Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field.

BACKGROUND: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. METHODS: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test. RESULTS: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR. CONCLUSIONS: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

An Adolescent Boy With Hypoxia, Microscopic Hematuria, and Hypertension.

A 13-year-old boy presented with hypoxia, microscopic hematuria, and elevated blood pressures. Persistent microscopic hematuria and hypertension led to investigation of glomerular and non-glomerular causes of hematuria. After reviewing his clinical course, family history, and laboratory testing, an additional test was sent, revealing the diagnosis.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. PATIENTS AND METHODS: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. RESULTS: One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. CONCLUSION: Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

Successful whole lung lavage in a child with pulmonary alveolar proteinosis secondary to hematologic malignancy.

Pulmonary alveolar proteinosis (PAP) describes the accumulation of surfactant in the alveolar space. Secondary PAP has been reported in a variety of diseases, and in rare cases has been associated with hematologic malignancy. Treatment for PAP is based on the underlying disease process, and may include whole lung lavage, inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor, or statins. PAP secondary to hematologic malignancy has been reported to demonstrate poor response to whole lung lavage. We report a case of successful treatment of a pediatric patient with acute myeloid leukemia and secondary PAP using whole lung lavage.

Association of Sex With Postoperative Mortality Among Patients With Heart Failure Who Underwent Elective Noncardiac Operations.

Importance: Sex differences in postoperative outcomes in patients with heart failure (HF) have not been well characterized. Women generally experience a lower postoperative mortality risk after noncardiac operations. It is unclear if this pattern holds among patients with HF. Objectives: To determine if the risk of postoperative mortality is associated with sex among patients with HF who underwent noncardiac operations and to determine if sex is associated with the relationship between HF and postoperative mortality. Design, Setting, and Participants: This multisite cohort study used data from the US Department of Veterans Affairs Surgical Quality Improvement Project database for all patients who underwent elective noncardiac operations from October 1, 2009, to September 30, 2016, with a minimum of 1 year follow-up. The data analysis was conducted from May 1, 2018, to August 31, 2018. Exposures: Heart failure, left ventricular ejection fraction, and sex. Main Outcomes and Measures: Postoperative mortality at 90 days. Results: Among 609 735 patients who underwent elective noncardiac operations from 2009 to 2016, 47 997 patients had HF (7.9%; mean [SD] age, 68.6 [10.1] years; 1391 [2.9%] women) and 561 738 patients did not have HF (92.1%; mean [SD] age, 59.4 [13.4] years; 50 862 [9.1%] women). Among patients with HF, female sex was not independently associated with 90-day postoperative mortality (adjusted odds ratio [aOR], 0.97; 95% CI, 0.71-1.32). Although HF was associated with increased odds of postoperative mortality in both sexes compared with their peers without HF, the odds of postoperative mortality were higher among women with HF (aOR, 2.44; 95% CI, 1.73-3.45) than men with HF (aOR, 1.64; 95% CI, 1.54-1.74), suggesting that HF may negate the general protective association of female sex with postoperative mortality (P for interaction of HF × sex = .03). This pattern was consistent across all levels of left ventricular ejection fraction. Conclusions and Relevance: Although HF was associated with increased odds of postoperative mortality in both sexes compared with their peers without HF, the odds of postoperative mortality were higher among women with HF than men with HF, suggesting that HF may negate the general protective association of female sex with postoperative mortality risk in noncardiac operations.

Association Between Heart Failure and Postoperative Mortality Among Patients Undergoing Ambulatory Noncardiac Surgery.

Importance: Heart failure is an established risk factor for postoperative mortality, but how heart failure is associated with operative outcomes specifically in the ambulatory surgical setting is not well characterized. Objective: To assess the risk of postoperative mortality and complications in patients with vs without heart failure at various levels of echocardiographic (left ventricular systolic dysfunction) and clinical (symptoms) severity who were undergoing ambulatory surgery. Design, Setting, and Participants: In this US multisite retrospective cohort study of all adult patients undergoing ambulatory, elective, noncardiac surgery in the Veterans Affairs Surgical Quality Improvement Project database during fiscal years 2009 to 2016, a total of 355 121 patient records were identified and analyzed with 1 year of follow-up after surgery (final date of follow-up September 1, 2017). Exposures: Heart failure, left ventricular ejection fraction, and presence of signs or symptoms of heart failure within 30 days of surgery. Main Outcomes and Measures: The primary outcomes were postoperative mortality at 90 days and any postoperative complication at 30 days. Results: Among 355 121 total patients, outcome data from 19 353 patients with heart failure (5.5%; mean [SD] age, 67.9 [10.1] years; 18 841 [96.9%] male) and 334 768 patients without heart failure (94.5%; mean [SD] age, 57.2 [14.0] years; 301 198 [90.0%] male) were analyzed. Compared with patients without heart failure, patients with heart failure had a higher risk of 90-day postoperative mortality (crude mortality risk, 2.00% vs 0.39%; adjusted odds ratio [aOR], 1.95; 95% CI, 1.69-2.44), and risk of mortality progressively increased with decreasing systolic function. Compared with patients without heart failure, symptomatic patients with heart failure had a greater risk of mortality (crude mortality risk, 3.57%; aOR, 2.76; 95% CI, 2.07-3.70), as did asymptomatic patients with heart failure (crude mortality risk, 1.85%; aOR, 1.85; 95% CI, 1.60-2.15). Patients with heart failure had a higher risk of experiencing a 30-day postoperative complication than did patients without heart failure (crude risk, 5.65% vs 2.65%; aOR, 1.10; 95% CI, 1.02-1.19). Conclusions and Relevance: In this study, among patients undergoing elective, ambulatory surgery, heart failure with or without symptoms was significantly associated with 90-day mortality and 30-day postoperative complications. These data may be helpful in preoperative discussions with patients with heart failure undergoing ambulatory surgery.

Association of Left Ventricular Ejection Fraction and Symptoms With Mortality After Elective Noncardiac Surgery Among Patients With Heart Failure.

Importance: Heart failure is an established risk factor for postoperative mortality, but how left ventricular ejection fraction and heart failure symptoms affect surgical outcomes is not fully described. Objectives: To determine the risk of postoperative mortality among patients with heart failure at various levels of echocardiographic (left ventricular systolic dysfunction) and clinical (symptoms) severity compared with those without heart failure and to evaluate how risk varies across levels of surgical complexity. Design, Setting, and Participants: US multisite retrospective cohort study of all adult patients receiving elective, noncardiac surgery in the Veterans Affairs Surgical Quality Improvement Project database from 2009 through 2016. A total of 609 735 patient records were identified and analyzed with 1 year of follow-up after having surgery (final study follow-up: September 1, 2017). Exposures: Heart failure, left ventricular ejection fraction, and presence of signs or symptoms of heart failure within 30 days of surgery. Main Outcome and Measure: The primary outcome was postoperative mortality at 90 days. Results: Outcome data from 47 997 patients with heart failure (7.9%; mean [SD] age, 68.6 [10.1] years; 1391 women [2.9%]) and 561 738 patients without heart failure (92.1%; mean [SD] age, 59.4 [13.4] years; 50 862 women [9.1%]) were analyzed. Compared with patients without heart failure, those with heart failure had a higher risk of 90-day postoperative mortality (2635 vs 6881 90-day deaths; crude mortality risk, 5.49% vs 1.22%; adjusted absolute risk difference [RD], 1.03% [95% CI, 0.91%-1.15%]; adjusted odds ratio [OR], 1.67 [95% CI, 1.57-1.76]). Compared with patients without heart failure, symptomatic patients with heart failure (n = 5906) had a higher risk (597 deaths [10.11%]; adjusted absolute RD, 2.37% [95% CI, 2.06%-2.57%]; adjusted OR, 2.37 [95% CI, 2.14-2.63]). Asymptomatic patients with heart failure (n = 42 091) (2038 deaths [crude risk, 4.84%]; adjusted absolute RD, 0.74% [95% CI, 0.63%-0.87%]; adjusted OR, 1.53 [95% CI, 1.44-1.63]), including the subset with preserved left ventricular systolic function (1144 deaths [4.42%]; adjusted absolute RD, 0.66% [95% CI, 0.54%-0.79%]; adjusted OR, 1.46 [95% CI, 1.35-1.57]), also experienced elevated risk. Conclusions and Relevance: Among patients undergoing elective noncardiac surgery, heart failure with or without symptoms was significantly associated with 90-day postoperative mortality. These data may be helpful in preoperative discussions with patients with heart failure undergoing noncardiac surgery.

Long-term follow-up of pediatric head trauma patients treated at Mulago National Referral Hospital in Uganda.

In Brief: This study used telephone surveys as a novel method of measuring health outcomes and tracking healthcare utilization in pediatric head trauma patients at the national referral hospital in Uganda. As the first-ever long-term follow-up of this patient population in Uganda, this work establishes a baseline of pediatric head trauma outcomes and lays the groundwork for tracking and improving outcomes for similar patients in low-resource settings.

Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. METHODS: Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). RESULTS: With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000/QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000/QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000/QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000/QALY or $150,000/QALY willingness-to-pay threshold in all scenarios. CONCLUSION: The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation; however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

Life After the Neurosurgical Ward in Sub-Saharan Africa: Neurosurgical Treatment and Outpatient Outcomes in Uganda.

BACKGROUND: In the past decade, neurosurgery in Uganda experienced increasing surgical volume and a new residency training program. Although research has examined surgical capacity, minimal data exist on the patient population treated by neurosurgery and their eventual outcomes in sub-Saharan Africa. METHODS: Patients admitted to Mulago National Referral Hospital neurosurgical ward over 2 years (2014 and 2015) were documented in a prospective database. In total, 1167 were discharged with documented phone numbers and thus eligible for follow-up. Phone surveys were developed and conducted in the participant's language to assess mortality, neurologic outcomes, and follow-up health care. RESULTS: During the study period, 2032 patients were admitted to the neurosurgical ward, 80% for traumatic brain injury. A total of 7.8% received surgical intervention. The in-hospital mortality rate was 18%. A total of 870 patients were reached for phone follow-up, a 75% response rate, and 30-day and 1-year mortality were 4% and 8%, respectively. Almost one-half of patients had not had subsequent health care after the initial encounter. Most patients had Glasgow Outcome Scale-Extended scores consistent with good recovery and mild disability, with patients experiencing trauma faring best and patients with tumor faring worst. A total of 85% felt they returned to baseline work performance, and 76% of guardians felt that children returned to baseline school performance. CONCLUSIONS: The neurosurgical service provided health care to a large proportion of nonoperative patients. Phone surveys captured data on patients in whom nearly one-half would be lost to subsequent health care. Although mortality during initial hospitalization was high, more than 90% of those discharged survived at 1-year follow up, and the vast majority returned to work and school.

Beyond Infrastructure: Understanding Why Patients Decline Surgery in the Developing World: An Observational Study in Cameroon.

OBJECTIVE: The aim of this study was to quantify and describe a population of patients in rural Cameroon who present with a surgically treatable illness but ultimately decline surgery, and to understand the patient decision-making process and identify key socioeconomic factors that result in barriers to care. BACKGROUND: An estimated 5 billion people lack access to safe, affordable surgical care and anesthesia when needed, and this unmet need resides disproportionally in low-income countries (LICs). An understanding of the socioeconomic factors underlying decision-making is key to future efforts to expand surgical care delivery in this population. We assessed patient decision-making in a LIC with a cash-based health care economy. METHODS: Standardized interviews were conducted of a random sample of adult patients with treatable surgical conditions over a 7-week period in a tertiary referral hospital in rural Cameroon. Main outcome measures included participant's decision to accept or decline surgery, source of funding, and the relative importance of various factors in the decision-making process. RESULTS: Thirty-four of 175 participants (19.4%) declined surgery recommended by their physician. Twenty-six of 34 participants declining surgery (76.4%) cited procedure cost, which on average equaled 6.4 months' income, as their primary decision factor. Multivariate analysis revealed female gender [odds ratio (OR) 3.35, 95% confidence interval (95% CI) 2.14-5.25], monthly earnings (OR 0.83, 95% CI, 0.77-0.89), supporting children in school (OR 1.22, 95% CI 1.13-1.31), and inability to borrow funds from family or the community (OR 6.49, 95% CI 4.10-10.28) as factors associated with declining surgery. CONCLUSION: Nearly one-fifth of patients presenting to a surgical clinic with a treatable condition did not ultimately receive needed surgery. Both financial and sociocultural factors contribute to the decision to decline care.