Physician perspectives on compassionate use in pediatric oncology.

BACKGROUND: Targeted cancer treatments are almost always first studied in adults, even when there is a biologically plausible potential for efficacy in children. Through compassionate use programs, children who are not eligible for a clinical trial and for whom there are no known effective therapies may obtain access to investigational agents, including drugs under development for adults. However, little is known about pediatric oncologists' experiences with applying for and obtaining compassionate use agents. METHODS: This study surveyed 132 pediatric oncologists to assess awareness and utilization of compassionate use programs, to identify barriers to their use, and to evaluate available institutional support and resources. RESULTS: We found that the process of applying for access to drugs in development is poorly understood, which presents a barrier to obtaining investigational drugs. Fifty-seven percent of the pediatric oncologists applied for compassionate use. Providers from larger institutions or with more than 15 years of clinical experience were more likely to complete an application and obtain investigational agents for their patients. CONCLUSION: Identified perceived and actual barriers to compassionate use application submission suggest pediatric oncologists may benefit from educational resources and support to ensure children with cancer equal access to investigational agents and care.

Postchemotherapy Immunization Practices for Non-HSCT Pediatric Oncology Patients.

Pediatric oncology patients treated with antineoplastic therapy have impaired immune systems that lead to loss of protective antibodies. They require reimmunization to protect against vaccine-preventable diseases. There are a paucity of studies on the clinical practice of pediatric oncologists and the available recommendations are heterogenous. This study describes current reimmunization practices among pediatric oncologists. We surveyed the Children's Oncology Group (COG)-identified principle investigators to capture clinical practices among pediatric oncologists within their institutions regarding reimmunization of non-hematopoietic stem cell transplantation patients. The majority of respondents did not routinely assess vaccine-related immune status; those who did most frequently assessed 6 months after cessation of therapies. Methods of assessment included type of therapy received, vaccine titers, and absolute lymphocyte counts. Providers from smaller institutions were more likely to check vaccine titers than those from larger institutions. More than half of the surveyed institutions did not have standardized guidelines available for practitioners. There are variations in reimmunization practices among pediatric oncologists despite available guidelines on recommended schedules. Further research is needed to identify the safest and most cost-effective way to insure immunity to infectious disease after the treatment of childhood cancer.

Characterizing Asian American medical students' experiences with microaggression and the impact on their well-being.

PURPOSE: This mixed-methods study quantified and characterized incidents of microaggressions experienced by Asian American medical students. The authors report on their impact and suggest improvements to create a more equitable and supportive learning environment. METHOD: Quantitative and qualitative data were collected from 305 participants who self-identified as Asian American or Pacific Islander. An online, anonymous survey was sent to US medical students through the Asian Pacific American Medical Student Association (APAMSA). Questions explored incidence, characteristics of, and response to microaggressions. We conducted four focus groups to further characterize students' experiences. Data were organized and coded, and thematic analysis was used to identify core themes. RESULTS: Racial microaggressions were prevalent among Asian American medical students. Nearly 70% (n = 213) of survey respondents reported experiencing at least one incident during their medical training to date. The most common perpetrators were patients (n = 151, 70.9%) and fellow medical students (n = 126, 59.2%), followed by professors (n = 90, 42.3%). The most prevalent themes included being perceived as a perpetual foreigner, the assumption of timidness, and ascription of the model minority myth. Students rarely reported the incident and usually did not respond immediately due to fear of retaliation, uncertainties about the experience or how to respond appropriately, and perception that they would bear the burden of advocacy alone. Experiences with microaggressions led to feelings of frustration and burnout and had a negative impact on mental health. Recommendations were made to improve the anonymous reporting systems in medical schools, and to increase diversity and inclusion in medical education and leadership. CONCLUSIONS: Asian American medical students face high exposure to racial microaggressions during their medical education that adversely impact their mental health. Changes are needed in medical training to create a more equitable and inclusive learning environment.

Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors.

Background: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens. Methods: We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens. Results: Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least 1 line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Conclusions: Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its anti-proliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable anti-tumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

Differential associations between the food environment near schools and childhood overweight across race/ethnicity, gender, and grade.

Epidemiologic studies have observed influences of the food environment near schools on children's overweight status but have not systematically assessed the associations by race, sex, and grade. The authors examined whether the associations between franchised fast food restaurant or convenience store density near schools and overweight varied by these factors using data for 926,018 children (31.3% white, 55.1% Hispanic, 5.7% black, and 8% Asian) in fifth, seventh, or ninth grade, nested in 6,362 schools. Cross-sectional data were from the 2007 California physical fitness test (also known as "Fitnessgram"), InfoUSA, the California Department of Education, and the 2000 US Census. In adjusted models, the overweight prevalence ratio comparing children in schools with 1 or more versus 0 fast food restaurants was 1.02 (95% confidence interval (CI): 1.01, 1.03), with a higher prevalence ratio among girls compared with boys. The association varied by student's race/ethnicity (P = 0.003): Among Hispanics, the prevalence ratio = 1.02 (95% CI: 1.01, 1.03); among blacks, the prevalence ratio = 1.03 (95% CI: 1.00, 1.06), but among Asians the prevalence ratio = 0.94 (95% CI: 0.91, 0.97). For each additional convenience store, the prevalence ratio was 1.01 (95% CI: 1.00, 1.01), with a higher prevalence ratio among fifth grade children. Nuanced understanding of the impact of food environments near schools by race/ethnicity, sex, and grade may help to elucidate the etiology of childhood overweight and related race/ethnic disparities.

Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma.

Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.

Post-Chemotherapy Titer Status and Need for Revaccination After Treatment for Childhood Cancer.

Objectives. To evaluate the strategy of checking vaccine titers after completion of chemotherapy. Study Design. Retrospective review of pediatric oncology patients who completed chemotherapy. Demographics, post-chemotherapy titers, and absolute lymphocyte counts (ALCs) were analyzed. Results. Ninety patients met inclusion criteria, and 87% of patients had at least one titer checked. Comparing patients <7 years and those ≥7 years at diagnosis, there was no difference in incidence of negative titers except mumps; those <7 years old were more likely to have negative titers (58% vs 20%, P = .003). Comparing those <13 years old to ≥13 years old, there was no difference in negative titers except mumps (45% vs 19%, P = .02) and tetanus (44% vs 0%, P = .002). No patient maintained all protective titers after completion of chemotherapy. Time to ALC recovery was not predictive of positive titers. Conclusion. Checking titers after chemotherapy is not recommended. Providers should assume loss of immunity.