Long-Term Survival after Blood and Marrow Transplantation: Comparison with an Age- and Gender-Matched Normative Population

AbstractA plateau in long-term survival patterns of patients undergoing blood and marrow transplantation (BMT) from allogeneic donors is apparent, but whether their expected survival ever parallels that of the normative population is unclear. This study attempts to identify a cutoff time for classifying BMT patients as long-term survivors and compares their actual survival with the expected survival of an age- and gender-matched “normal” population. In this study, the records of 1386 patients who underwent allogeneic BMT at Princess Margaret Hospital between 1970 and 2002 were reviewed. Hazard rates (HRs), Kaplan-Meier survival estimates, and loess curves were used to propose a cutoff time classifying patients as long-term survivors. Factors predictive of overall survival and survival for long-term survivors were investigated. Actual survival for these patients was compared with the expected survival of the Canadian “normal” population. A cutoff time of 6 years post-BMT was proposed to define long-term survivors based on loess curves of hazard ratios and yearly survival statistics. The only statistically significant predictor of survival among long-term survivors was having a male donor (HR = 0.39; 95% confidence interval [CI] = 0.17–0.88). Although only 62% of patients survived the first year post-BMT, 98.5% of patients alive after 6 years survived at least another year. Almost 1/3 (31%) of the deaths in long-term survivors resulted from causes unrelated to transplantation or relapse. The observed number of deaths among BMT patients exceeded the expected number from the Canadian population; however, the difference in life expectancy decreased the longer that a patient survived. The 95% CIs for the observed/expected number of deaths cover 1, indicative of no difference, after the tenth year post-BMT. A cutoff of 6 years is proposed to define long-term survivorship after BMT. Life expectancy remained reduced compared with that of the “normal” population; however, this difference decreased the longer that a patient survived. Known risk factors of short-term survival disappeared, with only donor gender predictive of survival among long-term survivors

Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs)

Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

On the complexity of intersecting multiple circles for graphical display

Many experiments in the biomedical field generate vast amounts of data. This is especially true for microarray experiments which measure the expression levels of thousands of genes simultaneously. In this context the display of functional information attributed to the individual gene is important to obtain an overview of the major processes involved. This set data can be displayed as Euler/Venn diagrams in which the circle size corresponds to the cardinality of the set. Efficient algorithms for the calculation of intersections of circles and their resulting boundary have not been published so far. We present two algorithms (one optimal) for intersecting these different sized circles to display set relationships