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ASO Visual Abstract: Robotic Techniques in Esophagogastric Cancer Surgery: An Assessment of Short- and Long-Term Clinical Outcomes.
No full textResults of a UK real world study of polatuzumab vedotin, bendamustine, and rituximab for relapsed/refractory large B-cell lymphoma.
No full textThe addition of polatuzumab vedotin to bendamustine and rituximab (Pola-BR) has been shown to improve overall survival (OS) in stem cell transplant (SCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). It is also increasingly used as bridging to CAR T-cell therapy (CAR-T). We retrospectively analysed the efficacy of Pola-BR in 133 patients at 28 UK institutions. Treatment intent was bridging to CAR-T for N=40, re-induction with planned SCT for N=13 and stand-alone treatment for N=78. The overall response rate (ORR) was 57.0% (complete response (CR) 32.8%). After median 7.7 months follow-up, median PFS and OS were 4.8 months and 8.2 months respectively. For stand-alone treatment shortened PFS was associated with bulk disease (>7.5cm) (HR 2.32 (95% CI 1.23-4.38), p=0.009), >1 prior treatment (HR 2.17 (95% CI 1.19-3.95), p=0.01) and refractoriness to the last treatment (HR 3.48 (95% CI 1.79-6.76), p<0.001). For CAR-T bridging the ORR was 42.1% (CR 18.4%) and for treatment after CAR-T failure the ORR was 43.8% (CR 18.8%). These data demonstrate efficacy for Pola-BR as a treatment for SCT-ineligible patients with R/R DLBCL, help to delineate which patients may benefit most, and provide preliminary evidence of efficacy as bridging to CAR-T and after CAR-T failure
Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance.
No full textBACKGROUND
Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to: (i) Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies. (ii) Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences.
METHODS
The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS-Standards for Development recommendations (COS-STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared.
RESULTS
Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE-both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS.
CONCLUSIONS
The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS.
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Survival benefit of adjuvant chemotherapy following neoadjuvant therapy and oesophagectomy in oesophageal adenocarcinoma.
No full textBACKGROUND
The evidence assessing the additional benefits of adjuvant chemotherapy (AC) following neoadjuvant therapy (NAT; i.e. chemotherapy or chemoradiotherapy) and oesophagectomy for oesophageal adenocarcinoma (EAC) are limited. This study aimed to determine whether AC improves long-term survival in patients receiving NAT and oesophagectomy.
METHODS
Patients receiving oesophagectomy for EAC following NAT from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). To account for immortality bias, patients with survival ≤3 months were excluded to account for immortality bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival.
RESULTS
Overall, 12,972 (91%) did not receive AC and 1,255 (9%) received AC. After PSM there were 2,485 who did not receive AC and 1,254 who did. After matching, AC was associated with improved survival (median: 38.5 vs 32.3 months, p < 0.001), which remained after multivariable adjustment (HR: 0.78, CI: 0.71-0.87). On multivariable interaction analyses, this benefit persisted in subgroup analysis for nodal status: N0 (HR: 0.85, CI: 0.69-0.96), N1 (HR: 0.66, CI: 0.56-0.78), N2/3 (HR: 0.80, CI: 0.66-0.97) and margin status: R0 (HR: 0.77, CI: 0.69-0.86), R1 (HR: 0.60, CI: 0.43-0.85). Further, patients with stable disease following NAT (HR: 0.60, CI: 0.59-0.80) or downstaged (HR: 0.80, CI: 0.68-0.95) disease had significant survival benefit after AC, but not patients with upstaged disease.
CONCLUSION
AC following NAT and oesophagectomy is associated with improved survival, even in node-negative and margin-negative disease. NAT response may be crucial in identifying patients who will benefit maximally from AC, and thus future research should be focused on identifying molecular phenotype of tumours that respond to chemotherapy to improve outcomes
High generation of reactive oxygen species from neutrophils in patients with severe COVID-19.
No full textNeutrophilia and an elevated neutrophil:lymphocyte ratio are both characteristic features of severe COVID-19 infection. However, functional neutrophil responses have been poorly investigated in this setting. We utilised a novel PMA-based stimulation assay to determine neutrophil-derived reactive oxygen species (ROS) generation in patients with severe COVID-19 infection, non-COVID related sepsis and healthy study participants. ROS production was markedly elevated in COVID-19 patients with median values ninefold higher than in healthy controls and was particularly high in patients on mechanical ventilation. ROS generation correlated strongly with neutrophil count and elevated levels were also seen in patients with non-COVID related sepsis. Relative values, adjusted for neutrophil count, were high in both groups but extreme low or high values were seen in two patients who died shortly after testing, potentially indicating a predictive value for neutrophil function. Our results show that the high levels of neutrophils observed in patients with COVID-19 and sepsis exhibit functional capacity for ROS generation. This may contribute to the clinical features of acute disease and represents a potential novel target for therapeutic intervention
Comparison between the difficulty of laparoscopic limited liver resections of tumors located in Segment 7 vs. Segment 8: an international multicenter propensity-score matched study.
No full textBACKGROUND
Presently, according to different difficulty scoring systems, there is no difference in complexity estimation of laparoscopic liver resection (LLR) of segments 7 and 8. However, there is no published data supporting this assumption. To date, no studies are comparing the outcomes of laparoscopic parenchyma-sparing resection of the liver segments 7 and 8.
METHODS
A posthoc analysis of patients undergoing LLR of segments 7 and 8 in 46 centers between 2004 and 2020 was performed. 1:1 Propensity score matching (PSM) was used to compare isolated LLR of segments 7 and 8. Subset analyses were also performed to compare atypical resections and segmentectomies of 7 and 8.
RESULTS
2411 patients were identified, and 1691 patients met the inclusion criteria. Comparison after PSM between the entire cohort of segment 7 and segment 8 resections revealed inferior results for segment 7 resection in terms of increased blood loss, blood transfusions, and conversions to open surgery. Subset analyses of only atypical resections similarly demonstrated poorer outcomes for segment 7 in terms of increased blood loss, operation time, blood transfusions, and conversions to open surgery. Conversely, a subgroup analysis of segmentectomies after PSM found better outcomes for segment 7 in terms of a shorter operation time and hospital stay.
CONCLUSION
Differences in the outcomes of segments 7 and 8 resections suggest a greater difficulty of laparoscopic atypical resection of segment 7 compared to segment 8, and greater difficulty of segmentectomy 8 compared to segmentectomy 7
Development of the ParaOesophageal hernia SympTom (POST) tool.
No full textBACKGROUND
The aim of this study was to develop a symptom severity instrument (ParaOesophageal hernia SympTom (POST) tool) specific to para-oesophageal hernia (POH).
METHODS
The POST tool was developed in four stages. The first was establishment of a Steering Committee. In the second stage, items were generated through a systematic review and online scoping survey of international experts. In the third stage, a three-round modified Delphi consensus process was conducted with a group of international experts who were asked to rate the importance of candidate items. An a priori threshold for inclusion was set at 80 per cent. The modified Delphi process culminated in a consensus meeting to develop the first iteration of the tool. In the final stage, two international patient workshops were held to assess the content validity and acceptability of the POST tool.
RESULTS
The systematic review and scoping survey generated 64 symptoms, refined to 20 for inclusion in the modified Delphi consensus process. Twenty-six global experts participated in the Delphi consensus process. Five symptoms reached consensus across two rounds: difficulty getting solid foods down, chest pain after meals, difficulty getting liquids down, shortness of breath only after meals, and an early feeling of fullness after eating. The subsequent patient workshops deemed these five symptoms to be relevant and suggested that reflux should be included; these were taken forward to create the final POST tool.
CONCLUSION
The POST tool is the first instrument designed to capture POH-specific symptoms. It will allow clinicians to standardize reporting of symptoms of POH and evaluate the response to surgical intervention
Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset.
No full textReal-world data on the efficacy and tolerability of isatuximab with pomalidomide and dexamethasone (IsaPomDex) in relapsed/refractory myeloma patients have not been reported. In this UK-wide retrospective study, IsaPomDex outcomes were evaluated across 24 routine care cancer centers. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR) for patients who achieved an objective response (≥partial response [PR]), and adverse events (AEs). In a total cohort 107 patients, median follow up (interquartile range [IQR]) was 12.1 months (10.1-18.6 mo), median age (IQR) was 69 years (61-77). Median (IQR) Charlson Comorbidity Index (CCI) score was 3 (2-4); 43% had eGFR <60 mL/min. Median (IQR) number of prior therapies was 3 (3-3). Median (IQR) number of IsaPomDex cycles administered was 7 (3-13). ORR was 66.4%, with responses categorized as ≥ very good partial response: 31.8%, PR: 34.6%, stable disease: 15.9%, progressive disease: 15%, and unknown 2.8%. Median PFS was 10.9 months. Median DOR was 10.3 months. There was no statistical difference in median PFS by age (<65: 10.2 versus 65-74 13.2 versus ≥75: 8.5 mo, log-rank = 0.4157), by CCI score (<4: 10.2 mo versus ≥4: 13.2, log-rank = 0.6531), but inferior PFS was observed with renal impairment (≥60: 13.2 versus <60: 7.9 mo, log-rank = 0.0408). Median OS was 18.8 months. After a median of 4 cycles, any grade AEs were experienced by 87.9% of patients. The most common ≥G3 AEs were neutropenia (45.8%), infections (18.7%), and thrombocytopenia (14%). Our UK-wide IsaPomDex study demonstrated encouraging efficacy outcomes in the real world, comparable to ICARIA-MM trial
