Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Cancer Diagnoses during Active Conflict: Experience from a Cancer Program in Northwest Syria.

Background Protracted conflict has destroyed Syria's health system with severe impacts on the diagnosis and treatment of chronic and high-cost diseases including cancer. Here, we review the type and (where possible) the stage of cancers diagnosed in a pathology laboratory serving Northwest Syria. Methods We retrospectively reviewed all pathology reports which reported a diagnosis of cancer from a pathology department in Northwest Syria from January to December 2020. Results A total of 397 new cancers were diagnosed during 2020 of which 191 were among males (48.1%) and 20 cases were in children aged 17 years or under (5%). The most common cancer in men was bladder cancer (15.7%) and skin cancers (14.7%) followed by cancers in the lymph nodes (includes primary and secondary; 9.9%.) In women, breast cancer (38.3%) followed by skin cancer skin (9.7%) and uterine cancer (8.7%) was the most common. The overall proportion of cancer diagnoses were breast cancer (20.2%), skin cancer (12.1%), cancer affecting lymph nodes (8.8%), and urinary bladder (8.3%) and colorectal cancer (7.3%). Discussion This preliminary analysis is the first report of cancer types and demographics in areas outside of government control in Syria since the onset of the conflict. Despite limitations, it presents some indication of the burden of oncological diagnoses in this area. Further research which aims to describe and address the burden of cancer on populations under ongoing conflict and humanitarian crises remains essential, especially in Northwest Syria given ongoing attacks and severe underfunding. There is a particular need to investigate how best to apply interventions and support health systems and cancer services within conflict settings. More support and resources need to be allocated to cancer centers with long-term health partnership models. The underresourced and understaffed conditions of the hospital are significant limits to a more detailed report.

Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19. Objective: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021. Interventions: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis. Results: Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15). Conclusions and Relevance: Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience.

Yttrium-90 transarterial radioembolization (TARE) is a locoregional therapy (LRT) for hepatocellular carcinoma (HCC). In this study, we present overall survival (OS) outcomes in a 1,000-patient cohort acquired over a 15-year period. Between December 1, 2003 and March 31, 2017, 1,000 patients with HCC were treated with TARE as part of a prospective cohort study. A comprehensive review of toxicity and survival outcomes was performed. Outcomes were stratified by baseline Child-Pugh (CP) class, United Network for Organ Sharing (UNOS), and Barcelona Clinic Liver Cancer (BCLC) staging systems. Albumin and bilirubin laboratory toxicities were compared to baseline. OS outcomes were reported using censoring and intention-to-treat methodologies. All treatments were outpatient, with a median one treatment per patient. Five hundred six (51%) were CP A, 450 (45%) CP B, and 44 (4%) CP C. Two hundred sixty-three (26%) patients were BCLC A, 152 (15%) B, 541 (54%) C, and 44 (4%) D. Three hundred sixty-eight (37%) were UNOS T1/T2, 169 (17%) T3, 147 (15%) T4a, 223 (22%) T4b, and 93 (9%) N/M. In CP A patients, censored OS for BCLC A was 47.3 (confidence interval [CI], 39.5-80.3) months, BCLC B 25.0 (CI, 17.3-30.5) months, and BCLC C 15.0 (CI, 13.8-17.7) months. In CP B patients, censored OS for BCLC A was 27 (CI, 21-30.2) months, BCLC B 15.0 (CI, 12.3-19.0) months, and BCLC C 8.0 (CI, 6.8-9.5) months. Forty-nine (5%) and 110 (11%) patients developed grade 3/4 albumin and bilirubin toxicities, respectively. CONCLUSION: Based on our experience with 1,000 patients over 15 years, we have made a decision to adopt TARE as the first-line transarterial LRT for patients with HCC. Our decision was informed by prospective data and incrementally reported demonstrating outcomes stratified by BCLC, applied as either neoadjuvant or definitive treatment. (Hepatology 2017).

Metastatic Malignant Paraganglioma: A Case Report and Review of Literature.

Metastasis is a rare presentation of non-secretory paraganglioma. Consequently, there is no standard of care for the treatment of metastatic malignant paraganglioma. The most widely used chemotherapy regimen for non-resectable cases includes cyclophosphamide, vincristine, and dacarbazine (CVD). CVD has been previously studied with variable therapeutic response. However, yttrium-90 (Y90) radioembolization has not been previously studied in the treatment of hepatic metastasis in patients diagnosed with malignant paraganglioma. This case report follows the treatment of a patient with stage IV mediastinal paraganglioma with metastasis to the liver. Treatment consisted of the CVD chemotherapy regimen and Y90 radioembolization of the hepatic lesions. After 10 cycles of CVD, the tumor size has decreased from 6.0 × 8.8 to 5.5 × 3.0 × 3.4 cm on computed tomography scan. The prominent metastatic liver lesions responded after Y90 radioembolization of both the right and left hepatic arteries. The prominent right hepatic lobe lesion has decreased in size from 2.6 × 3.4 × 3.0 cm to 2.6 × 2.8 × 2.9 cm. The prominent left hepatic lobe lesion originally measuring 1.6 cm in diameter completely resolved on follow-up imaging studies. After completion of 12 cycles of chemotherapy, the most recent positron emission testing scan determined no evidence of disease regarding both the primary mass and the hepatic lesions. This study demonstrates the first case of combination chemotherapy and Y90 radioembolization with a complete response per response evaluation criteria in solid tumors criteria. The approaches toward diagnosis and treatment corresponding to this case of malignant metastatic paraganglioma are also reviewed in this study.

War is the Enemy of Health. Pulmonary, Critical Care, and Sleep Medicine in War-Torn Syria.

The Syrian crisis, now in its fifth year, has created an unprecedented strain on health services and systems due to the protracted nature of the warfare, the targeting of medics and health care infrastructure, the exodus of physicians and nurses, the shortage of medical supplies and medications, and the disruption of medical education and training. Within a few short years, the life expectancy of resident Syrians has declined by 20 years. Over the first 4 years of the conflict, more than 75,000 civilians died from injuries incurred in the violence. More than twice as many civilians, including many women and children, have died prematurely of infectious and noninfectious chronic diseases for want of adequate health care. Doctors, local administrators, and nongovernmental organizations are struggling to manage the consequences of the conflict under substandard conditions, often using unorthodox methods of health care delivery in field hospitals and remotely by telehealth communication. Much-needed medical supplies are channeled through dangerous routes across the borders from Lebanon, Jordan, and Turkey. Physicians in the United States and other western nations have helped Syrian physicians make the most of the situation by providing training on introducing innovations in technology and treatment. Portable ultrasound machines have been introduced and are being used extensively in the management of trauma and shock. This report, prepared by members of the Syrian American Medical Society, documents current needs for health care relief within Syria, focusing on pulmonary, critical care, and sleep medicine, and some of the efforts currently underway to meet those needs.

Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy.

PURPOSE: The aim of this study was to analyze the safety, treatment characteristics and survival outcomes of Yttrium-90 (Y90) radioembolization for unresectable colorectal carcinoma (CRC) liver metastases refractory to standard of care therapy. METHODS: A total of 214 patients with CRC metastases were treated with Y90 radioembolization over 12 years. Toxicity was assessed using National Cancer Institute common terminology criteria. Overall survival was analyzed from date of diagnosis of primary cancer, hepatic metastases and from the first Y90. Uni/multivariate analyses were performed. Substratification by era of chemotherapeutics was performed. RESULTS: Most patients were male (60 %) and <65 years old (61 %). Of them, 98 % had been exposed to chemotherapy. Grade 3 lymphocyte, bilirubin, albumin, ALP and AST toxicities were observed in 39 %, 11 %, 10 %, 8 % and 4 % of patients, respectively. Grade 4 lymphocyte and ALP toxicities were observed in 5 % and 3 % of patients, respectively. Median overall survival was 43.0, 34.6, and 10.6 months from date of diagnosis of primary cancer, hepatic metastases and first Y90, respectively. Survival was significantly longer in patients: (1) who received ≤2 cytotoxic drugs (n = 104) than those who received 3 (n = 110) (15.2 vs. 7.5 months, p = 0.0001); and (2) who received no biologic agents (n = 52) compared with those that did (n = 162) (18.6 vs. 9.4 months, p = 0.0001). Multivariate analyses identified ≤2 cytotoxic agents, no exposure to biologics, ECOG 0, tumor burden <25 %, lack of extrahepatic disease and albumin >3 g/dL as independent predictors of survival. CONCLUSION: In this largest metastatic CRC series published to date, Y90 radioembolization was found to be safe; survival varied by prior therapy. Further studies are required to further refine the role of Y90 in metastatic CRC.

Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature.

Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response.

Evaluation of a short-term medical mission to Syrian refugee camps in Turkey.

BACKGROUND: The escalating political and humanitarian crisis in Syria has left thousands detained, killed or displaced in neighboring countries. Given the permission and co-operation of the Turkish health authorities, a short-term medical mission to the Syrian refugee camps in the Hatay province was arranged. MATERIALS AND METHODS: To assess this mission's impact and potential expansion to serve other more emergently inflicted areas both inside and outside the Syrian borders, an evaluation was conducted via survey questionnaire of participating physicians. RESULTS: While almost all respondents found the experience worthwhile and fulfilling, medical, social and educational challenges as well as possible solutions were outlined. CONCLUSION: The use of several specified principles to further guide efforts towards providing service, education, relief, and awareness would result in greater effect, sustainability and growth of the mission.

Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes.

PURPOSE: To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. METHODS AND MATERIALS: This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with (90)Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: The median dose was 113 Gy (29-299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (p < 0.0001), tumor burden ≤25% (p = 0.0019), albumin ≥3.5 g/dL (p = 0.017), and bilirubin ≤1.2 mg/dL (p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis (p = 0.0001 and p = 0.02). CONCLUSION: Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines recommending radioembolization as a potential option for unresectable hepatic neuroendocrine metastases.

Radiation segmentectomy: a novel approach to increase safety and efficacy of radioembolization.

PURPOSE: To describe a technique of segmental radioembolization for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Radiation segmentectomy was defined as radioembolization of two or fewer hepatic segments. We sought to (1) calculate dose when activity is delivered segmentally assuming uniform and nonuniform distribution and, (2) determine safety and efficacy of this novel technique. METHODS AND MATERIALS: A total of 84 patients with HCC who were treated with (90)Y radioembolization using a segmental approach were included in this analysis. The dose delivered to the segment was calculated assuming uniform and nonuniform microsphere distribution within the treatment volume. To calculate dose assuming nonuniform distribution, a tumor hypervascularity ratio was assigned. Posttreatment response (using size and necrosis guidelines), toxicity, time to progression, and survival were determined. RESULTS: The median treatment volume was 110 cm(3). The median radiation-naïve liver volume was 1403 cm(3). The median dose delivered to the segment(s) assuming uniform distribution was 521 Gy. Taking into account tumor hypervascularity (nonuniform distribution), the median dose delivered to the tumor and normal infused hepatic volume was 1214 Gy and 210 Gy, respectively. Response by size and necrosis guidelines was seen in 59% and 81% of patients. Grade 3/4 biochemical toxicities were observed in 8 patients (9%). Median time to progression was 13.6 months (95% confidence interval, 9.3-18.7 months); median survival was 26.9 months (95% confidence interval, 20.5-30.2 months). CONCLUSIONS: Radiation segmentectomy is a safe and efficacious method of selectively delivering high dose to the tumor with minimal exposure of normal parenchyma.

Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chemoembolization is one of several standards of care treatment for hepatocellular carcinoma (HCC). Radioembolization with Yttrium-90 microspheres is a novel, transarterial approach to radiation therapy. We performed a comparative effectiveness analysis of these therapies in patients with HCC. METHODS: We collected data from 463 patients who were treated with transarterial locoregional therapies (chemoembolization or radioembolization) over a 9-year period. We excluded patients who were not appropriate for comparison and analyzed data from 245 (122 who received chemoembolization and 123 who received radioembolization). Patients were followed for signs of toxicity; all underwent imaging analysis at baseline and follow-up time points. Overall survival was the primary outcome measure. Secondary outcomes included safety, response rate, and time-to-progression. Uni- and multivariate analyses were performed. RESULTS: Abdominal pain and increased transaminase activity were more frequent following chemoembolization (P < .05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P = .104). Although time-to-progression was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P = .046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P = .232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P = .42). CONCLUSIONS: Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization. Post hoc analyses of sample size indicated that a randomized study with > 1000 patients would be required to establish equivalence of survival times between patients treated with these two therapies.

Does multidetector CT attenuation change in colon cancer liver metastases treated with 90Y help predict metabolic activity at FDG PET?

PURPOSE: To evaluate the correlation between change in attenuation and tumor metabolic activity assessed by using fluorodeoxyglucose (FDG) positron emission tomography (PET) in colon cancer liver metastases treated with yttrium 90 ((90)Y) radioembolization. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant retrospective study was approved by the institutional review board; patient informed consent was waived. Unresectable chemorefractory colon cancer liver metastases treated with (90)Y radioembolization in 28 patients were evaluated at pre- and posttreatment multidetector computed tomographic (CT) and FDG PET scans. Maximum cross-sectional diameter, volume, and overall attenuation of target lesions were calculated. The percentage change (%Delta) in these parameters after treatment was calculated and correlated with the standardized uptake value (SUV) analysis at FDG PET. The accuracy of the radiologic parameters in helping predict response to treatment at FDG PET was assessed. Data were analyzed by using the Student t, Wilcoxon matched pair, Mann-Whitney, Spearman rank correlation, and chi(2) tests. The significance level was set at .05. RESULTS: Seventy-four metastatic lesions in 10 women and 18 men (mean age, 61.5 years +/- 14.3 [standard deviation]) were evaluated. Mean follow-up interval for multidetector CT after treatment was 30 days. A significant reduction in maximum cross-sectional diameter, volume, and attenuation was observed from pre- to posttreatment multidetector CT (P < .05). The %Delta in attenuation had higher correlation with %Delta in SUV (r = 0.61) than diameter (r = 0.39) or volume (r = 0.49) and also predicted the metabolic activity at FDG PET with higher sensitivity (P < .001). By using a threshold level of a reduction in attenuation of 15% or greater, attenuation showed 84.2% sensitivity and 83.3% specificity in predicting response at FDG PET evaluation. CONCLUSION: Changes in attenuation of colon cancer liver metastases treated with (90)Y radioembolization correlate highly with metabolic activity at FDG PET and may be useful as an early surrogate marker for assessing treatment response.