Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.

Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.

Effect of BMI on toxicities and survival among adolescents and young adults treated on DFCI Consortium ALL trials.

Adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) treated with asparaginase-containing pediatric regimens are commonly overweight or obese. We studied the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.3%) and overweight/obese in 181 (46.7%). Patients who were overweight or obese experienced higher nonrelapse mortality (NRM; 4-year, 11.7% vs 2.8%, P = .006), worse event-free survival (4-year, 63% vs 77%, P = .003), and worse overall survival (OS; 4-year, 64% vs 83%, P = .0001). Because younger (aged 15-29 years) AYAs more frequently had a normal BMI (79% vs 20%, P < .0001), we conducted separate analyses in each BMI group. We found excellent OS among younger and older (30-50 years) AYAs with normal BMI (4-year OS, 83% vs 85%, P = .89). Conversely, in AYAs who were overweight/obese, worse outcomes were seen in older AYAs (4-year OS, 55% vs 73%, P = .023). Regarding toxicity, AYAs who were overweight/obese experienced higher rates of grade 3/4 hepatotoxicity and hyperglycemia (60.7% vs 42.2%, P = .0005, and 36.4% vs 24.4%, P = .014, respectively) but had comparable rates of hypertriglyceridemia (29.5% vs 24.4%, P = .29). In a multivariable analysis, higher BMI was associated with worse OS, hypertriglyceridemia was associated with improved OS, and age was not associated with OS. In conclusion, among AYAs treated on DFCI Consortium ALL regimens, elevated BMI was associated with increased toxicity, increased NRM, and decreased OS. The deleterious effect of elevated BMI was more pronounced in older AYAs.

Cancer Demographics and Time-to-Care in Belize.

BACKGROUND: Belize is a middle-income Caribbean country with poorly described cancer epidemiology and no comprehensive cancer care capacity. In 2018, GO, Inc., a US-based NGO, partnered with the Ministry of Health and the national hospital in Belize City to create the first public oncology clinic in the country. Here, we report demographics from the clinic and describe time intervals to care milestones to allow for public health targeting of gaps. PATIENTS AND METHODS: Using paper charts and a mobile health platform, we performed a retrospective chart review at the Karl Heusner Memorial Hospital (KHMH) clinic from 2018 to 2022. RESULTS: During this time period, 465 patients with cancer presented to the clinic. Breast cancer (28%) and cervical cancer (12%) were most common. Most patients (68%) presented with stage 3 or 4 disease and were uninsured (78%) and unemployed (79%). Only 21% of patients ever started curative intent treatment. Median time from patient-reported symptoms to a biopsy or treatment was 130 and 189 days. For the most common cancer, breast, similar times were seen at 140 and 178 days. Time intervals at the clinic: <30 days from initial visit to biopsy (if not previously performed) and <30 days to starting chemotherapy. CONCLUSION: This study reports the first clinic-based cancer statistics for Belize. Many patients have months between symptom onset and treatment. In this setting, the clinic has built infrastructure allowing for minimal delays in care despite an underserved population. This further affirms the need for infrastructure investment and early detection programs to improve outcomes in Belize.

Nelarabine combination therapy for relapsed or refractory T-cell acute lymphoblastic lymphoma/leukemia.

Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (<18 years). After a median of 1 (range, 1-3) cycle of treatment, 24 patients (55%) achieved complete remission, 62% (18/29) with combination therapy and 40% (6/15) with monotherapy (P = .21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (95% confidence interval, 6.93-not reached) in the entire cohort and was higher in the combination therapy than in the monotherapy group (24-month OS, 53% vs 8%; P = .003). The rate of neurotoxicity was similar between groups (27% vs 17%; P = .46) and grade 3/4 anemia and thrombocytopenia were more frequent in the combination group (76% vs 20%; P < .001% and 66% vs 27%; P = .014, respectively). In a multivariate analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (hazard ratio, 0.41; P = .04 and hazard ratio, 0.25; P = .008, respectively). In conclusion, compared with monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with R/R T-ALL/LBL.

Race and Ethnicity and the Utilization of Security Responses in a Hospital Setting.

BACKGROUND: Security emergency responses (SERs) are utilized by hospitals to ensure the safety of patients and staff but can cause unintended morbidity. The presence of racial and ethnic inequities in SER utilization has not been clearly elucidated. OBJECTIVE: To determine whether Black and Hispanic patients experience higher rates of SER and physical restraints in a non-psychiatric inpatient setting. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients discharged from September 2018 through December 2019. EXPOSURE: Race and ethnicity, as reported by patients at time of registration. MAIN OUTCOMES: The primary outcome was whether a SER was called on a patient. The secondary outcome was the incidence of physical restraints among patients who experienced a SER. KEY RESULTS: Among 24,212 patients, 18,755 (77.5%) patients identified as white, 2,346 (9.7%) as Black, and 2,425 (10.0%) identified with another race. Among all patients, 1,827 (7.6%) identified as Hispanic and 21,554 (89.0%) as non-Hispanic. Sixty-six (2.8%) Black patients had a SER activated during their first admission, compared to 295 (1.6%) white patients. In a Firth logit multivariable model, Black patients had higher adjusted odds of a SER than white patients (adjusted odds ratio (aOR) 1.37 [95% confidence interval: 1.02, 1.81], p = 0.037). Hispanic patients did not have higher odds of having a SER called than non-Hispanic patients. In a Poisson multivariable model among patients who had a SER called, race and ethnicity were not found to be significant predictors of restraint. CONCLUSION: Black patients had higher odds of a SER compared to white patients. No significant differences were found between Hispanic and non-Hispanic patients. Future efforts should focus on assessing the generalizability of these findings, the underlying mechanisms driving these inequities, and effective interventions to address them.

Orthopaedic adverse events among adolescents and adults treated with asparaginase for acute lymphoblastic leukaemia.

Osteonecrosis (ON) is a complication of acute lymphoblastic leukaemia (ALL) treatment with patient- (age, female sex, genetic polymorphisms, presence of metabolic syndrome) and treatment-specific (glucocorticoid type and schedule) risk factors described. The potential role of asparaginase in increasing risk of ON via effects on coagulation, lipid metabolism, and steroid clearance is now also recognised. Paediatric studies consistently identify age as a key risk factor for ON, with adolescents at higher risk than young children. Fewer studies comprehensively report on risk of ON in adults, but available evidence suggests that adolescents and young adults (AYAs) treated with corticosteroid and asparaginase-containing paediatric-inspired regimens are more at risk than older adults treated with paediatric-inspired or traditional adult regimens. There are few proven strategies to prevent or mitigate the severity of ON and other orthopaedic complications of ALL therapy. Future clinical trials should carefully ascertain orthopaedic adverse events in adults. Evidence-based guidelines should be developed for management of orthopaedic adverse events in adults being treated for ALL, especially high-risk AYAs being treated with paediatric-inspired regimens.

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials.

Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

A woman presenting with an unusual cause of fulminant liver failure and sepsis.

We present the case of a 61-year-old woman who presented with acutely worsening right upper quadrant pain and was found to be in acute liver failure with Klebsiella pneumoniae bacteremia. Despite aggressive intensive care management, the patient ultimately died of refractory shock attributed to sepsis and fulminant liver failure. On autopsy, she was found unexpectedly to have diffuse intrahepatic cholangiocarcinoma with metastases to regional lymph nodes and intravascular spread to the lungs. The case highlights a rare instance where intrahepatic cholangiocarcinoma presents with acute liver failure and discusses key intensive care management principles of this clinical syndrome.

Euglycemic Diabetic Ketoacidosis With COVID-19 Infection in Patients With Type 2 Diabetes Taking SGLT2 Inhibitors.

OBJECTIVE: Diabetes mellitus is associated with poor outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Diabetic ketoacidosis (DKA) has also been reported to occur with this virus. A cluster of cases of euglycemic DKA (euDKA) was identified in patients with type 2 diabetes mellitus using sodium-glucose cotransporter-2 inhibitors (SGLT2is) who developed SARS-CoV-2 infection. METHODS: The cases were identified by the authors while providing clinical care, and details were collected. RESULTS: Five cases of euDKA, presenting with glucose levels <300 mg/dL, were identified over the course of 2 months by the endocrinology consult service. All patients had a history of type 2 diabetes mellitus with no known history of DKA. All were taking SGLT2is. Oral antihyperglycemic medications were stopped for all patients on admission. All received intravenous insulin infusion to treat DKA before being transitioned to a subcutaneous insulin regimen. SGLT2i use was discontinued for all patients who were discharged. CONCLUSION: EuDKA has been seen in the setting of acute illness in patients using SGLT2is, but this cluster of cases suggests that there is a specific association with SARS-CoV-2 infection. In addition to the known risk of euDKA with SGLT2i use, coronavirus disease 2019-specific mechanisms may include a direct toxic effect of the virus on the pancreatic islets, an accelerated inflammatory response promoting ketosis, and the diuretic effect of SGLT2i in conjunction with anorexia and vomiting. It is crucial to counsel patients to stop SGLT2is when sick, especially if SARS-CoV-2 infection is suspected.

Better evidence: prospective cohort study assessing the utility of an evidence-based clinical resource at the University of Rwanda.

OBJECTIVE: Evidence-based clinical resources (EBCRs) have the potential to improve diagnostic and therapeutic accuracy. The majority of US teaching medical institutions have incorporated them into clinical training. Many EBCRs are subscription based, and their cost is prohibitive for most clinicians and trainees in low-income and middle-income countries. We sought to determine the utility of EBCRs in an East African medical school. SETTING: The University of Rwanda (UR), a medical school located in East Africa. PARTICIPANTS: Medical students and faculty members at UR. INTERVENTIONS: We offered medical students and faculty at UR free access to UpToDate, a leading EBCR and conducted a cohort study to assess its uptake and usage. Students completed two surveys on their study habits and gave us permission to access their activity on UpToDate and their grades. RESULTS: Of the 980 medical students invited to enrol over 2 years, 547 did (56%). Of eligible final year students, 88% enrolled. At baseline, 92% of students reported ownership of an internet-capable device, and the majority indicated using free online resources frequently for medical education. Enrolled final year students viewed, on average, 1.24 topics per day and continued to use UpToDate frequently after graduation from medical school. Graduating class exam performance was better after introduction of UpToDate than in previous years. CONCLUSIONS: Removal of the cost barrier was sufficient to generate high uptake of a leading EBCR by senior medical students and habituate them to continued usage after graduation.

Patterns of Hydrocephalus in Rural Haiti: A Computed Tomography-Based Study.

INTRODUCTION/OBJECTIVE: Hydrocephalus is a common neurosurgical disorder that can lead to significant disability or death if not promptly identified and treated. Data on the burden of hydrocephalus in low-income countries are limited, given a lack of radiologic resources for the diagnosis of this condition. Here, we present an analysis of patterns of hydrocephalus from a large sample of computed tomography (CT) scans of the head performed at a public hospital in rural Haiti, a low-income country in the Caribbean. METHODS: We analyzed reports from 3614 CT scans of the head performed between July 2013 and January 2016 for findings that were consistent with a diagnosis of hydrocephalus (report indicating "hydrocephalus," "ventriculomegaly," or "enlargement of the ventricles"). Extracted data included demographics, study indication, radiologic findings, and reported etiology of hydrocephalus. RESULTS: In total, 119 scans had findings concerning for hydrocephalus (3.5% of all scans, 6.3% of abnormal scans; age range 0-90 years; median age 35.5 years; 49.6% male). Pediatric patients (<18 years of age) accounted for 39% of cases. In total, 113 of 119 (95%) scans had indications for possible neurosurgical intervention. Among these 113 scans, 36 (30%) scans demonstrated communicating hydrocephalus, 66 (55%) scans demonstrated noncommunicating hydrocephalus (primarily due to intraventricular hemorrhage [27 scans, 23%] or brain tumors [24, 20%]), and 11 (9%) scans were indeterminate regarding whether the hydrocephalus was communicating versus noncommunicating. CONCLUSIONS: In a large sample of CTs performed in a rural low-income setting, hydrocephalus was common, predominantly noncommunicating, and often associated with potentially operable intracranial lesions. Data of this nature can inform research, policy, and clinical collaborations that strengthen the neurosurgical capacity of low-income countries.

Bone marrow drives central nervous system regeneration after radiation injury.

Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow-derived monocytes and macrophages are essential for structural and functional repair mechanisms, including regeneration of cerebral white matter and improvement in neurocognitive function. Using a granulocyte-colony stimulating factor (G-CSF) receptor knockout mouse model in combination with bone marrow cell transplantation, MRI, and neurocognitive functional assessments, we demonstrate that bone marrow-derived G-CSF-responsive cells home to the injured brain and are critical for altering neural progenitor cells and brain repair. Additionally, compared with untreated animals, animals that received G-CSF following radiation injury exhibited enhanced functional brain repair. Together, these results demonstrate that, in addition to its known role in defense and debris removal, the hematopoietic system provides critical regenerative drive to the brain that can be modulated by clinically available agents.

Measuring and improving student engagement in clinical training.

PURPOSE: Volunteer service learning activities, including Student Run Clinics (SRCs), are becoming an increasingly popular extracurricular component of medical education. While there are reports that student clinicians generally enjoy their educational experiences at SRCs, it is not understood how to optimize and measure student engagement in them. To identify key drivers of student engagement a tool was created to measure volunteer experience at the Crimson Care Collaborative (CCC), a primary care SRC. METHODS: CCC volunteers were asked to complete an online engagement survey. Cross-sectional survey data were collected for 149 CCC volunteers (53% response rate). RESULTS: Multivariate linear regression showed that overall 'likelihood to recommend CCC to a friend' was significantly associated with students' perception of the clarity of their role within the clinic, frequency of interprofessional interactions, and overall quality of medical education. Students who volunteer more frequently and for longer periods of time had higher engagement scores. CONCLUSIONS: Measuring engagement is feasible in volunteer settings. Engagement appears to be dependent on both structural and experiential components. Easily modifiable components of job design (role definition, expected frequency of volunteering), are key drivers of volunteer engagement.

Head CT findings at a public hospital in rural Haiti.

BACKGROUND: Neuroimaging is often unavailable in low-income countries, creating challenges for precise diagnosis of neurologic disease in individual patients, and impeding acquisition of precise neuroepidemiologic data for program and policy development. METHODS: We analyzed reports from 3614 head CTs performed between July 2013 and January 2016 at Hôpital Universitaire de Mirebalais, a public academic hospital in rural Haiti, extracting patients' age, study indication, and radiologic findings. RESULTS: The most common indications for head CT were headache (27%), trauma (19.9%), abnormal neurological exam (12.2%), and stroke (11.3%). The most common categories of neurologic abnormalities were traumatic (31%), vascular (25.8%), and infectious (12%). Of 291 strokes, 64% were ischemic (median age at diagnosis 60.8years, SD 17.4) and 36% were hemorrhagic (median age 52.0, SD 15.5). In patients undergoing head CT for seizures or epilepsy, 17.5% had evidence of neurocysticercosis. In patients with head trauma, 42.6% had intracranial hemorrhage or fracture. Atrophy was noted on 10% of CTs (median age 57.1; SD 23.8), and was characterized as out of proportion to age in 2% (median age 34.1, SD 15.3). CONCLUSIONS: Median age of stroke patients in this rural low-income population is lower than in high-income countries and proportion of stroke due to intracerebral hemorrhage is higher. Neurocysticercosis is present in nearly one fifth of patients with seizures/epilepsy. These findings can inform policies and programs for prevention and treatment of neurologic disease in low-income settings.

Evidence-based medicine for all: what we can learn from a programme providing free access to an online clinical resource to health workers in resource-limited settings.

The rapidly changing landscape of medical knowledge and guidelines requires health professionals to have immediate access to current, reliable clinical resources. Access to evidence is instrumental in reducing diagnostic errors and generating better health outcomes. UpToDate, a leading evidence-based clinical resource is used extensively in the USA and other regions of the world and has been linked to lower mortality and length of stay in US hospitals. In 2009, the Global Health Delivery Project collaborated with UpToDate to provide free subscriptions to qualifying health workers in resource-limited settings. We evaluated the provision of UpToDate access to health workers by analysing their usage patterns. Since 2009, ∼2000 individual physicians and healthcare institutions from 116 countries have received free access to UpToDate through our programme. During 2013-2014, users logged into UpToDate ∼150 000 times; 61% of users logged in at least weekly; users in Africa were responsible for 54% of the total usage. Search patterns reflected local epidemiology with 'clinical manifestations of malaria' as the top search in Africa, and 'management of hepatitis B' as the top search in Asia. Our programme demonstrates that there are barriers to evidence-based clinical knowledge in resource-limited settings we can help remove. Some assumed barriers to its expansion (poor internet connectivity, lack of training and infrastructure) might pose less of a burden than subscription fees.