Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Introduction: Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. Methods: This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Results: Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. Discussion: These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

Do Cancer Genetics Impact Treatment Decision Making? Immunotherapy and Beyond in the Management of Advanced and Metastatic Urothelial Carcinoma.

Bladder cancer is one of the most commonly diagnosed genitourinary malignancies. For many years, the primary treatment for metastatic urothelial cancer (mUC) was predicated on the use of platinum-based chemotherapy. More recently, immune checkpoint inhibitors (ICIs) were approved by regulatory agencies such as the US FDA for use in both the first- and second-line settings. This review outlines the approved ICIs for mUC in the second-line setting and as an alternative to chemotherapy in the first-line setting, as well as the novel agents that have also been incorporated into the treatment of this malignancy. Single-agent ICIs are often used in second-line settings in mUC, and there are three drugs currently approved for those who progress after receiving platinum-based chemotherapy. In the first-line setting, the preferred treatment regimen remains cisplatin-based chemotherapy. However, single-agent ICI can be an alternative first-line treatment for those who are not candidates for cisplatin-based therapy. There are also clinical trials adding ICIs to chemotherapy as combination regimens. However, treatment for mUC has now expanded even beyond immunotherapy. Newer targeted agents such as erdafitinib, a fibroblast growth factor receptor inhibitor, and two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been recently approved. As new drug agents are discovered, it will be important to assess both the treatment outcomes as well as the effects on patients' quality of life. Furthermore, integrating genetic and molecular information can help guide treatment decisions as next-generation sequencing is more commonly acquired during the evaluation of newly diagnosed patients with advanced and metastatic cancer.

Management and Outcomes of Adults Diagnosed with Acute Pulmonary Embolism in Primary Care: Community-Based Retrospective Cohort Study.

BACKGROUND: The management and outcomes of patients diagnosed with acute pulmonary embolism in primary care have not been characterized. OBJECTIVE: To describe 30-day outcomes stratified by initial site-of-care decisions DESIGN: Multicenter retrospective cohort study PARTICIPANTS: Adults diagnosed with acute pulmonary embolism in primary care in a large, diverse community-based US health system (2013-2019) MAIN MEASURES: The primary outcome was a composite of 30-day serious adverse events (recurrent venous thromboembolism, major bleeding, and all-cause mortality). The secondary outcome was 7-day pulmonary embolism-related hospitalization, either initial or delayed. KEY RESULTS: Among 652 patient encounters (from 646 patients), median age was 64 years; 51.5% were male and 70.7% identified as non-Hispanic white. Overall, 134 cases (20.6%) were sent home from primary care and 518 cases (79.4%) were initially referred to the emergency department (ED) or hospital. Among the referred, 196 (37.8%) were discharged home from the ED without events. Eight patients (1.2%; 95% CI 0.5-2.4%) experienced a 30-day serious adverse event: 4 venous thromboemboli (0.6%), 1 major bleed (0.2%), and 3 deaths (0.5%). Seven of these patients were initially hospitalized, and 1 had been sent home from primary care. All 3 deaths occurred in patients with known metastatic cancer initially referred to the ED, hospitalized, then enrolled in hospice following discharge. Overall, 328 patients (50.3%) were hospitalized within 7 days: 322 at the time of the index diagnosis and 6 following initial outpatient management (4 clinic-only and 2 clinic-plus-ED patients). CONCLUSIONS: Patients diagnosed with acute pulmonary embolism in this primary care setting uncommonly experienced 30-day adverse events, regardless of initial site-of-care decisions. Over 20% were managed comprehensively by primary care. Delayed 7-day pulmonary embolism-related hospitalization was rare among the 51% treated as outpatients. Primary care management of acute pulmonary embolism appears to be safe and could have implications for cost-effectiveness and patient care experience.

Comprehensive management of acute pulmonary embolism in primary care using telemedicine in the COVID-era.

A healthy, active woman in her 70s reported intermittent exertional dyspnoea for 2 months, notable during frequent open-water swimming. Symptoms were similar to an episode of travel-provoked pulmonary embolism 3 years prior. She denied chest pain, cough, fever, extremity complaints and symptoms at rest. Due to the COVID-19 pandemic, her healthcare system was using secure telemedicine to evaluate non-critical complaints. During the initial video visit, she appeared well, conversing normally without laboured breathing. An elevated serum D-dimer prompted CT pulmonary angiography, which identified acute lobar pulmonary embolism. After haematology consultation and telephone conversation with the patient, her physician prescribed rivaroxaban. Her symptoms rapidly improved. She had an uneventful course and is continuing anticoagulation indefinitely. The pandemic has increased the application of telemedicine for acute care complaints. This case illustrates its safe and effective use for comprehensive management of acute pulmonary embolism in the primary care setting.

"Outpatient Management" of Pulmonary Embolism Defined in the Primary Literature: A Narrative Review.

PURPOSE: The evidence for the effectiveness of outpatient treatment of low-risk patients with acute pulmonary embolism (PE) continues to mount. However, lack of definitional clarity may hinder understanding of this emerging management strategy and impede translation into clinical practice. We describe the range of definitions provided in the primary outpatient PE literature. METHODS: We undertook a narrative review of the English-language medical literature indexed in PubMed and Embase through the end of 2019. We identified studies of outpatient treatment of patients with acute PE. RESULTS: Fifty-one studies met our criteria. All studies provided some degree of definition of "outpatient," even if implicit or broad. Forty-six studies (90%) reported 1 or 2 sites of patient discharge (or departure) to home: emergency department (ED)/ambulatory care unit (n = 31), inpatient ward (n = 13), and secondary care clinic (n = 8). Of the 31 ED-based studies, 9 (29%) delimited duration of care (from < 24 to < 48 hours). All inpatient studies placed an outer boundary on the time to discharge within their definition of outpatient care. CONCLUSION: Definitions of outpatient care in the PE literature vary considerably. The sites, duration, and intensity of care involved in outpatient PE management prior to home discharge range from comprehensive specialty clinic care to an ED evaluation, sometimes coupled with 1 to 5 days of additional inpatient care. Research on the outpatient management of acute PE would benefit from greater definitional clarity as clinicians, departments, and health systems seek to translate this research into real-world clinical practice.

Challenges in Managing Isolated Subsegmental Pulmonary Embolism.

This commentary explores the clinical conundrums arising when caring for patients with acute pulmonary embolism isolated to the subsegmental pulmonary arteries. We discuss ways to confirm the radiologic diagnosis, how to distinguish patients for whom anticoagulation is indicated from those who are eligible for structured surveillance without anticoagulation, what surveillance entails, and why ensuring continuity of care matters. We report a case from our own experience that illustrates these decision-making crossroads and highlights the importance of cross-disciplinary collaboration. Because the evidence in the literature is currently weak and indirect, we draw on expert opinion in US and European guidelines, a recent statement from a multidisciplinary consensus panel, and several ongoing well-designed clinical trials. This discussion will help clinicians better manage the spectrum of patients who present with isolated subsegmental embolism.

Managing acute pulmonary embolism in primary care in a patient declining emergency department transfer: a case report.

BACKGROUND: For patients with acute pulmonary embolism (PE) diagnosed in the primary care setting, transfer to a higher level of care, like the emergency department, has long been the convention. Evidence is growing that outpatient management, that is, care without hospitalization, is safe, effective, and feasible for selected low-risk patients with acute PE. Whether outpatient care can be provided entirely in the primary care setting has not been well-studied. We report a case of outpatient management of a low-risk patient with acute PE without emergency department transfer. CASE SUMMARY: A 74-year-old woman with a history of recent surgery and immobilization presented to a primary care physician with 10 days of mild, non-exertional pleuritic chest pain. Her D-dimer concentration was elevated. Computed tomography pulmonary angiography identified a lobar embolus without right ventricular dysfunction. She declined emergency department transfer but was classified as low risk (class II) on the PE Severity Index and met the criteria of the European Society of Cardiology (ESC) for outpatient care. Her physician provided comprehensive clinic-based PE management, discharging her to home with education, anticoagulation, and close follow-up. She completed her 3-month treatment course without complication. DISCUSSION: This case describes patient-centred, comprehensive, outpatient PE management in the primary care setting for a woman meeting explicit ESC outpatient criteria. This case illustrates the elements of care that clinics can put in place to facilitate PE management without having to transfer eligible low-risk patients to a higher level of care.

Primary care physicians comprehensively manage acute pulmonary embolism without higher-level-of-care transfer: A report of two cases.

RATIONALE: The evidence for outpatient pulmonary embolism (PE) management apart from hospitalization is expanding. The availability and ease of direct oral anticoagulants have facilitated this transition. The literature, however, is sparse on the topic of comprehensive management of pulmonary embolism in the primary care clinic setting. As such, the role of the primary care physician in the complete diagnosis, risk stratification for outpatient eligibility, and initiation of treatment is unclear. CASE PRESENTATIONS: Case 1: A 33-year-old man with known heterozygous Factor V Leiden mutation and a remote history of deep vein thrombosis presented to his primary care physician's office with 2 days of mild pleuritic chest pain and a dry cough after a recent transcontinental flight. Case 2: A 48-year-old man with a complex medical history including recent transverse myelitis presented to his primary care family physician with dyspnea and pleuritic chest pain for 6 days. DIAGNOSIS: Case 1: Computed tomographic pulmonary angiography that same afternoon showed multiple bilateral segmental and subsegmental emboli as well as several small pulmonary infarcts. Case 2: The patient's D-dimer was elevated at 1148 ng/mL. His physician ordered a computed tomographic pulmonary angiography, performed that evening, which showed segmental and subsegmental PE. INTERVENTIONS: Both patients were contacted by their respective physicians shortly after their diagnoses and, in shared decision-making, opted for treatment at home with 5 days of enoxaparin followed by dabigatran. OUTCOMES: Neither patient developed recurrence nor complications in the subsequent 3 months. LESSONS: These cases, stratified as low risk using the American College of Chest Physicians criteria and the PE Severity Index, are among the first in the literature to illustrate comprehensive primary care-based outpatient PE management. Care was provided within an integrated delivery system with ready, timely access to laboratory, advanced radiology, and allied health services. This report sets the stage for investigating the public health implications of comprehensive primary care-based PE management, including cost-savings as well as enhanced patient follow-up and patient satisfaction.