Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25 mM) for up to 48 h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.

The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit. Here, we show that cholangiocytes express histidine decarboxylase and its inhibition reduces CCA growth. MC recruitment in the tumor microenvironment increased CCA growth. MC infiltration and MC markers were detected by toluidine blue staining and real-time PCR in human biopsies and in tumors from athymic mice treated with saline, histamine, histidine decarboxylase inhibitor, or cromolyn sodium. Tumor growth, angiogenesis, and epithelial-mesenchymal transition (EMT)/extracellular matrix (ECM) markers were measured in mice treated with cromolyn sodium. In vitro, human CCA cells were treated with MC supernatant fluids before evaluating angiogenesis and EMT/ECM expression. Migration assays were performed with CCA cells treated with the stem cell factor inhibitor. MC supernatant fluids increased CCA histidine decarboxylase, vascular endothelial growth factor, and MC/EMT/ECM expression that decreased with pretreatment of cromolyn sodium. MCs were found in human biopsies. In mice treated with cromolyn sodium, MC infiltration and tumor growth decreased. Inhibition of CCA stem cell factor blocked MC migration and MC/EMT/ECM in CCA. MCs migrate into CCA tumor microenvironment via c-Kit/stem cell factor and increase tumor progression, angiogenesis, EMT switch, and ECM degradation. Cholangiocarcinoma (CCA) cancers are primary tumors that arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts of the liver.1 CCA is the second most prevalent liver tumor after hepatocellular carcinoma and accounts for 10% to 20% of deaths caused by hepatobiliary malignancies.2 Increased risk of developing CCA is associated with primary sclerosing cholangitis, liver fluke infestation, hepatitis C virus infection, and other diseases that lead to chronic biliary obstruction and inflammation.3 CAA is a metastatic cancer, and studies have found its potential to migrate outside of the biliary tract. 4 We have found that histamine via the H4 histamine receptor (HR)

SARS-CoV-2 has been associated with an increased rate of venous thromboembolism in critically ill patients. Since surgical patients are already at higher risk of venous thromboembolism than general populations, this study aimed to determine if patients with peri-operative or prior SARS-CoV-2 were at further increased risk of venous thromboembolism. We conducted a planned sub-study and analysis from an international, multicentre, prospective cohort study of elective and emergency patients undergoing surgery during October 2020. Patients from all surgical specialties were included. The primary outcome measure was venous thromboembolism (pulmonary embolism or deep vein thrombosis) within 30 days of surgery. SARS-CoV-2 diagnosis was defined as peri-operative (7 days before to 30 days after surgery); recent (1-6 weeks before surgery); previous (≥7 weeks before surgery); or none. Information on prophylaxis regimens or pre-operative anti-coagulation for baseline comorbidities was not available. Postoperative venous thromboembolism rate was 0.5% (666/123,591) in patients without SARS-CoV-2; 2.2% (50/2317) in patients with peri-operative SARS-CoV-2; 1.6% (15/953) in patients with recent SARS-CoV-2; and 1.0% (11/1148) in patients with previous SARS-CoV-2. After adjustment for confounding factors, patients with peri-operative (adjusted odds ratio 1.5 (95%CI 1.1-2.0)) and recent SARS-CoV-2 (1.9 (95%CI 1.2-3.3)) remained at higher risk of venous thromboembolism, with a borderline finding in previous SARS-CoV-2 (1.7 (95%CI 0.9-3.0)). Overall, venous thromboembolism was independently associated with 30-day mortality ). In patients with SARS-CoV-2, mortality without venous thromboembolism was 7.4% (319/4342) and with venous thromboembolism was 40.8% (31/76). Patients undergoing surgery with peri-operative or recent SARS-CoV-2 appear to be at increased risk of postoperative venous thromboembolism compared with patients with no history of SARS-CoV-2 infection. Optimal venous thromboembolism prophylaxis and treatment are unknown in this cohort of patients, and these data should be interpreted accordingly.

Background Widespread healthcare restructuring due to the COVID-19 pandemic led to modifications in the timing and delivery of care for breast cancer patients. Our study explores patient concerns relating to COVID-19, breast cancer, and changes to breast cancer care. Patients and Methods Breast cancer patients who presented for surgical consultation at an academic, multidisciplinary clinic completed the electronically distributed validated COVID-19 Impact and Healthcare Related Quality of Life questionnaire between August 2020 and February 2021. This questionnaire uses Likert score responses to assess COVID-specific concerns within domains, including distress and financial hardship. Scale scores were determined by averaging items within each domain, and scores > 2 indicated greater disruption. Semistructured interviews were conducted with patients who indicated interest in participating in the questionnaire. Results Of 381 patients recruited, 133 patients completed the questionnaire and 20 patients completed interviews. Sixty-three percent of survey participants reported attending a telemedicine appointment for their cancer care, and the majority (67%) were satisfied with their experience. Half of the participants (50%) reported fear about how the COVID-19 pandemic will impact their cancer care or recovery, and 66% reported anxiety about contracting COVID-19. Twenty-two percent of participants reported decreased income due to COVID-19. Patient interviews revealed tangible changes to care and provided in-depth information on the advantages and disadvantages of telehealth. Conclusions Breast cancer patients report anxiety about COVID-19 infection and potential care modifications. Our study identifies impacts on patients’ care and quality of life. Further investigation will inform interventions to improve psychosocial outcomes for patients and the telehealth experience. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-021-11209-1.