Vern-Gross, T.Z.

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive, malignant embryonal tumor with dismal long-term survival despite aggressive multimodal therapy. While this tumor typically presents in infancy or early childhood, there are published case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. A 25-year-old female with Down syndrome presented with dysphagia and facial droop and was found to have an avidly enhancing, cerebellopontine angle mass. Histology demonstrated sheets of rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing detected a frameshift SMARCB1 mutation and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton beam irradiation, followed by chemotherapy on a modified regimen due to concern for heightened risk of treatment-related toxicity. On most recent follow-up 22 months from diagnosis, the patient remains without evidence of disease. This report represents the first known case of ATRT in a young adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Further studies are needed to define an appropriate risk-adapted and standardized therapeutic approach for this patient population.

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

AbstractBackgroundIn patients with extremity soft tissue sarcoma (eSTS), we describe outcomes of preoperative external beam radiation therapy (EBRT), limb‐sparing surgery (LSS), and intraoperative electron radiation therapy (IOERT).MethodsOne hundred and eighteen patients with eSTS treated between October 17, 2002 and July 28, 2021 were identified. EBRT was delivered preoperatively followed by LSS and IOERT.ResultsThe median follow‐up was 24.9 months. The presentation was primary in 102 (94%) patients and recurrent in 6 (6%) patients. Tumor location was lower extremity in 82 (76%) patients and upper extremity in 26 (24%) patients. Stage distribution was as follows: 3 (3%) IA, 24 (22%) IB, 31 (29%) II, 24 (22%) IIIA, and 25 (23%) IIIB. Final surgical margins were negative in 96 (89%) patients. The 5‐year local control, failure‐free survival, and overall survival were 94%, 75%, and 64%, respectively. Univariate analysis identified age >50, lower extremity, and higher grade as significant negative prognostic factors for overall survival. Grade 3 fracture or osteoradionecrosis requiring surgical fixation, neuropathy, and lymphedema occurred in 7 (6%), 1 (1%), and 0 patients, respectively.ConclusionsThis study represents one of the largest series using preoperative EBRT, LSS, and IOERT for eSTS, with high local control and a low rate of late severe toxicity.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons <0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-03.

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

AbstractRadiosurgery and brachytherapy are potentially useful treatment techniques that are sparingly applied in pediatric oncology. They are often used in the setting of reirradiation for recurrent or metastatic tumors. Reirradiation in children with recurrent tumors is complicated by the tolerance of critical organs and the potential risks for overall long‐term dose‐dependent complications. We review the current literature available in support of reirradiation and the use of radiosurgery and brachytherapy in pediatric patients.