Citations

Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.

The Microbes and Social Equity working group was formed in 2020 to foster conversations on research, education, and policy related to how microorganisms connect to personal, societal, and environmental health, and to provide space and guidance for action. In 2021, we designed our first virtual symposium to convene researchers already working in these areas for more guided discussions. The symposium organizing team had never planned a research event of this scale or style, and this perspective piece details that process and our reflections. The goals were to (1) convene interdisciplinary audiences around topics involving microbiomes and health, (2) stimulate conversation around a selected list of paramount research topics, and (3) leverage the disciplinary and professional diversity of the group to create meaningful agendas and actionable items for attendees to continue to engage with after the meeting. Sixteen co-written documents were created during the symposium which contained ideas and resources, or identified barriers and solutions to creating equity in ways which would promote beneficial microbial interactions. The most remarked-upon aspect was the working time in the breakout rooms built into the schedule. MSE members agreed that in future symposia, providing interactive workshops, training, or collaborative working time would provide useful content, a novel conference activity, and allow attendees to accomplish other work-oriented goals simultaneously.

Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Abstract Children’s Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Background Patients with heterotaxy syndromes (right and left atrial isomerism) are at high risk of poor outcomes after single-ventricle palliation. However, the long-term outcomes and specific parameters associated with poor outcomes are incompletely understood. Methods A retrospective review was performed of all patients with atrial isomerism who had a Fontan at our institution from 1973 to 2020. Standard demographic, as well as pre-, peri-, and postoperative parameters were collected. Features and outcomes of patients with polysplenia were compared to asplenia. Outcomes were analyzed for effect during 4 eras: (1: 1973-1984; n = 27), (2: 1985-1994; n = 93), (3: 1995-2004; n = 28), and (4: 2005-2020; n = 10). Results Of the 1176 patients who had a Fontan operation, 158 (14%) had a heterotaxy syndrome. The median age at the time of Fontan was 8 (9) years. Early mortality was 20% and was greater in patients with asplenia compared to polysplenia (27% vs. 12%, p = .019). But it substantially improved over time (61% in era 1 vs. 7%-10% in the more recent eras ( p < .001)), as did transplant-free survival (22% at 10 years in era 1 vs. 88% in era 4, p < .001). Transplant-free survival was significantly lower in patients with asplenia versus those with polysplenia ( p = .014), and patients with heterotaxy had lower survival than nonheterotaxy ( p = .01). This was largely due to the asplenia group ( p < .001) (hazard ratio = 3.05, p = .007). Conclusions After Fontan operation, patients with heterotaxy, particularly asplenia, continue to demonstrate worse transplant-free survival than nonheterotaxy patients. Early mortality and long-term transplant-free survival have improved in more recent eras.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT549.