Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.

A Translational Randomized Trial of Perioperative Arginine Immunonutrition on Natural Killer Cell Function in Colorectal Cancer Surgery Patients.

BACKGROUND: Surgery results in severe impairment of natural killer (NK) cell cytotoxicity (NKC) and activity (NKA, cytokine secretion), and a dramatic drop in arginine levels. Postoperative immunosuppression is associated with increased complications and recurrence. Perioperative arginine is reported to reduce postoperative complications. Because arginine modulates NK cell function, this study aimed to determine whether perioperative consumption of arginine-enriched supplements (AES) can improve NK cell function in colorectal cancer (CRC) surgery patients. METHODS: This study randomized 24 CRC patients to receive the AES or isocaloric/isonitrogenous control supplement three times a day for five days before and after surgery. The AES contained 4.2 g of arginine per dose (12.6 g/day). The primary objective was to determine whether AES improved NKC by 50 % compared with the control group after surgery. RESULTS: On surgery day (SD) 1, NKC was significantly reduced postoperatively in the control group by 50 % (interquartile range [IQR], 36-55 %; p = 0.02) but not in the AES group (25 % reduction; IQR, 28-75 %; p = 0.3). Furthermore, AES had no benefit in terms of NKA or NK cell number. Compliance was much greater preoperatively (>91 %) than postoperatively (<46 %). However, despite excellent preoperative compliance, arginine was rapidly cleared from the blood within 4 h after consumption and therefore, did not prevent the postoperative drop in arginine. CONCLUSIONS: Oral consumption of arginine immunonutrition resulted in a modest improvement in NKC after surgery but was unable to prevent postoperative arginine depletion or the suppression of NKA (ClinicalTrials.gov NCT02987296).

Perioperative arginine prevents metastases by accelerating natural killer cell recovery after surgery.

Profound natural killer (NK) cell suppression after cancer surgery is a main driver of metastases and recurrence, for which there is no clinically approved intervention available. Surgical stress is known to cause systemic postoperative changes that negatively modulate NK cell function including the expansion of surgery-induced myeloid-derived suppressor cells (Sx-MDSCs) and a marked reduction in arginine bioavailability. In this study, we determine that Sx-MDSCs regulate systemic arginine levels in the postoperative period and that restoring arginine imbalance after surgery by dietary intake alone was sufficient to significantly reduce surgery-induced metastases in our preclinical murine models. Importantly, the effects of perioperative arginine were dependent upon NK cells. Although perioperative arginine did not prevent immediate NK cell immunoparalysis after surgery, it did accelerate their return to preoperative cytotoxicity, interferon gamma secretion, and activating receptor expression. Finally, in a cohort of patients with colorectal cancer, postoperative arginine levels were shown to correlate with their Sx-MDSC levels. Therefore, this study lends further support for the use of perioperative arginine supplementation by improving NK cell recovery after surgery.

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis.

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.

Intraoperative Red Blood Cell Transfusion Decision-making: A Systematic Review of Guidelines.

OBJECTIVES: The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base. SUMMARY OF BACKGROUND DATA: RBC transfusions are common during surgery and there is evidence of wide variability in practice. METHODS: Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines. RESULTS: Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (<30%) triggers. In the absence of objective transfusion rules, CPGs recommended considering other parameters such as blood loss (n = 7), signs of end organ ischemia (n = 5), and hemodynamics (n = 4). Evidence supporting intraoperative recommendations was extrapolated primarily from the nonoperative setting. There was wide variability in the quality of included guidelines based on AGREE II scores. CONCLUSION: This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.

Shells of the bivalve Astarte moerchi give new evidence of a strong pelagic-benthic coupling shift occurring since the late 1970s in the North Water polynya.

Climate changes in the Arctic may weaken the currently tight pelagic-benthic coupling. In response to decreasing sea ice cover, arctic marine systems are expected to shift from a 'sea-ice algae-benthos' to a 'phytoplankton-zooplankton' dominance. We used mollusc shells as bioarchives and fatty acid trophic markers to estimate the effects of the reduction of sea ice cover on the food exported to the seafloor. Bathyal bivalve Astarte moerchi living at 600 m depth in northern Baffin Bay reveals a clear shift in growth variations and Ba/Ca ratios since the late 1970s, which we relate to a change in food availability. Tissue fatty acid compositions show that this species feeds mainly on microalgae exported from the euphotic zone to the seabed. We, therefore, suggest that changes in pelagic-benthic coupling are likely due either to local changes in sea ice dynamics, mediated through bottom-up regulation exerted by sea ice on phytoplankton production, or to a mismatch between phytoplankton bloom and zooplankton grazing due to phenological change. Both possibilities allow a more regular and increased transfer of food to the seabed. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.

Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies.

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

Gender and academic promotion of Canadian general surgeons: a cross-sectional study.

BACKGROUND: Gender disparities in faculty rank have yet to be studied among Canadian physicians. The purpose of this study was to determine whether differences in region, training, research productivity and years in practice explain gender differences in academic promotion among Canadian general surgeons. METHODS: We developed a cross-sectional database of faculty-appointed general surgeons practising in the hospitals affiliated with the 17 universities within the Association of Faculties of Medicine of Canada in 2017 using publicly available directories, university and hospital websites, and direct communication. The data were collected between October and December 2018 and included gender, residency completion year, graduate education, fellowships, number of publications and Scopus h-index; faculty lists and professorship status were verified by program administrators or division heads of their respective divisions. The dependent variable was binary: full professor or not. A combined outcome of associate or full professor was also analyzed. We analyzed all variables in a multivariable logistic regression model. RESULTS: Of the 17 institutions contacted, all but 1 confirmed the faculty lists and professorship status. A total of 405 surgeons were included, of whom 111 (27.4%) were women. Sixty-eight women (61.3%) and 120 men (40.8%) were assistant professors, and 9 women (8.1%) and 75 men (25.5%) were full professors. Although on average women had completed residency more recently than men (15.2 yr v. 19.2 yr, p < 0.001), there was no difference between men and women in the mean number of publications as residents (2.98 v. 2.74, p = 0.7) or per year of practice (3.12 v. 2.09, p = 0.2), number of fellowships pursued (p = 0.7) or graduate education (p = 0.2). In the multivariable model (C-statistic = 0.88), gender remained significantly associated with full professorship (odds ratio 2.79, 95% confidence interval 1.13 to 6.92), along with years in practice (odds ratio 1.61, 95% confidence interval 1.13 to 2.30). INTERPRETATION: After controlling for years in practice, training and research productivity measures, we found that female surgeons with faculty appointments in Canada were less likely than their male counterparts to receive promotion to full professor. Pervasive inequities in systems of promotion must be addressed.

Guidelines on the intraoperative transfusion of red blood cells: a protocol for systematic review.

INTRODUCTION: A significant proportion of red blood cell (RBC) transfusions are administered intraoperatively; yet there is limited evidence to guide transfusion decisions in this setting. The objective of this systematic review is to explore the availability, quality and content of clinical practice guidelines (CPGs) reporting on the indication for allogenic RBC transfusion during surgery. METHODS: Major electronic databases (MEDLINE, EMBASE and CINAHL), guideline clearinghouses and Google Scholar, will be systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative allogenic RBC transfusion. Characteristics of eligible guidelines will be reported in a summary table. The AGREE II instrument will be used to appraise the quality of identified guidelines. Recommendations advising on indications for intraoperative RBC transfusion will be manually extracted and presented to allow for comparison of similarities and/or discrepancies in the literature. ETHICS AND DISSEMINATION: The results of this systematic review will be disseminated through relevant conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: CRD42018111487.

Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery.

BACKGROUND: Surgical stress results in a significant reduction in natural killer (NK) cell cytotoxicity (NKC), which has been linked to postoperative cancer metastases. However, few studies have measured the impact of surgical stress upon NK cell IFNγ secretion (NKA), a cytokine with essential roles in controlling infection and metastases. The objective of this study was to investigate the impact of surgical stress on NKA in colorectal cancer (CRC) surgery patients. METHODS: Peripheral blood was collected from CRC surgery patients (n = 42) preoperatively and on postoperative day (POD) 1, 3, 5, 28, and 56. Healthy donor blood (n = 27) was collected for controls. We assessed NKA by production of IFNγ following whole blood cytokine stimulation, NKC by 51Cr-release assay, and immune cell profiling by flow cytometry. RESULTS: The mean reduction in NKA on POD1 compared with baseline was 83.1% (standard deviation 25.2%; confidence interval 75-91), and therefore the study met the primary endpoint of demonstrating a > 75% decrease in a cohort of CRC surgery patients (p < 0.0001). The profound and universal suppression of NKA persisted with 65.5% (19/29) and 33.3% (4/12) of patients with levels measuring < 75% of baseline on POD28 and POD56 respectively. The NKC was significantly reduced on POD1, but the degree was less pronounced (24.6%, p = 0.0024). Immune cell profiling did not reveal differences in the absolute number of NK cells (CD3-CD56+) or the ratio of CD56dim-to-CD56bright subsets. CONCLUSIONS: NKA is significantly suppressed for up to two months following surgery in CRC patients, a degree of surgery-induced immunosuppression far worse than previously reported.

Prognostic significance of a positive radial margin after esophageal cancer resection.

OBJECTIVE: The prognostic significance of an incomplete esophageal cancer resection due to a positive microscopic radial margin remains unclear. The aim of this study is to examine the relationship between radial margin status and oncologic outcomes. METHODS: We performed a retrospective review of esophageal cancer resections between 2004 and 2012. Radial margin status was defined according to the College of American Pathologists. Exclusion criteria were complete pathologic response (n = 12), positive proximal or distal margin (n = 11), R2 resection (n = 5), and carcinoma in situ (n = 2). RESULTS: Of 154 patients, 30 (19%) had a positive radial margin (RM+) and 124 (81%) had a complete resection (R0). The 2 groups were similar with respect to age, gender, proportion of squamous tumors, middle thoracic tumor location, rate of neoadjuvant chemoradiation and adjuvant radiation, transhiatal approach, number of examined lymph nodes, and length of proximal and distal margins. In patients with stage III, the locoregional recurrence-free interval was similar between groups; however, RM+ was associated with a 17-month decrease in the median time to distant recurrence (RM+ = 7 months [95% confidence interval, 4-14]; R0 = 24 months [median not reached]; P < .01). The median survival was also significantly decreased by 12 months in the RM+ group (RM+ = 13 months [95% confidence interval, 7-26]; R0 = 25 months [95% confidence interval, 20-30]; P = .04). CONCLUSIONS: An isolated, positive microscopic radial margin was associated with a greater risk for distant recurrence. There was no impact on locoregional disease control. The role of adjuvant, systemic therapy in patients with an isolated, microscopically RM+ merits further evaluation.

Patterns of DNA barcode variation in Canadian marine molluscs.

BACKGROUND: Molluscs are the most diverse marine phylum and this high diversity has resulted in considerable taxonomic problems. Because the number of species in Canadian oceans remains uncertain, there is a need to incorporate molecular methods into species identifications. A 648 base pair segment of the cytochrome c oxidase subunit I gene has proven useful for the identification and discovery of species in many animal lineages. While the utility of DNA barcoding in molluscs has been demonstrated in other studies, this is the first effort to construct a DNA barcode registry for marine molluscs across such a large geographic area. METHODOLOGY/PRINCIPAL FINDINGS: This study examines patterns of DNA barcode variation in 227 species of Canadian marine molluscs. Intraspecific sequence divergences ranged from 0-26.4% and a barcode gap existed for most taxa. Eleven cases of relatively deep (>2%) intraspecific divergence were detected, suggesting the possible presence of overlooked species. Structural variation was detected in COI with indels found in 37 species, mostly bivalves. Some indels were present in divergent lineages, primarily in the region of the first external loop, suggesting certain areas are hotspots for change. Lastly, mean GC content varied substantially among orders (24.5%-46.5%), and showed a significant positive correlation with nearest neighbour distances. CONCLUSIONS/SIGNIFICANCE: DNA barcoding is an effective tool for the identification of Canadian marine molluscs and for revealing possible cases of overlooked species. Some species with deep intraspecific divergence showed a biogeographic partition between lineages on the Atlantic, Arctic and Pacific coasts, suggesting the role of Pleistocene glaciations in the subdivision of their populations. Indels were prevalent in the barcode region of the COI gene in bivalves and gastropods. This study highlights the efficacy of DNA barcoding for providing insights into sequence variation across a broad taxonomic group on a large geographic scale.

Discovery, optimization and validation of an optimal DNA-binding sequence for the Six1 homeodomain transcription factor.

The Six1 transcription factor is a homeodomain protein involved in controlling gene expression during embryonic development. Six1 establishes gene expression profiles that enable skeletal myogenesis and nephrogenesis, among others. While several homeodomain factors have been extensively characterized with regards to their DNA-binding properties, relatively little is known of the properties of Six1. We have used the genomic binding profile of Six1 during the myogenic differentiation of myoblasts to obtain a better understanding of its preferences for recognizing certain DNA sequences. DNA sequence analyses on our genomic binding dataset, combined with biochemical characterization using binding assays, reveal that Six1 has a much broader DNA-binding sequence spectrum than had been previously determined. Moreover, using a position weight matrix optimization algorithm, we generated a highly sensitive and specific matrix that can be used to predict novel Six1-binding sites with highest accuracy. Furthermore, our results support the idea of a mode of DNA recognition by this factor where Six1 itself is sufficient for sequence discrimination, and where Six1 domains outside of its homeodomain contribute to binding site selection. Together, our results provide new light on the properties of this important transcription factor, and will enable more accurate modeling of Six1 function in bioinformatic studies.

A large population of 'Lyman-break' galaxies in a protocluster at redshift z approximately 4.1.

The most massive galaxies and the richest clusters are believed to have emerged from regions with the largest enhancements of mass density relative to the surrounding space. Distant radio galaxies may pinpoint the locations of the ancestors of rich clusters, because they are massive systems associated with 'overdensities' of galaxies that are bright in the Lyman-alpha line of hydrogen. A powerful technique for detecting high-redshift galaxies is to search for the characteristic 'Lyman break' feature in the galaxy colour, at wavelengths just shortwards of Lyalpha, which is due to absorption of radiation from the galaxy by the intervening intergalactic medium. Here we report multicolour imaging of the most distant candidate protocluster, TN J1338-1942 at a redshift z approximately 4.1. We find a large number of objects with the characteristic colours of galaxies at that redshift, and we show that this excess is concentrated around the targeted dominant radio galaxy. Our data therefore indicate that TN J1338-1942 is indeed the most distant cluster progenitor of a rich local cluster, and that galaxy clusters began forming when the Universe was only ten per cent of its present age.