The Toronto General Hospital (TGH) is a major teaching hospital in Toronto, Ontario, Canada and the flagship campus of University Health Network (UHN). It is located in the Discovery District of Downtown Toronto along University Avenue's Hospital Row; it is directly north of The Hospital for Sick Children, across Gerrard Street West, and east of Princess Margaret Cancer Centre and Mount Sinai Hospital. The hospital serves as a teaching hospital for the University of Toronto Faculty of Medicine. In 2021, Newsweek ranked TGH as the 4th best hospital in the world and 1st in Canada. In 2019, the hospital was ranked first for research in Canada by Research Infosource for the ninth consecutive year.The emergency department now treats 28,065 persons each year, while the hospital also houses the major transplantation service for Ontario, performing heart, lung, kidney, liver, pancreas, and small intestine, amongst others, for patients referred from all over Canada. The hospital is the largest organ transplant center in North America, performing 639 transplants in 2017. The hospital is also renowned for cardiac and thoracic surgery. The world's first single and double lung transplants were performed at TGH in 1983 and 1986 and the world's first valve-sparing aortic root replacement was done by Tirone David at Toronto General Hospital in 1992. The Lung Transplant program is currently the largest in the world, performing 167 lung transplants in 2017. In 2015, surgeons performed the world's first triple organ transplant (lung, liver and pancreas) in 19 year old Reid Wylie at Toronto General Hospital. TGH teaches resident physicians, nurses, and technicians; it also conducts research through the Toronto General Research Institute.Currently, Sophie, Countess of Wessex, as a member of the Canadian Royal Family, is patron of the hospital.
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and presents major therapeutic challenges due to its intrinsic heterogeneity and frequent development of resistance to immunotherapy. Although recent advances in immunotherapeutic strategies, including immunomodulatory drugs (IMiDs), chimeric antigen receptor T-cell (CAR-T) therapies, monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs), have significantly improved patient outcomes, disease relapse remains nearly inevitable. This review systematically categorizes resistance mechanisms to immunotherapy in MM by examining intrinsic tumor cell factors, including genetic and epigenetic alterations, modulation or loss of target antigens, immune effector cell dysfunction such as T-cell exhaustion, and the complex suppressive features of the bone marrow microenvironment. In addition, we discuss the application of emerging technologies such as single-cell sequencing and CRISPR/Cas9-based functional screening to uncover resistance pathways and guide target discovery. Finally, we highlight rational strategies to overcome resistance, including synergistic combination regimens, development of next-generation therapeutics, and approaches to reprogram the tumor microenvironment. These insights provide a conceptual framework for the design of more effective and durable immunotherapeutic interventions in MM.
To compare perioperative, oncological, and survival outcomes of total gastrectomy (TG) versus subtotal gastrectomy (SG) in patients with locally advanced distal diffuse gastric adenocarcinoma treated with perioperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy. Diffuse distal gastric cancer is characterized by infiltrative growth patterns and early nodal metastasis. Whilst radical resection remains the cornerstone of curative treatment, the optimal extent of surgery with TG or SG, remains debated. This international multicenter cohort study analyzed data from patients with histologically confirmed diffuse gastric adenocarcinoma, located > 5 cm from the gastroesophageal junction. Endpoints included surgical margin status, nodal yield, perioperative morbidity, recurrence patterns, time-to-recurrence (TTR), and overall survival (OS). Outcomes were compared using multivariate analyses. In total, 188 (39.0
Abstract Background Lung transplant is a life-saving therapy for end stage lung disease. However, the shortage of donor organs limits its availability. The safety of utilizing lungs from COVID-19-positive donors remains uncertain due to potential transmission risks and variable practice patterns. This study aimed to compare allografts from COVID-19-positive donors and COVID-19-negative donors during lung transplantation, with a focus on survival, length of hospital stay, dialysis, 30-day graft failure, 30-day mortality and postoperative ECMO support. Methods PubMed, Scopus, and Embase were assessed. Four studies including 5,921 patients were included. Overall survival was estimated by the Kaplan-Meier method and compared with Cox proportional hazards models. Random-effects models were applied for all pooled analyses. Results There was no difference in overall survival (HR 1.35; 95% CI 0.67–2.71; p = 0.40), and dialysis (RR = 1.38; 95% CI 0.52–3.64; p = 0.52) between groups. Recipients of allografts from COVID-19-positive donors had longer hospital stay (MD = 6.43 days; 95% CI 1.53–11.33; p = 0.01). There were no significant differences between groups for 30-day graft failure (RR = 1.08; 95% CI 0.83–1.39; p = 0.58), 30-day mortality (RR = 1.76; 95% CI 0.75–4.13; p = 0.19), or ECMO within 72 h (RR = 0.61; 95% CI 0.14–2.58; p = 0.50). Conclusions Although outcomes of transplantation were comparable, recipients of lungs from COVID-19-negative donors had shorter hospital stay. However, these results should be interpreted with caution due to the limited number of available comparative studies reflecting the current evidence base, and variations in methods of ascertaining COVID-19 positivity across studies.
Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (n = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (n = 15) or placebo (n = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (n = 10/15) versus 27.3% (n = 3/11), P = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (n = 7/11) versus 12.5% (n = 1/8), P = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were -7.1, -5.5 and -4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (n = 16/20); placebo, 56.3% (n = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: NCT04146051 .
Nosocomial infections are common in patients receiving extracorporeal membrane oxygenation (ECMO), with ECMO cannula-site infections (ECMO-CSI) being the most frequent infections directly related to the ECMO run. These infections can significantly impact patient outcomes. Currently, no adult guidelines exist for the prevention, diagnosis, and/or treatment of peripheral ECMO-CSI, resulting in heterogeneity in both clinical practice and research findings. We conducted a Delphi study involving 39 international experts in ECMO management. The experts participated in four Delphi rounds to reach consensus on various aspects of ECMO-CSI complicating peripheral ECMO (central ECMO excluded), including definition, clinical suspicion, diagnostic methods, preventive measures, and treatment. Consensus was defined as ≥ 70
