Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

IMPORTANCE: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. OBJECTIVE: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. EXPOSURE: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. MAIN OUTCOMES AND MEASURES: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. RESULTS: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). CONCLUSIONS AND RELEVANCE: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

A Stroke of Bad Luck

Introduction Unusual case of adrenal masses in a normotensive patient Clinical case A 37 year old female, no significant medical history, presented with sudden onset of right sided weakness and dysarthria. On presentation she was normotensive but exhibited expressive aphasia and complete right hemiplegia. Initial CT Head demonstrated a dense left MCA infarct with no hemorrhage. Echo was normal. Abdominal Ultra sonogram and CT revealed large bilateral cystic and solid adrenal masses, right measured 22x12.5x11cm, weighing 2058g and left measured 16x11.5x7.7cm, weighing 672g; highly suspicious for neoplastic disease. A repeat CT head showed increasing edema and brainstem herniation which necessitated emergent decompressive frontotemporoparietal craniectomy and durotomy. 24-hour urine studies were metanephrine 130,896 µg (35-460 µg), normetanephrine 25,938 µg (110-1050 µg) and vanillylmandelic acid 127.2 mg (1.8-6.7 mg). TSH and serum calcitonin were normal. MEN2 screening for RET proto-oncogene mutation was negative. Hypercoagulable work up was negative. Patient was pretreated with phenoxybenzamine and had exploratory laparotomy and bilateral adrenalectomy. Pathology and immunohistochemical staining confirmed the diagnosis of bilateral benign pheochromocytomas. Patient was discharged with daily hydrocortisone and fludrocortisone. 24-hour urinary fractionated metanephrines measured 2 weeks post-surgery were normal. The triad of episodic headache, sweating and tachycardia is infrequent; pheochromocytomas may present as paroxysmal hypertension, acute pulmonary edema, myocardial infarction or stroke. Plasma metanephrines were normal though urinary metanephrines were elevated. Patient was not on medication that might alter catecholamine metabolism. Conclusion Manifestations of catecholamine hypersecretion are common. Though adrenal masses were found incidentally in our patient, pheochromocytoma should be considered in young patients presenting with acute stroke

A rare cutaneous manifestation of immune checkpoint inhibitor therapy

Abstract Leukocytoclastic vasculitis can be an uncommon and/or underreported adverse event of immune checkpoint inhibitor therapy, an established cancer treatment option. Differentiation among other cutaneous manifestations of adverse medication reactions—such as Stevens–Johnson syndrome, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—is crucial for guiding management

Treatment of Anaphylaxis unmasks another Life-Treatening condition-Pheochromocytoma

Introduction We report an unusual case of pheochromocytoma unmasked by anaphylaxis. Clinical case A 65 year old male with a history of hypertension, non-insulin dependent diabetes mellitus presented after multiple wasp stings. He was hypertensive with swelling of his tongue, face and neck. He was treated with epinephrine, diphenhydramine, methylprednisolone and famotidine. After few hours, he had acute onset of dyspnea with hypoxia and profound hypertension. Examination revealed acute pulmonary edema with a blood pressure of 265/140.He was treated with 100% oxygen, IV furosemide, IV enalapril and a nitroglycerin infusion. Troponin I was elevated at 1.77 ng/mL (0.00-1.5) and EKG showed acute T wave inversions in V4-6. Echocardiogram showed mild concentric left ventricular hypertrophy, ejection fraction 35%, and moderate global hypokinesis with moderate aortic stenosis. Left heart catheterization revealed mild luminal irregularities and moderate aortic stenosis. Given his severe hypertension with acute pulmonary edema after two doses of epinephrine, pheochromocytoma was suspected. 24-hr urine fractionated metanephrine was 20605 ug( 35-460) and normetanephrine was 5895 ug (110-1050).24-hr urine vanillylmandelic acid was 61.5mg (1.8-6.7).Serum aldosterone ,renin and calcitonin were 22.5ng/dL (1.0-16.0) ,37.22ng/ml/hr and 22.3 pg/ml(0.0-11.5) respectively. TSH was normal. CT and MRI of the abdomen showed a large left adrenal gland measuring 4.4 cm x 4.7 cm with central areas of necrosis and heterogeneous enhancement pattern suggesting pheochromocytoma. Patient was pretreated with phenoxybenzamine, labetalol and metyrosine and had elective left transabdominal radical adrenalectomy. Screening for MEN2 mutation in the RET proto-oncogene was negative. He was continued on labetalol, furosemide and insulin and subsequent echocardiogram showed improved left ventricular function. Conclusion Pheochromocytoma is a great masquerader that may present atypically with acute myocardial infarction, pulmonary edema, dilated cardiomyopathy or cardiogenic shock. In our case, the patient became profoundly hypertensive with acute pulmonary edema after receiving two doses of epinephrine for treatment of anaphylaxis likely due to already high amounts of epinephrine in the circulatory system. Given effective treatment options that significantly improve survival, it is essential to entertain the diagnosis with atypical presentations such as unexplained acute pulmonary edema

Metastasis of Ewing Sarcoma to the Pancreas: Case Report and Literature Review

Ewing sarcoma (ES) is a highly aggressive malignant bone cancer. ES is part of the Ewing sarcoma family of tumors (ESFT), which express characteristic t(11;22) translocation as well as higher levels of CD99. Given that metastasis and tumor burden are significant prognostic factors in patient’s response to treatment, prompt diagnosis is needed to effectively treat ESFT patients. However, the challenges in classifying and characterizing ESFT complicate effective management and treatment of ES. In this report, we present a rare case of ES metastasis to the pancreas. Upon review of the literature, we found 39 cases of ESFT involving the pancreas, but only 3 were metastatic to the pancreas while the remaining cases of ESFT primarily originated from the pancreas. Given the rarity of such metastasis, the positive outcome in our patient’s case may explain the importance of prompt diagnosis in order to initiate appropriate treatment

Hemophagocytic Lymphohistiocytosis induced by human granulocytic anaplasmosis: A case report and literature review into the immunopathogenesis

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous collection of immunological disorders characterized by severely disrupted immune homeostasis and dysregulated macrophage overactivation resulting in hyperinflammation, hypercytokinemia, histiocytic phagocytosis in hematolymphoid systems, and life-threatening organ damage. Human granulocytic anaplasmosis (HGA) is caused by Anaplasma phagocytophilum (Ap), one of the most common tick-borne diseases in North America and worldwide. The pathophysiology by which anaplasmosis triggers the development of human HLH remains unclear. Herein, we report a case of severe Anaplasma infection in Central Pennsylvania presenting with classical clinical features and laboratory findings of acquired, secondary HLH. From basic science to clinicopathological studies, we review and summarize the literature emphasizing the unique immunopathogenesis that informs diagnosis and management of Anaplasma-induced HLH

An ounce of prevention: The importance of calcium and vitamin D supplementation prior to using Denosumab

Objective: We present an uncommon case of severe hypocalcemia after two doses of denosumab injection. Case Presentation: 82 year old male who has prostate cancer with osseous metastasis was admitted with epigastric pain, nausea and constipation. He received two doses of 120mg SC denosumab, one dose of IM leuprolide acetate 22.5mg and was taking oral bicalutamide 50mg daily. His blood tests were as follows: calcium 5.7mg/dL(8.3-10.1);ionized calcium 0.76 mmol/ L(1.12-1.32);albumin 2.6g/dL(3.5-5.0); parathyroid hormone(PTH) 1053.9pg/ml (14-72);phosphorus 0.6mg/ dl (2.3-4.1);25-hydroxy vitamin D 10.8ng/ml(30- 100);magnesium 2.0mg/dL(1.6-2.6);creatinine 0.89mg/ dL(0.6-1.3)and alkaline phosphatase(ALP) 380 U/L(50- 136). Serum calcium, albumin and ALP prior to starting denosumab were 8.4 mg/dL (8.3-10.1), 2.9 g/dL (3.5-5.0) and 541 U/L (50-136) respectively. There was no prior 25-hydroxy vitamin D level. On physical examination he had mild epigastric tenderness but no paresthesia or tetany. He was treated with multiple ampules of IV calcium gluconate, calcium chloride and IV calcitriol and was started on weekly ergocalciferol (vitamin D2) 50000 units along with daily cholecalciferol (vitamin D3) 2000 units and calcium-vitamin D3. He was also supplemented with daily sodium potassium phosphate. After three weeks, the serum calcium was 7.4mg/dL (8.3-10.1), ionized calcium 1.02mmol/L (1.12-1.32), phosphorus 1.3mg/dL (2.3-4.1) and PTH 617.9pg/ml (14-72). Calcitriol was given to counteract the secondary hyperparathyroidism. He was discharged home on daily calcitriol, calcium-vitamin D3, cholecalciferol and sodium potassium phosphate. Discussion: Denosumab is a monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) that reduces osteoclastogenesis causing net influx of calcium into the bone resulting in low serum calcium. Hypocalcemia leads to secondary hyperparathyroidism causing phosphaturia resulting in hypophosphatemia. Most do not become hypocalcemic because of compensatory increase in PTH secretion, which may be blocked in vitamin D deficiency. The profound hypocalcemia could be due to concomitant vitamin D deficiency which resulted in an inability to up regulate gastrointestinal absorption of calcium. The guidelines suggest supplementation with calcium and vitamin D daily prior to initiation of denosumab, unless contraindicated. Most patients should receive a total of 1g of calcium (diet plus supplement) and 800 to 1200 IU of vitamin D daily. Conclusion: We present a case of severe hypocalcemia that is temporally related to denosumab injection which could have been probably avoided with regular supplementation of calcium and vitamin D prior to initiation of denosumab therapy