Scleral ectasia stabilization following intra-arterial chemotherapy in an eye with recurrent retinoblastoma.

Purpose: To report a case of recurrent retinoblastoma following transpupillary thermotherapy (TTT) with development of scleral ectasia, as well as their successful treatment with intra-arterial chemotherapy. Observations: A 15-month-old girl with bilateral retinoblastoma presented with recurrent retinoblastoma and associated scleral ectasia with concern for extraocular extension after receiving multiple round of systemic chemotherapy and TTT. Given her negative systemic evaluation, decision was made to pursue intra-arterial chemotherapy. After completion of six rounds of 3-agent intra-arterial chemotherapy, the recurrent retinoblastoma had completely regressed and the scleral ectasia had improved and fibrosed. Conclusions and importance: The sclera is classically viewed as hyperthermy-resistant to TTT. Here, we describe scleral ectasia due to aggressive TTT with recurrence of the retinoblastoma. Our treatment with intra-arterial chemotherapy not only caused complete regression of the recurrent retinoblastoma, but it also contributed to the stabilization and improvement of the weakened scleral.

Adolescents and Young Adults With Sickle Cell Disease: Nociplastic Pain and Pain Catastrophizing as Predictors of Pain Interference and Opioid Consumption.

OBJECTIVES: Some patients with sickle cell disease (SCD) have features of nociplastic pain. While research suggests that many patients with nociplastic pain consume more opioids due to opioid nonresponsiveness, little is known about the impact of nociplastic pain and pain catastrophizing on opioid consumption and pain interference among adolescents and young adults (AYA) with SCD. The purpose of this study was to (1) characterize nociplastic pain and pain catastrophizing among AYA with SCD, and (2) determine whether these characterizations are associated with subsequent opioid consumption and pain interference 1 month after characterization. METHODS: Participants completed surveys characterizing nociplastic pain and catastrophizing at a routine clinic visit (baseline). Thereafter, participants received weekly text messages that included pain interference and opioid consumption surveys. Multipredictor 2-part models were used to evaluate the predictive relationships between baseline characterizations and subsequent pain interference, and opioid consumption. RESULTS: Forty-eight AYA aged 14 to 35 completed baseline measures. Twenty-five percent of participants had scores suggestive of nociplastic pain. Greater nociplastic pain features significantly increased the odds of consuming opioids (odds ratio=1.2) and having greater interference from pain (odds ratio=1.46). Regression analyses found that greater baseline nociplastic pain characteristics were significantly associated with opioid consumption (ß=0.13) and pain interference (ß=0.061); whereas higher pain catastrophizing scores predicted less opioid consumption (ß=-0.03) and less pain interference (ß=-0.0007). DISCUSSION: In this sample of AYA with SCD, features of nociplastic pain predicted higher subsequent opioid consumption and pain interference. Being aware of nociplastic pain features in patients with SCD may better guide individualized pain management.

Comparing internal versus external carotid artery branch delivery of intraarterial chemotherapy for the treatment of retinoblastoma.

PURPOSE: The goal of this study was to compare the efficacy of intraarterial chemotherapy (IAC) for retinoblastoma delivered via the ophthalmic artery (OA) division of the internal carotid artery (ICA) versus alternative branches of the external carotid artery (ECA). METHODS: We performed a retrospective chart review of patients receiving IAC for retinoblastoma at a single institution. Subjects were divided into three groups: those that received IAC solely through the OA branch of the ICA, those that initially received IAC through the OA branch of the ICA but were later switched to the ECA, and those that only received IAC through the ECA. The main outcomes compared included globe salvage rate and reduction in tumor thickness and size. RESULTS: A total of 30 eyes from 26 patients were included. A total of 91 (58%) sessions of IAC were performed through the OA division of the ICA and 65 (42%) were performed through branches of the ECA. Eleven eyes (37%) solely received IAC through the OA branch of the ICA, 16 eyes (53%) were converted to ECA treatment, and 3 eyes solely received IAC through branches of the ECA. Statistical analysis did not show any significant difference in globe salvage rate or reduction in tumor thickness and size. CONCLUSION: The use of alternative approaches for IAC when the OA branch of the ICA catheterization is not feasible allows for safe continued delivery of highly effective IAC, leading to similar outcomes in terms of globe salvage and reduction in tumor size.

Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR).

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m2 /day and cyclophosphamide at 330-400 mg/m2 /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m2 /day, etoposide 100 mg/m2 /day, and cyclophosphamide 400 mg/m2 /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.

Perspectives from a Predominantly African American Community about Biobank Research and a Biobank Consent Form.

Minority populations have been underrepresented in clinical trials, as well as in research biobanks that are created to conduct research with participants' biospecimens and related medical and research data. Biobank research raises issues about informed consent and privacy and the confidentiality of participants' personal data. Our study involved three focus groups of 10 adults each that were conducted in a medically underserved, predominantly African American community to elucidate questions and concerns regarding an institutional biobank. Transcripts from the discussion were qualitatively analyzed. Three main themes that arose from the focus groups included the importance of trust, the importance of the community in research, and suggestions to improve trust. The concerns identified in this study provide a starting point for future research to help research institutions become more trustworthy to the communities they serve.

Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001).

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m2 . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations.

Ethical Perspectives of Chinese and United States Physicians at Initiation of a Research Collaborative.

Variances in perceived standards regarding research integrity appear to exist between China and the U.S. An established joint institute for translational and clinical research between one Chinese and one U.S. health system provides a valuable venue in which to evaluate these perceptions better. We therefore undertook a survey of 209 physicians at the two institutions in 2013-14. The vast majority of physicians from both institutions understood the necessity of obtaining informed consent from research participants, the need to provide a description of the risks of participation, and the voluntary nature of research participation. However, there were differences in responses between the two sites in willingness to report plagiarism (U.S. 95.65% vs. Chinese 40.21%; p < .0001) and data falsification (U.S. 100% vs. Chinese 81.25%; p < .0001) and in willingness to attend biomedical industry-funded promotional events (U.S. 11.0% vs. Chinese 74.0%; p < .0001). When planning to conduct collaborative clinical research across cultures, particularly when uncertainty regarding the similarity of research cultures exists, exploration of cultural and ethical norms in research may be informative regarding educational needs and the risks of research and academic misconduct.

Palliative care is not associated with decreased intensity of care: Results of a chart review from a large children's hospital.

BACKGROUND: Palliative care is an important component of pediatric oncology care, especially for children who will not be cured of their disease. However, barriers remain to integration of this service. One barrier is the perception that it indicates "giving up." This study examined if palliative care involvement was associated with a decreased intensity of care at the end of life for children with malignancy at a large academic center with a well-established palliative care program. PROCEDURE: This is a retrospective chart review that measured intensity of care as the number of emergency department visits, hospital days, and intensive care unit days in the last one and three months of life. The data were compared for patients with and without palliative care involvement and with and without hospice involvement. RESULTS: Palliative involvement was not associated with a decrease in the intensity of care in the last three months of life. Hospice care was associated with a decreased intensity of care. These results held true in analyses adjusted for age at death, gender, and type of malignancy. CONCLUSIONS: These data can reassure patients, families, and providers that palliative involvement does not necessitate decreased intensity of care. Patients and families often choose hospice care to decrease the amount of time spent at the hospital and it was associated with meeting that goal.

Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of Long-Term Morbidity: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy. METHODS: Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures. RESULTS: HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition (P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8). CONCLUSION: This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy.

Vincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in a subgroup of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual's quality of life. Currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. Contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient's susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. In accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. Our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients.

Supporting Pediatric Patients and Their Families at the End of Life: Perspectives From Bereaved Parents.

BACKGROUND: Cancer remains the leading cause of death by disease for children in the United States. It is imperative to optimize measures to support patients and families facing the end of a child's life. This study asked bereaved parents to reflect on their child's end-of-life care to identify which components of decision-making, supportive services, and communication were helpful, not helpful, or lacking. METHODS: An anonymous survey about end-of-life experiences was sent to families of children treated at a single institution who died of a malignancy between 2010 and 2017. RESULTS: Twenty-eight surveys were returned for a 30.8% response rate. Most of the bereaved parents (61%) reported a desire for shared decision-making; this was described by 52% of families at the end of their child's life. There was a statistically significant association between how well death went and whether the parental perception of actual decision-making aligned with desired decision-making (P = .002). Families did not utilize many of the supportive services that are available including psychology and psychiatry (only 22% used). Respondents felt that additional services would have been helpful. CONCLUSIONS: Health care providers should strive to participate in decision-making models that align with the preferences of the patient and family and provide excellent communication. Additional resources to support families following the death of a child should be identified for families or developed and funded if a gap in available services is identified.

Experiences at the End of Life From the Perspective of Bereaved Parents: Results of a Qualitative Focus Group Study.

BACKGROUND: Palliative care principles are known to support the experiences of children and their families throughout the illness trajectory. However, there is little knowledge of the parental perceptions of care delivered and gaps experienced by families receiving end-of-life care. We report the most helpful aspects of care provided during the end of life and identify opportunities to improve care delivery during this critical time. METHODS: This study consists of 2 one-hour focus group sessions with 6 participants each facilitated by a clinical psychologist to explore the experiences of bereaved parents of pediatric oncology patients at the end of their child's life. The data were transcribed and coded using constant comparative analysis and evaluated for inter-rater reliability using intraclass correlation coefficient. RESULTS: Four common themes were identified through qualitative analysis: (1) valued communication qualities, (2) valued provider qualities, (3) unmet needs, and (4) parental experiences. The most prevalent of these themes was unmet needs (mentioned 51 times). Subthemes were identified and evaluated. Parents described struggling with communication from providers, loss of control in the hospital environment, and challenges associated with transition of care to hospice services. CONCLUSION: Interventions that support the complex needs of a family during end-of-life care are needed, especially with regard to coordination of care.

18F-2-fluoro-2-deoxyglucose uptake in white adipose tissue on pediatric oncologic positron emission tomography (PET)/computed tomography (CT).

BACKGROUND: Altered biodistribution of [F-18]2-fluoro-2-deoxyglucose (FDG) is sometimes encountered in pediatric patients undergoing chemotherapy for lymphoma on post-induction positron emission tomography (PET) imaging. A characteristic pattern of increased FDG uptake in white adipose tissue can be seen, particularly in the buccal regions, body wall and gluteal regions, with a shift of radiotracer away from the blood pool and liver. This altered biodistribution has been attributed to effects of corticosteroids in pediatric and adult patients and is important to recognize because of its potential for limiting the diagnostic quality of the PET scan and interfering with therapeutic response assessment. OBJECTIVE: In contrast to the well-known metabolically active brown fat seen on up to one-third of pediatric PET scans, white fat is usually non-metabolically active. We sought to determine the incidence of altered distribution of FDG in subcutaneous white adipose tissue in pediatric patients undergoing PET imaging and to assess the association with corticosteroid use. MATERIALS AND METHODS: We reviewed the medical records and imaging for four children in whom altered biodistribution in white adipose tissue was present on post-induction FDG PET/CT, identified during routine clinical practice. All four were receiving corticosteroids as part of their chemotherapy. We then retrospectively reviewed oncology FDG PET/CT scans over a 2-year period (1,361 scans in 689 patients) to determine the incidence of uptake in white fat by qualitative visual assessment. In the children identified with altered biodistribution, we measured maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean) in areas of subcutaneous white fat, the buccal regions, body wall or gluteal soft-tissue regions, liver and blood pool. We reviewed all medical records, including medication lists. We summarize the relevant clinical and imaging findings of 13 pediatric patients, including the 4 index patients. RESULTS: We determined the incidence of FDG uptake in white fat to be rare, found in 9 of 1,361 (0.6%) PET scans performed for pediatric cancer evaluation. FDG uptake was increased in subcutaneous adipose tissue, particularly in the buccal regions, body wall and gluteal regions, with a shift of radiotracer away from the blood pool and liver. The degree of increased uptake in peripheral white fat varied from marked to mild, and the biodistribution was distinct from that of brown adipose tissue. Children with this altered biodistribution were uniformly receiving corticosteroids as part of induction treatment for their cancer, and these findings were only identified on post-induction PET/CT. Follow-up PET/CT documented resolution of this effect after treatment with corticosteroids ceased. CONCLUSION: Our findings support the current understanding that characteristic uptake of FDG in white adipose tissue is mediated by corticosteroid effect. Although this altered biodistribution is rare (<1% of PET scans) it could impair the diagnostic quality of the scan, affecting image interpretation, and should be recognized when present.

A single-center multidisciplinary approach to managing the global Erwinia asparaginase shortage.

The availability of Erwinia Asparaginase has been limited across the world due to manufacturing shortages or for some countries due to the high acquisition cost, putting patients at risk for inferior outcomes. This manuscript provides guidance on how to manage hypersensitivity reactions and utilize therapeutic drug monitoring (TDM) to conserve and limit Erwinia use. The clinical and financial impact of a multidisciplinary committee are also discussed. Faced with a global Erwinia shortage, a multidisciplinary asparaginase allergy committee was created to review all hypersensitivity reactions to asparaginase therapy, staff education was performed on the management of asparaginase hypersensitivity reactions, an institution-wide premedication policy was mandated, and standardized guidelines were created for TDM. This multidisciplinary approach reduced the PEG-asparaginase to Erwinia switch rate from 21% (35 of 163) to 7% (10 of 134) (p = .0035). A multifaceted approach can safely maintain patients on PEG-asparaginase and conserve Erwinia for patients who need it most.

Do Deauville Scores Improve the Clinical Utility of End-of-Therapy FDG PET Scans for Pediatric Hodgkin Lymphoma?

OBJECTIVE: The purpose of this study was to evaluate the clinical utility of Deauville scores in interpretation of end-of-chemotherapy FDG PET scans. CONCLUSION: Deauville scores improve the clinical utility of end-of-chemotherapy PET, as evidenced by an increase in positive predictive value to 72.7% from 44.4% on the basis of report alone. The negative predictive value remains greater than 95%.

Genetic Variants Associated With Vincristine-Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia.

Vincristine is one of the core chemotherapy agents used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, one of the major toxicities resulting from vincristine exposure is vincristine-induced peripheral neuropathy (VIPN). When VIPN results in significant morbidity, the vincristine dose may need to be reduced, thus potentially decreasing the effectiveness of treatment. To date, there are no robust biomarkers used clinically to determine which patients will be at risk for worse neuropathy. The current study included genomewide association study (GWAS) in two independent cohorts: Pediatric Oncology Group (POG) ALL trials and a multicenter study based at Indiana University in children with ALL. A meta-analysis of the cohorts identified two single-nucleotide polymorphisms (SNPs), rs1045644 and rs7963521, as being significantly (P value threshold 0.05/4749 = 1.05E-05) associated with neuropathy. Subsequently these SNPs may be effective biomarkers of VIPN in children with ALL.