The Journey of Insulin: Leaving a Legacy as a Medical Student

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Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone

BackgroundGiant cell lesions are locally aggressive intraosseous neoplasms with capacity to metastasize. The role of immune surveillance in the pathophysiology of giant cell lesions is poorly understood, and understanding what role the immune system plays in giant cell lesions may lead to the development of more effective treatment. The aim of this study was to explore the role of immune surveillance in giant cell lesions by examining the expression of the HLA class I and class II antigens and tumor infiltrating lymphocytes. In addition, we examined the role of the immune modulating surface antigen B7-H3, which belongs to the B7 superfamily, a group of molecules that modulates T-cell responses.Questions/purposes(1) Is an immune response elicited by giant cell lesions? (2) Do clinically relevant human leukocyte antigen (HLA) defects exist in giant cell lesions? (3) Is B7-H3 a clinically relevant immune modulator?MethodsThe study sample was derived from the population of patients presenting to the Massachusetts General Hospital for evaluation and management of giant cell lesions from 1993 to 2008. We included patients with histologically confirmed giant cell lesions with a minimum followup of 6 months. Patients with systemic diseases (n = 4 [3%]), syndromes associated with giant cell lesions (n = 4 [3%]), and those without sufficient followup (n = 26 [19%]), inadequate records (n = 7 [5%]), or inadequate tissue available (n = 2 [1%]) were excluded. Tissue microarray, containing 288 tissue cores for 93 patients, was carefully constructed. This contained tissue from 45 patients with maxillofacial lesions, 38 with aggressive and seven with nonaggressive lesions, and 48 patients with axial and appendicular lesions, 30 with aggressive lesions and 18 with nonaggressive lesions. The population mean age was 28 ± 12 years and the duration of followup was 4 ± 3 years. The tissue microarray was immunohistochemically stained with monoclonal antibodies specific for HLA classes I and II and B7-H3 antigens and analyzed for tumor infiltrating lymphocytes. Antigen expression was examined in multinucleated giant cells and mononuclear stromal cells. The results were correlated with local invasion and tumor aggressiveness, which is based on accepted staging criteria.ResultsTumor infiltrating lymphocytes were detected in all the tumors. The mean number of CD8+ T cell infiltration was lower in aggressive tumors (median, 4.8; interquartile range [IQR], 0.4-13.4), when compared with nonaggressive tumors (median, 15.8; IQR, 4.3-46.3; p = 0.007). HLA class I antigens were highly expressed by multinucleated giant cells in all tumors, but were lightly expressed on mononuclear stromal cells in 53% (45 of 84) to 73% (56 of 77) of tumors. HLA class I antigen low expression in mononuclear stromal cells was associated with tumor aggressiveness (odds ratio [OR], 4.3; p = 0.005). Low HLA class I expression combined with low CD8+ T cell infiltration was most highly associated with tumor aggressiveness (OR, 7.81; p = 0.011). B7-H3 antigen was expressed in 36.9% mononuclear stroma cells and also was associated with local tumor invasion (OR, 1.36; p < 0.001). Similarly, giant cell lesions with high B7-H3 expression and low CD8+ tumor infiltrating lymphocytes were associated with increased tumor aggressiveness (OR, 8.89; p = 0.0491).ConclusionsLocally aggressive giant cell lesions are associated with low HLA class 1 antigen expression, low CD8+T cell infiltration, and high expression of the immune modulator B7-H3.Clinical relevanceFailure of immune surveillance implies that there may be an opportunity to target aspects of the immune surveillance machinery to treat giant cell lesions

Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone

Giant cell lesions are locally aggressive intraosseous neoplasms with capacity to metastasize. The role of immune surveillance in the pathophysiology of giant cell lesions is poorly understood, and understanding what role the immune system plays in giant cell lesions may lead to the development of more effective treatment. The aim of this study was to explore the role of immune surveillance in giant cell lesions by examining the expression of the HLA class I and class II antigens and tumor infiltrating lymphocytes. In addition, we examined the role of the immune modulating surface antigen B7-H3, which belongs to the B7 superfamily, a group of molecules that modulates T-cell responses. (1) Is an immune response elicited by giant cell lesions? (2) Do clinically relevant human leukocyte antigen (HLA) defects exist in giant cell lesions? (3) Is B7-H3 a clinically relevant immune modulator? The study sample was derived from the population of patients presenting to the Massachusetts General Hospital for evaluation and management of giant cell lesions from 1993 to 2008. We included patients with histologically confirmed giant cell lesions with a minimum followup of 6 months. Patients with systemic diseases (n = 4 [3%]), syndromes associated with giant cell lesions (n = 4 [3%]), and those without sufficient followup (n = 26 [19%]), inadequate records (n = 7 [5%]), or inadequate tissue available (n = 2 [1%]) were excluded. Tissue microarray, containing 288 tissue cores for 93 patients, was carefully constructed. This contained tissue from 45 patients with maxillofacial lesions, 38 with aggressive and seven with nonaggressive lesions, and 48 patients with axial and appendicular lesions, 30 with aggressive lesions and 18 with nonaggressive lesions. The population mean age was 28 ± 12 years and the duration of followup was 4 ± 3 years. The tissue microarray was immunohistochemically stained with monoclonal antibodies specific for HLA classes I and II and B7-H3 antigens and analyzed for tumor infiltrating lymphocytes. Antigen expression was examined in multinucleated giant cells and mononuclear stromal cells. The results were correlated with local invasion and tumor aggressiveness, which is based on accepted staging criteria. Tumor infiltrating lymphocytes were detected in all the tumors. The mean number of CD8+ T cell infiltration was lower in aggressive tumors (median, 4.8; interquartile range [IQR], 0.4-13.4), when compared with nonaggressive tumors (median, 15.8; IQR, 4.3-46.3; p = 0.007). HLA class I antigens were highly expressed by multinucleated giant cells in all tumors, but were lightly expressed on mononuclear stromal cells in 53% (45 of 84) to 73% (56 of 77) of tumors. HLA class I antigen low expression in mononuclear stromal cells was associated with tumor aggressiveness (odds ratio [OR], 4.3; p = 0.005). Low HLA class I expression combined with low CD8+ T cell infiltration was most highly associated with tumor aggressiveness (OR, 7.81; p = 0.011). B7-H3 antigen was expressed in 36.9% mononuclear stroma cells and also was associated with local tumor invasion (OR, 1.36; p < 0.001). Similarly, giant cell lesions with high B7-H3 expression and low CD8+ tumor infiltrating lymphocytes were associated with increased tumor aggressiveness (OR, 8.89; p = 0.0491). Locally aggressive giant cell lesions are associated with low HLA class 1 antigen expression, low CD8+T cell infiltration, and high expression of the immune modulator B7-H3. Failure of immune surveillance implies that there may be an opportunity to target aspects of the immune surveillance machinery to treat giant cell lesions

PD-L1 and HLA class i antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma

Purpose: More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells. Experimental Design: Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated. Results: Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8+ T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. Conclusions: ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study

Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis. Setting Prospective, international, multicentre, observational cohort study. Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative). Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality. Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787). Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups. Trial registration number NCT0432364