The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Feasibility study of busulfan, fludarabine, and thiotepa conditioning regimen for allogeneic hematopoietic stemcell transplantationfor children and young adults with nonmalignant disorders.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is the only curative treatment for several pediatric non-malignant disorders. A widely used conditioning backbone is busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG). Thiotepa has improved engraftment when added to this regimen, however the minimum effective dose (MED) of thiotepa to achieve engraftment while minimizing toxicities has not been well established. OBJECTIVES: The primary objective of this prospective feasibility study was to determine the MED of thiotepa (5mg/kg) in combination with reduced-dose busulfan, fludarabine or cyclophosphamide, and rATG required to achieve engraftment in >90% of HSCT recipients for non-malignant disorders with acceptable toxicity. RESULTS: Six patients who received fully matched HSCT were enrolled. Patient diagnoses included Wiskott-Aldrich syndrome (n = 1), CD40L deficiency (n = 1), sickle cell disease (n = 2), autoinflammatory syndrome (n = 1), and paroxysmal nocturnal hemoglobinuria (n = 1). All six patients achieved engraftment prior to Day +42 and five patients had stable full donor engraftment. Two of the six patients (33%) developed acute GVHD and/or chronic GHVD, both of whom had sickle cell disease. At a median follow-up of 2.25 years post-transplant, all patients were alive without evidence of disease recurrence. None of the patients experienced grade 4 or 5 toxicities. Three out of six patients (50%) developed grade 3 adverse events. Neurocognitive functioning of children under 10 years of age was not adversely affected by this regimen. CONCLUSION: This approach shows acceptable toxicity and reliable engraftment in children with non-malignant disorders receiving related or unrelated HLA-matched transplants.

Race as a factor in donor selection and survival of children with hematologic malignancies undergoing hematopoietic stem cell transplant in Florida.

BACKGROUND: Previous studies have explored posthematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. PROCEDURE: This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 at one of the five Florida pediatric HCT centers. RESULTS: We found no differences between W and B children in transplant characteristics, other than donor type. There was a significant difference in use of human leukocyte antigen (HLA)-mismatched donors (HLA-MMD) (53% W, 71% B, p = .01). When comparing HLA-MMD use to fully HLA-matched donors, B had relative risk (RR) of 1.47 (95% CI 0.7-3) of receiving a mismatched unrelated donor (MMUD), RR of 2.34 (95% CI 1.2-4.4) of receiving a mismatched related donor (MMRD), and RR of 1.9 (95% CI 0.99-3.6) of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p = .1, or cGVHD (19% W, 28% B, p = .1), or primary cause of death. Overall 24-month survival was 61% (95% CI 55%-68%) for W, and 60% (95% CI 48-75) for B children, log-rank p = .7. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. CONCLUSIONS: In this contemporary cohort of children with HM, we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.

Pediatric HCT in Florida (2014 -2016): A report from the FPBCC.

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes.

Primary pulmonary artery sarcoma in the pediatric patient: Review of literature and a case report.

Primary pulmonary artery sarcoma (PAS) is extremely rare in children. Nevertheless, distinguishing primary PAS from pulmonary embolism is critical to a child's survival. Primary PAS is commonly misdiagnosed as a pulmonary embolism due to similar presenting symptoms and radiographic findings. However, compared to adults, pulmonary embolism is rare in children, especially in patients who do not have predisposing factors or hypercoagulable state. We present a child with primary PAS which mimicked pulmonary embolism on presentation but eventually was resected and is doing well 5 years after resection. In the absence of predisposing factors or hypercoagulable state, solid tumors such as primary PAS should be considered when assessing a pediatric patient with presumed pulmonary embolism.

Infusion of Hematopoietic Stem Cell Products Using Pump Mechanism: An Approach Worth Consideration?

Hematopoietic stem cell transplantation using progenitor cells is a potentially curative treatment option for patients with high-risk malignancies and nonmalignant hematologic, immunologic, and genetic conditions. There is a need for evidence regarding safe practices and controlled infusion processes. Syringe and intravenous infusion pumps are not commonly used to deliver hematopoietic stem cell products (HPCs) due to a paradigm of thought that suggests that the pressure from the pump might damage the HPCs. Here, we describe a retrospective analysis of 114 patients who received HPC infusions using either a syringe or intravenous pump, providing support for this method along with successful engraftment data. This method may be a viable option to obtain reliable and consistent infusion rates, especially in pediatrics. To the best of our knowledge, this is the only study to date demonstrating safely using syringe and intravenous pump mechanisms in the setting of autologous and allogeneic pediatric stem cell transplantation.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

OBJECTIVES: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). MATERIALS AND METHODS: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). RESULTS: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. CONCLUSIONS: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

A Case Presentation: Rare Occurrence of an Adolescent Male Presenting With an ATRT and Simultaneous Low-grade Glioneuronal Tumor.

Atypical rhabdoid/teratoid tumor (ATRT) is an uncommon and highly malignant tumor of the central nervous system. The majority of ATRT tumors occur in infancy and young children located in the posterior fossa. The ideal treatment for cure remains controversial and prognosis is typically unfavorable. We present a case of an atypical presentation of ATRT, presenting in adolescence with an additional low-grade glioneuronal tumor discovered at diagnosis.

The budget impact of using enteric-coated aspirin 325 mg + immediate-release omeprazole 40 mg to prevent recurrent cardiovascular events.

OBJECTIVE: Aspirin (acetylsalicylic acid; ASA) is commonly used for secondary prevention of cardiovascular (CV) events, but may be associated with gastrointestinal (GI) adverse events, which can reduce adherence. Use of ASA co-therapy with proton pump inhibitors in patients at risk may be suboptimal. PA32540 (Yosprala™) is a coordinated-delivery tablet combining EC-ASA 325 mg and immediate-release omeprazole 40 mg. The objective of this flexible budget impact model was to project the financial consequences of introducing PA32540 325 mg/40 mg to prevent recurrent CV events, while reducing ASA-associated GI events in US adults. METHODS: A Markov Model was employed to estimate health state transitions associated with ASA 75-325 mg, ASA 75-325 mg + generic delayed-release omeprazole 40 mg, PA32540, or clopidogrel 75 mg to prevent recurrent CV events. Health states included ulcers, GI bleeding, CV events, and death. Model inputs included demographics, treatment dosages, treatment costs, adverse GI and CV events, and premature death. Data from peer-reviewed literature and censuses enabled appropriate allocation of CV and GI disease prevalence and mortality. The PA32540 non-adherence rate was conservatively set at 20%. PA32540 market share was set to 50%. RESULTS: The model projected annual savings of $81.0 million to $190.9 million within 1-5 years after PA32540 introduction to the plan, which included 134,558 members at risk for recurrent CV events. These values translate into savings of $602 (year 5) to $1,419 (year 1) per patient per year, and $81 (year 5) to $191 (year 1) per member per year. These values were robust to variations in parameters under a deterministic sensitivity analysis. CONCLUSION: PA32540 use to prevent recurrent CV events was associated with cost reductions in each year examined with the model. From a health plan perspective, PA32540 is likely to have a net overall effect, resulting in significant cost savings.

Aspirin Use in Secondary Cardiovascular Protection and the Development of Aspirin-Associated Erosions and Ulcers.

Aspirin for secondary cardiovascular disease prevention is well established, but treatment discontinuation, often because of gastrointestinal mucosal injury or symptoms, can lead to increased risk for cardiovascular events. Proton pump inhibitor therapy is recommended for aspirin-treated patients at gastrointestinal risk. PA32540 [enteric-coated aspirin (EC-ASA) 325 mg + immediate-release omeprazole 40 mg] was compared with EC-ASA 325 mg alone once daily for 6 months in 2 duplicate, randomized double-blind trials in gastrointestinal-risk patients taking aspirin for ≥3 months for secondary prevention. In this post hoc analysis, we determined the prevalence of endoscopic upper gastrointestinal ulcers at screening and whether baseline endoscopic gastric erosions impacted subsequent ulcer development. At the screening endoscopy, 6% of subjects had upper gastrointestinal ulcers (not eligible for randomization) and 40% had gastric erosions. Conditional logistic regression modeling showed that baseline gastric erosions are significantly associated with endoscopic gastric ulcer development (OR = 2.12, 95% confidence interval, 1.26-3.57). In subjects with baseline gastric erosion, 4.2% of PA32540-treated versus 13.0% of EC-ASA-treated subjects (P = 0.001) subsequently developed endoscopic gastric ulcers. These data suggest that gastric injury predisposes to gastric ulcer development when taking EC-ASA, and exposure to immediate-release omeprazole in the presence of aspirin therapy significantly reduces the likelihood of progressing to gastric ulcers.

Long-Term Safety of a Coordinated Delivery Tablet of Enteric-Coated Aspirin 325 mg and Immediate-Release Omeprazole 40 mg for Secondary Cardiovascular Disease Prevention in Patients at GI Risk.

INTRODUCTION: In two, 6-month, randomized, double-blind Phase 3 trials, PA32540 (enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) compared to aspirin alone was associated with fewer endoscopic gastric and duodenal ulcers in patients requiring aspirin therapy for secondary cardiovascular disease (CVD) prevention who were at risk for upper gastrointestinal (UGI) events. AIMS: In this 12-month, open-label, multicenter Phase 3 study, we evaluated the long-term cardiovascular and gastrointestinal safety of PA32540 in subjects who were taking aspirin 325 mg daily for ≥ 3 months for secondary CVD prevention and were at risk for aspirin-associated UGI events. Enrolled subjects received PA32540 once daily for up to 12 months and were assessed at baseline, month 1, month 6, and month 12. RESULTS: The overall safety population consisted of 379 subjects, and 290 subjects (76%) were on PA32540 for ≥ 348 days (12-month completers). Adverse events (AEs) caused study withdrawal in 13.5% of subjects, most commonly gastroesophageal reflux disease (1.1%). Treatment-emergent AEs occurred in 76% of the safety population (11% treatment-related) and 73% of 12-month completers (8% treatment-related). The most common treatment-related AE was dyspepsia (2%). One subject had a gastric ulcer observed on for-cause endoscopy. There were five cases of adjudicated nonfatal myocardial infarction, one nonfatal stroke, and one cardiovascular death, but none considered treatment-related. CONCLUSIONS: Long-term treatment with PA32540 once daily for up to 12 months in subjects at risk for aspirin-associated UGI events is not associated with any new or unexpected safety events.

Onset and durability of pain relief in knee osteoarthritis: Pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib.

OBJECTIVE: To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). METHODS: Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥ 50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. RESULTS: NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2-7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2-7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. CONCLUSION: Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.

Onset and durability of pain relief in knee osteoarthritis: pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib.

OBJECTIVE: To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). METHODS: Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. RESULTS: NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2-7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2-7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. CONCLUSION: Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.

Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant syndrome which is clinically diagnosed by the distinct facial features, short stature, cardiac anomalies and developmental delay. About 50% of cases are associated with gain of function mutations in PTPN11 gene which leads to activation of the RAS/mitogen-activated protein kinase signaling pathway. This is known to have a role in tumorigenesis. Despite this, only limited reports of solid tumors (Fryssira H, Leventopoulos G, Psoni S, et al. Tumor development in three patients with Noonan syndrome. Eur J Pediatr 2008;167:1025-1031; Schuettpelz LG, McDonald S, Whitesell K et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 2009;53:1147-1149; Sherman CB, Ali-Nazir A, Gonzales-Gomez I, et al. Primary mixed glioneuronal tumor of the central nervous system in a patient with Noonan syndrome. J Pediatr Hematol Oncol 2009;31:61-64; Sanford RA, Bowman R, Tomita T, et al. A 16 year old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 1999;30:47-52) and no prior reports of optic gliomas have been described in patients with NS. We present here a patient with NS with a PTPN11 mutation and an optic pathway pilomyxoid astrocytoma.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies.

BACKGROUND: Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS: Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS: Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS: PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Local control in non-metastatic medulloblastoma.

BACKGROUND: A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. MATERIAL AND METHODS: From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2-18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm(3) of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8-38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4-64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. RESULTS: Median follow-up was 15.7 years (range 0.3-44.4 years) for all patients and 26.6 years (range 7.3-44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. CONCLUSIONS: While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Late toxicity following craniospinal radiation for early-stage medulloblastoma.

BACKGROUND: The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. MATERIAL AND METHODS: Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2-18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8-38.4). The median total dose, including boost, was 54 Gy (range 42.4-64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up for all patients was 15.4 years (range 0.4-44.4) and for living patients it was 24 years (range 5.6-44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. CONCLUSION: Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel.

BACKGROUND: A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. METHODS AND RESULTS: A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 µM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. CONCLUSIONS: PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.