial Registration: NCT04737187 (SUNLIGHT) (ClinicalTrials.gov).

Transanal proximal rectosigmoidectomy: a single-center experience in surgically treated severe medically refractory idiopathic constipation.

PURPOSE: To present the functional results after a transanal proximal rectosigmoidectomy in patients with severe idiopathic constipation in which medical treatment has failed. METHODS: Patients with severe idiopathic constipation who underwent transanal proximal rectosigmoidectomy (TPRS) at Children's Hospital Colorado between June 2019 and March 2024 were included in the study. We compared multiple pre- and post-operative outcome measures and the patient's bowel regimen before and after resection. RESULTS: Fourteen patients underwent TPRS, 10 of whom were male. The average age at the time of surgery was 10.1 years (range 5-19). Seven patients have moderate to severe autism. Constipation-related clinic visits, family calls, procedural intervention, emergency room visits, and hospitalizations notably decreased frequency after TPRS. Laxative dosages and enema volume requirements were also reduced after surgery. Before surgery, all the patients suffered from daily fecal accidents, while post-operatively, all were completely free of stool accidents. CONCLUSION: In our experience, for patients who suffer from severe medically refractory idiopathic constipation, TPRS has provided improvement in their symptoms and decreased the complications inherent to this chronic disease. Parents and patients attest to a profound positive transformation in their quality of life after surgery.

Development and validation of a nomogram for predicting refractory peritoneal dialysis related peritonitis.

OBJECTIVE: To identify the risk factors of refractory peritoneal dialysis related peritonitis (PDRP) and construct a nomogram to predict the occurrence of refractory PDRP. METHODS: Refractory peritonitis was defined as the peritonitis episode with persistently cloudy bags or persistent dialysis effluent leukocyte count >100 × 109/L after 5 days of appropriate antibiotic therapy. The study dataset was randomly divided into a 70% training set and a 30% validation set. Univariate logistic analysis, LASSO regression analysis, and random forest algorithms were utilized to identify the potential risk factors for refractory peritonitis. Independent risk factors identified using multivariate logistic analysis were used to construct a nomogram. The discriminative ability, calibrating ability, and clinical practicality of the nomogram were evaluated using the receiver operating characteristic curve, Hosmer-Lemeshow test, calibration curve, and decision curve analysis. RESULTS: A total of 294 peritonitis episodes in 178 patients treated with peritoneal dialysis (PD) were enrolled, of which 93 were refractory peritonitis. C-reactive protein, serum albumin, diabetes mellitus, PD duration, and type of causative organisms were independent risk factors for refractory peritonitis. The nomogram model exhibited excellent discrimination with an area under the curve (AUC) of 0.781 (95% CI: 0.716-0.847) in the training set and 0.741 (95% CI: 0.627-0.855) in the validation set. The Hosmer-Lemeshow test and calibration curve indicated satisfactory calibration ability of the predictive model. Decision curve analysis revealed that the nomogram model had good clinical utility in predicting refractory peritonitis. CONCLUSION: This nomogram can accurately predict refractory peritonitis in patients treated with PD.

Treatment pattern among patients with relapsed/refractory multiple myeloma (RRMM) who had received pomalidomide-based regimens in Taiwan.

BACKGROUND/PURPOSE: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. METHODS: This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. RESULTS: Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. CONCLUSION: In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.

Potential prognostic indicators in dogs with advanced heart failure secondary to myxomatous mitral valve disease.

BACKGROUND: Advanced heart failure (AHF) secondary to myxomatous mitral valve disease (MMVD) in dogs has unclear predictive variables and survival time. METHODS: This retrospective study included 38 dogs with AHF and 38 with stable congestive heart failure (CHF), both due to MMVD. Predictive variables for AHF were analysed, and survival times were calculated using logistic regression and the Kaplan-Meier method. RESULTS: Left atrium to aortic root ratio, normalised left ventricular dimension at the end-diastole and end-systole, isovolumic relaxation time (IVRT) and early transmitral inflow velocity to IVRT ratio were associated with AHF progression. The median survival times were significantly longer in the stable group than in the AHF group. After AHF diagnosis, the median survival times for all-cause and cardiogenic mortality were 194 and 354 days, respectively. LIMITATIONS: This was a single-centre retrospective observational study. The study population was small, with breed bias (overrepresentation of Maltese dogs). Additionally, the treatment plans depended on clinical experience. CONCLUSIONS: AHF in dogs with CHF secondary to MMVD is linked to left heart chamber enlargement and increased left ventricular dimensions, significantly reducing survival time to around six months post-diagnosis. Early recognition and appropriate management may improve outcomes, highlighting the importance of advanced treatment strategies.

[Efficacy and safety of gilteritinib-based combination therapy bridging allo-HSCT in relapsed or refractory acute myeloid leukemia patients with positive FLT3-ITD mutation].

Objective: This study aims to evaluate the safety and effectiveness of gilteritinib (Gilt) -based combination therapy bridging allo-HSCT for FLT3-ITD(+) R/R AML. Additionally, it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT. Methods: The clinical data of 26 patients with FLT3-ITD(+) R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed. The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS) time, disease-free survival (DFS) time, and adverse events experienced by all enrolled patients. Results: A total of 26 patients with FLT3-ITD(+) R/R AML were enrolled, including 14 men and 12 women with a median age of 38 (18-65) years. A total of 18 cases were refractory, and eight cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 26.9% (7/26), the CR with hematology incomplete recovery was 57.7% (15/26), and the partial response (PR) rate was 7.7% (2/26). The CRc was 84.6% (22/26), and the minimal residual disease (MRD) negativity rate was 65.4%. The 12 month cumulative OS rate for all patients was 79.0%, and the 24 month cumulative OS rate was 72.0%. The median OS time was not determined. The median follow-up time was 16.0 months. Among the patients who responded to treatment, the 12 month cumulative DFS rate was 78.0%, and the 24 month cumulative DFS rate was 71.0%. The median DFS time was not determined. Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT (3.3 months, 95%CI 2.2-4.3 months, P=0.005). The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined, but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment (P=0.019). The FLT3-ITD mutation clearance rate in this study was 38.5%, and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (15.0 months; P=0.018). The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia (76.9%), neutropenia (76.9%), febrile neutropenia (61.5%), thrombocytopenia (69.2%), and anemia (57.7%). One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment, but his condition improved after treatment. Conclusion: The Gilt-based combination therapy is highly effective in treating FLT3-ITD(+) R/R AML. It demonstrates a high CRc, MRD negativity rate, and rapid onset, leading to a significant improvement in patients' survival. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients' survival. Closely monitoring and managing any adverse event that may occur during treatment are crucial.

Management of refractory disease and persistent symptoms in inflammatory arthritis: qualitative framework analysis of interviews with patients and healthcare professionals.

Objectives: This study aims to explore patients' and clinicians' experiences in managing and living with refractory disease (RD) and persistent physical and emotional symptoms (PPES) in patients with RA or polyarticular JIA from their perspectives through interviews and/or focus groups. Methods: A qualitative exploration with 25 patients and 32 multidisciplinary rheumatology healthcare professionals (HCPs) was conducted to obtain participants respective understanding and experiences of managing RD/PPES and its impact on the patient-professional relationship. A pragmatic epistemology approach with framework analysis was employed. Results: Four key themes were identified from both patients and professionals in the management of RD/PPES: risk/perpetuating factors/triggers; need for a patient-centred holistic approach to care, diagnosis and treatment; discordance and impact on the patient-practitioner relationship and current problems in managing RD/PPES. These themes covered 22 subthemes, with none being patient specific and seven being HCP specific. Suggestions for potential management strategies were highlighted throughout, such as involving other specialties or a multidisciplinary team, assessing/treating patient-reported outcome measures and psychosocial factors, patient (re)education, need for adjustments/aids or adaptations, checking the diagnosis and further investigations/imaging and optimizing medications. Conclusion: Management strategies need to be developed that enable appropriate treatment plans for those with RD/PPES that account for wider biopsychosocial factors beyond inflammation and reduce discordance in the patient-practitioner relationship.

Chemotherapy Rechallenge or Reintroduction Compared to Regorafenib or Trifluridine/Tipiracil for Pretreated Metastatic Colorectal Cancer Patients: A Propensity Score Analysis of Treatment Beyond Second Line (Proserpyna Study).

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated. PATIENTS AND METHODS: PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses. RESULTS: Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses. CONCLUSIONS: Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

Rapid identification of early infections in febrile patients after CD19 target CAR-T cell therapy for B-cell malignancies.

BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.

Staged hybrid ablation in left atrial appendage aneurysm a rare cause of refractory atrial tachyarrhythmia-a case report.

Background: Left atrial appendage aneurysm (LAAA) is a rare cardiac anomaly, which can be congenital or acquired in origin. Because most cases are asymptomatic, it is typically diagnosed incidentally in the second to third decades of life. We present a case of a 28-year-old male with refractory atrial tachyarrhythmias and significantly reduced exercise tolerance. The informed consent was given by patient for this manuscript. Case summary: We present a case of a 28-year-old male with refractory atrial tachyarrhythmias and significantly reduced exercise tolerance after an episode of COVID respiratory infection. He was referred by primary care physician for management of atrial fibrillation (AF) with CHA2DS2Vasc score zero. He had documented AF and atrial flutter (AFL) resistant to both chemical and electrical cardioversions. Initial portable focused transthoracic echocardiography documented borderline reduced left ventricular ejection fraction in context of AFL. Electrophysiological study confirmed the diagnosis of typical AFL. Successful radiofrequency ablation of cavo-tricuspid isthmus resulted in bidirectional isthmus conduction block. However, patient developed AF, which was electrically cardioverted at the end of procedure. Patient was discharged on bisoprolol, ramipril, and apixaban, and outpatient cardiac MRI was organized to look for post-COVID myocardial scarring. Patient had recurrence of symptoms, and this time it was due to AF. Multimodal imaging led to discovery of LAAA, in which after discussion in multidisciplinary meeting, he was accepted for and managed with surgical resection of LAAA with concomitant Cox-Maze IV procedure. On 9 months post-operative follow up, patient is maintaining sinus rhythm and has completely returned to baseline activities. Discussion: A young patient with refractory atrial arrhythmia should be referred for multimodal cardiovascular imaging to rule out any structural heart disease. Left atrial appendage aneurysm is rare and can be managed conservatively, but surgical excision is most reported and appears to favour arrhythmia-free survival.

An observational study to understand burden and cost of care in adults diagnosed with refractory chronic cough (RCC) or unexplained chronic cough (UCC).

BACKGROUND: Refractory and unexplained chronic cough (RCC and UCC) necessitate frequent referral for specialist evaluations, but data on healthcare resource utilisation and costs are lacking. METHODS: This observational study enrolled adults with RCC or UCC attending a specialist cough clinic and included a control cohort, both from North West England, matched 1:5 for age, gender and smoking history. Primary and secondary care data were obtained for the 5 years prior to and 2 years post initial clinic visit (index). The primary endpoint was the total 5-year healthcare cost to the UK NHS pre-RCC or UCC diagnosis compared to the control cohort. RESULTS: Mean age at index for the 200 RCC or UCC consented patients was 62.2 ± 11.4 years; 71% were female, and 68% had never smoked. Mean duration of symptoms pre-diagnosis was 8.0 ± 9.4 years. Mean cough severity score was 63.7 ± 23.2 mm at index on a Visual Analog Scale, and Leicester Cough Questionnaire total score was 10.9 ± 4.1. GP data were available for 80 patients and mean total cost over the 5 years pre-diagnosis (index date) was 3.0-fold higher (95% CI 2.3, 3.9) than in the control cohort (p < 0.001). Most excess costs were related to visits and procedures carried out in secondary care. RCC- or UCC-associated costs decreased post-diagnosis, but remained higher than those of controls. CONCLUSION: Diagnosis of RCC or UCC requires significant health resource utilisation in the 5 years prior to a specialist clinic diagnosis. Resource utilisation was less after diagnosis, but remained higher than in a matched control cohort.

Targeting cancer stem cells in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy of bone marrow (BM) plasma cells with excessive clonal expansion and is associated with the overproduction of light-chain or monoclonal immunoglobulins (Igs). MM remains incurable, with high rates of relapses and refractory disease after first-line treatment. Cancer stem cells (CSCs) have been implicated in drug resistance in MM; however, the evidence for CSCs in MM is not adequate, partly due to a lack of uniformity in the definitions of multiple myeloma stem cells (MMSCs). We review advances in understanding MMSCs and their role in drug resistance to MM therapies. We also discuss novel therapeutic strategies to overcome MMSC-mediated relapses and drug resistance.

Efficacy and safety of multikinase inhibitors for patients with refractory thyroid cancer: Systematic review and network meta-analysis.

CONTEXT: Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, included radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). OBJECTIVE: This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. DATA SOURCES: Comprehensive database searches of MEDLINE via PubMed, EMBASE and Cochrane performed from inception to December 2023. STUDY SELECTION: Three independent authors selected these studies. Randomised-controlled trials that compared the use of a MKI to other MKIs or placebo were included. DATA EXTRACTION AND SYNTHESIS: This review followed PRISMA guidelines. Risk of bias was analyzed using the Cochrane RoB 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. MAIN OUTCOMES AND MEASURES: Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. RESULTS: Cabozantinib 60 mg/d (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/d (LEN18 or LEN24), and apatinib. PFS was also improved in in aMTC patients received CAB 140 mg/d (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but which in aMTC patients were lack of statistical differences. Compared with the low-dose of MKIs, high-dose of MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CONCLUSION: CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Ruxolitinib plus basiliximab therapy for steroid-refractory acute graft-versus-host disease in unrelated cord blood transplantation: a large-scale study.

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation (allo-HSCT). We aimed to evaluate the effectiveness and safety of ruxolitinib plus basiliximab for treating SR-aGVHD after unrelated cord blood transplantation (UCBT). Among the 1154 patients with hematological malignancies who underwent UCBT between February 2014 and May 2022, 198 patients with grade II to IV SR-aGVHD were enrolled, 112 of whom were treated with basiliximab alone (basiliximab group) and 86 of whom received basiliximab plus ruxolitinib (combined therapy group). The combined therapy group demonstrated a significantly higher complete response rate (CRR) on day 28 (36.0%) than did the basiliximab group (12.5%, P < 0.001). SR-aGVHD patients were further stratified into standard-risk and high-risk groups using the refined Minnesota aGVHD risk score. For standard-risk patients, combined therapy significantly improved the CRR (51.1% versus 13.6%, P < 0.001) and 3-year overall survival (74.5% versus 52.4%, P = 0.033). However, high-risk patients did not exhibit the same benefits. Compared with basiliximab monotherapy, ruxolitinib plus basiliximab therapy was an effective therapy for patients with standard-risk SR-aGVHD following UCBT. The effectiveness of combined therapy in high-risk patients was not apparent, indicating the need for other treatments.