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Locally advanced cholangiocarcinoma has a poor prognosis, with long-term survival only for patients where complete surgical resection is achieved. Median overall survival with chemotherapy alone is less than 1 year. Novel strategies combining conventional chemotherapy and radiotherapy followed by targeted agents can lead to durable treatment responses and are applicable to cholangiocarcinoma management. Pediatric cholangiocarcinoma is exceedingly rare, with an estimate of 15–22 cases reported in the last 40 years. As such, no standard therapeutic regimen exists. We present a case of a 16-year-old previously healthy patient with unresectable cholangiocarcinoma whose tumor genetic sequencing revealed a novel, actionable neuregulin-1 (NRG1) gene translocation. The patient underwent standard systemic chemotherapy with gemcitabine and cisplatin followed by hypofractionated proton radiation therapy for local control. The patient then started an oral pan-ERBB (erythroblastic B receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4) family inhibitor as a maintenance medication, remaining with stable disease and excellent quality of life for over 2 years. This case highlights a novel NRG1 fusion in a rare clinical entity that provided an opportunity to utilize a multimodal therapeutic strategy in the pediatric setting. [ABSTRACT FROM AUTHOR]

We aimed to identify socioeconomic gaps in the administration of adjuvant radiotherapy (RT) for patients with atypical meningioma (AM) and secondarily to determine differences in survival between patients receiving radiation and those not receiving radiation at 12 and 60 months. The National Cancer Database was queried for patients receiving AM surgery between 2004 and 2019. Statistical analyses were performed to assess the association between receipt of adjuvant radiation and social determinants. Secondarily, Kaplan-Meir curves were used to compare overall patient survival between those that received radiation and those that did not. Adjuvant radiation was less likely to be administered to patients over 65 (95% confidence interval [CI] = 0.53–22 0.77) and more likely to be administered to males (95% CI = 1.07–1.38). Compared to the Southern USA, patients were more likely to receive RT in the Northeastern (95% CI 24 = 1.40–2.05), Midwestern (95% CI = 1.06–1.54), and Western parts of the USA (95% 25 CI = 1.31–2.00). Patients residing furthest from their facility were less likely to receive radiation (95% CI = 0.65–0.98). Insured patients were more likely to receive radiation (P = 0.048) than uninsured patients. On multivariate analysis, no differences were found between racial groups regarding adjuvant radiation. For patients unstratified, radiation was shown to improve survival at 12 and 60 months. Disparities exist in the administration of adjuvant RT for AM. Patients over 65, women, those residing in the Southern USA, those living further from their facilities and uninsured patients are less likely to receive radiation than their counterparts. [ABSTRACT FROM AUTHOR]

A PENTEC (Pediatric Normal Tissue Effects in the Clinic) review was performed to estimate the dose-volume effects of radiation therapy on spine deformities and growth impairment for patients who underwent radiation therapy as children. A systematic literature search was performed to identify published data for spine deformities and growth stunting. Data were extracted from 12 reports of children irradiated to the spine (N = 603 patients). The extracted data were analyzed to find associations between complication risks and the radiation dose (conventional fractionation throughout) as impacted by exposed volumes and age using the mixed-effects logistic regression model. When appropriate, corrections were made for radiation modality, namely orthovoltage beams. In the regression analysis, the association between vertebral dose and scoliosis rate was highly significant (P <.001). Additionally, young age at time of radiation was highly predictive of adverse outcomes. Clinically significant scoliosis can occur with doses ≥15 Gy to vertebrae during infancy (<2 years of age). For children irradiated at 2 to 6 years of age, overall scoliosis rates of any grade were >30% with doses >20 Gy; grade 2 or higher scoliosis was correlated with doses ≥30 Gy. Children >6 years of age remain at risk for scoliosis with doses >30 Gy; however, most cases will be mild. There are limited data regarding the effect of dose gradients across the spine on degree of scoliosis. The risk of clinically meaningful height loss was minimal when irradiating small volumes of the spine up to 20 Gy (eg, flank irradiation), except in infants who are more vulnerable to lower doses. Growth stunting was more frequent when larger segments of the spine (eg, the entire spine or craniospinal irradiation) were irradiated before puberty to doses >20 Gy. The effect was modest when patients were irradiated after puberty to doses >20 Gy. To reduce the risk of kyphoscoliosis and growth impairment, the dose to the spine should be kept to <20 Gy for children <6 years of age and to <10 to 15 Gy in infants. The number of vertebral bodies irradiated and dose gradients across the spine should also be limited when possible. [ABSTRACT FROM AUTHOR]

Primary meningeal melanomatosis is an extremely rare tumor with very few documented responses to treatment. A 3-year-old male with a complex past medical history, including prematurity and shunted hydrocephalus, was diagnosed with primary meningeal melanomatosis with peritoneal implants. Molecular testing revealed an NRAS Q61R mutation. The patient received proton craniospinal radiation followed by immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) IV every 3 weeks and, upon progression, he was switched to a higher dose of nivolumab (3 mg/kg IV every 2 weeks) and binimetinib (24 mg/m2/dose, twice a day). The patient had significant improvement of CNS disease with radiation therapy and initial immunotherapy but progression of extracranial metastatic peritoneal and abdominal disease. Radiation was not administered to the whole abdomen. After two cycles of nivolumab and treatment with the MEK inhibitor binimetinib, he had radiographic and clinical improvement in abdominal metastasis and ascitis. He ultimately died from RSV infection, Klebsiella sepsis, and subdural hemorrhage without evidence of tumor progression. This is the first report of a child with primary meningeal melanomatosis with extracranial metastatic disease with response to a combination of radiation, immunotherapy and MEK inhibitor therapy. [ABSTRACT FROM AUTHOR]

Purpose Although historical trials have established the role of surgical resection followed by whole brain irradiation (WBRT) for brain metastases, WBRT has recently been shown to cause significant neurocognitive decline. Many practitioners have employed postoperative stereotactic radiosurgery (SRS) to tumor resection cavities to increase local control without causing significant neurocognitive sequelae. However, studies analyzing outcomes of large brain metastases treated with resection and postoperative SRS are lacking. Here we compare outcomes in patients with large brain metastases >4 cm to those with smaller metastases ≤4 cm treated with surgical resection followed by SRS to the resection cavity. Methods and materials Consecutive patients with brain metastases treated at our institution with surgical resection and postoperative SRS were retrospectively reviewed. Patients were stratified into ≤4 cm and >4 cm cohorts based on preoperative maximal tumor dimension. Cumulative incidence of local failure, radiation necrosis, and death were analyzed for the 2 cohorts using a competing-risk model, defined as the time from SRS treatment date to the measured event, death, or last follow-up. Results A total of 117 consecutive cases were identified. Of these patients, 90 (77%) had preoperative tumors ≤4 cm, and 27 (23%) >4 cm in greatest dimension. The only significant baseline difference between the 2 groups was a higher proportion of patients who underwent gross total resection in the ≤4 cm compared with the >4 cm cohort, 76% versus 48%, respectively ( P <.01). The 1-year rates of local failure, radiation necrosis, and overall survival for the ≤4 cm and >4 cm cohorts were 12.3% and 16.0%, 26.9% and 28.4%, and 80.6% and 67.6%, respectively (all P >.05). The rates of local failure and radiation necrosis were not statistically different on multivariable analysis based on tumor size. Conclusions Brain metastases >4 cm in largest dimension managed by resection and radiosurgery to the tumor cavity have promising local control rates without a significant increase in radiation necrosis on our retrospective review. [ABSTRACT FROM AUTHOR]

Simple Summary: In this research study, the authors investigated the impact of specific genetic mutations on the survival of lung cancer patients with brain metastases who underwent surgical resection. These mutations, known as anaplastic lymphoma kinase (ALK)-rearranged and epidermal growth factor receptor (EGFR)-amplified mutations, have shown potential for targeted treatments. The study analyzed data from patients who received surgical treatment at Emory University Hospital between 2012 and 2022. Results showed that the overall survival and progression-free survival rates in this group were better than those seen in earlier studies. The study suggests that as more targeted therapies become available, the survival rates for lung cancer patients with brain metastases may continue to improve. The findings emphasize the importance of individualized treatments based on genetic mutations. In the context of the post-genomic era, where targeted oncological therapies like monoclonal antibodies (mAbs) and tyrosine-kinase inhibitors (TKIs) are gaining prominence, this study investigates whether these therapies can enhance survival for lung carcinoma patients with specific genetic mutations—EGFR-amplified and ALK-rearranged mutations. Prior to this study, no research series had explored how these mutations influence patient survival in cases of surgical lung brain metastases (BMs). Through a multi-site retrospective analysis, the study examined patients who underwent surgical resection for BM arising from primary lung cancer at Emory University Hospital from January 2012 to May 2022. The mutational statuses were determined from brain tissue biopsies, and survival analyses were conducted. Results from 95 patients (average age: 65.8 ± 10.6) showed that while 6.3% had anaplastic lymphoma kinase (ALK)-rearranged mutations and 20.0% had epidermal growth factor receptor (EGFR)-amplified mutations—with 9.5% receiving second-line therapies—these mutations did not significantly correlate with overall survival. Although the sample size of patients receiving targeted therapies was limited, the study highlighted improved overall survival and progression-free survival rates compared to earlier trials, suggesting advancements in systemic lung metastasis treatment. The study suggests that as more targeted therapies emerge, the prospects for increased overall survival and progression-free survival in lung brain metastasis patients will likely improve. [ABSTRACT FROM AUTHOR]

Purpose: At present, proton craniospinal irradiation (CSI) for growing children is delivered to the whole vertebral body (WVB) to avoid asymmetric growth. We aimed to demonstrate the feasibility and potential clinical benefit of delivering vertebral body sparing (VBS) versus WVB CSI with passively scattered (PS) and intensity modulated proton therapy (IMPT) in growing children treated for medulloblastoma.Methods and Materials: Five plans were generated for medulloblastoma patients, who had been previously treated with CSI PS proton radiation therapy: (1) single posteroanterior (PA) PS field covering the WVB (PS-PA-WVB); (2) single PA PS field that included only the thecal sac in the target volume (PS-PA-VBS); (3) single PA IMPT field covering the WVB (IMPT-PA-WVB); (4) single PA IMPT field, target volume including thecal sac only (IMPT-PA-VBS); and (5) 2 posterior-oblique (-35°, +35°) IMPT fields, with the target volume including the thecal sac only (IMPT2F-VBS). For all cases, 23.4 Gy (relative biologic effectiveness [RBE]) was prescribed to 95% of the spinal canal. The dose, linear energy transfer, and variable-RBE-weighted dose distributions were calculated for all plans using the tool for particle simulation, version 2, Monte Carlo system.Results: IMPT VBS techniques efficiently spared the anterior vertebral bodies (AVBs), even when accounting for potential higher variable RBE predicted by linear energy transfer distributions. Assuming an RBE of 1.1, the V10 Gy(RBE) decreased from 100% for the WVB techniques to 59.5% to 76.8% for the cervical, 29.9% to 34.6% for the thoracic, and 20.6% to 25.1% for the lumbar AVBs, and the V20 Gy(RBE) decreased from 99.0% to 17.8% to 20.0% for the cervical, 7.2% to 7.6% for the thoracic, and 4.0% to 4.6% for the lumbar AVBs when IMPT VBS techniques were applied. The corresponding percentages for the PS VBS technique were higher.Conclusions: Advanced proton techniques can sufficiently reduce the dose to the vertebral body and allow for vertebral column growth for children with central nervous system tumors requiring CSI. This was true even when considering variable RBE values. A clinical trial is planned for VBS to the thoracic and lumbosacral spine in growing children. [ABSTRACT FROM AUTHOR]

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15–39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867. [ABSTRACT FROM AUTHOR]

Adjuvant radiotherapy (RT) can help achieve local control (LC) and reduce hormonal overexpression for pituitary adenomas (PAs). Prior reports involved Gamma Knife or older linear accelerator (LINAC) techniques. The aim of this study was to report long-term outcomes for modern LINAC RT. Institutional retrospective review of LINAC RT for PAs with minimum 3 years of magnetic resonance imaging follow-up was performed. Hormonal control was defined as biochemical remission in absence of medications targeting hormone excess. LC defined using Response Evaluation Criteria in Solid Tumors on surveillance magnetic resonance imaging. Progression-free survival defined as time alive with LC without return of or worsening hormonal excess from secretory PA. Kaplan-Meier and Cox proportional hazard models used. From 2003 to 2017, 140 patients with PAs (94 nonsecretory, 46 secretory) were treated with LINAC RT (105 fractionated RT, 35 radiosurgery) with median follow-up of 5.35 years. Techniques included fixed gantry intensity-modulated radiotherapy (51.4%), dynamic conformal arcs (9.3%), and volumetric modulated arc therapy (39.3%). Progression-free survival at 5 years was 95.3% for secretory tumors and 94.8% for nonsecretory tumors. Worse progression-free survival was associated with larger planning target volume on multivariable analysis (hazard ratio 2.87, 95% confidence interval 1.01–8.21, P = 0.049). Hormonal control at 5 years was 50.0% and associated with higher dose to tumor (hazard ratio 1.05, 95% confidence interval 1.02–1.09, P = 0.005) and number of surgeries (hazard ratio 1.74, 95% confidence interval 1.05–2.89, P = 0.032). Patients requiring any pituitary hormone replacement increased from 57.9% to 70.0% after RT. Modern LINAC RT for patients with PAs was safe and effective for hormonal control and LC. No difference in LC was noted for functional versus nonfunctional tumors, possibly owing to higher total dose and daily image guidance. [ABSTRACT FROM AUTHOR]

Vestibular schwannomas are benign tumors of the cerebellopontine angle that are often treated with radiation therapy. Radiation therapy maintains good tumor control rates but involves a small risk of radiation-induced malignancies. We present a case of high-grade sarcoma arising within a previously irradiated vestibular schwannoma and a literature review of this rare but important clinical entity. A 66-year-old woman presented with rapid clinical and radiographic deterioration 17 years after receiving stereotactic radiosurgery for vestibular schwannoma. After resection, pathology revealed a high-grade sarcoma arising within a conventional schwannoma. After further decline and tumor growth, the patient died of her disease 7 months postoperatively. Literature review was performed using PubMed and EMBASE databases and key words "vestibular schwannoma," "acoustic," "triton," "malignant," "sarcoma," "malignant peripheral nerve sheath tumor," "radiation," and "radiosurgery." All previous cases and the clinical circumstances related to these radiation-induced malignancies were assessed and quantified. The systematic review yielded 20 prior cases of radiation-induced malignant transformation of a vestibular schwannoma in patients without neurofibromatosis. Most tumors (60%) transformed into malignant nerve sheath tumors. At the time of presentation, 70% of patients had new cranial neuropathies, and all had evidence of tumor growth with brainstem compression. Prognosis was poor with mean time to death of 7.6 months. Radiation-induced malignant transformation of vestibular schwannomas is a rare but important clinical entity. Given its scarcity, the risk of malignancy should not sway initial management, but rapid clinical deterioration and radiographic growth during follow-up should prompt consideration of malignant transformation. [ABSTRACT FROM AUTHOR]

Objective Both stereotactic radiosurgery (SRS) and fractionated radiation therapy (FRT) techniques are used for treatment of intracranial meningiomas with excellent local control (LC) rates. Although SRS techniques are convenient, toxicity including treatment-related edema can significantly impact patient quality of life. The long-term clinical outcomes of patients with magnetic resonance imaging (MRI)–defined meningiomas treated with radiation therapy (RT) alone are reported. Methods The charts of 211 patients with meningiomas diagnosed by contrast-enhanced MRI treated with either SRS or FRT between 1991 and 2012 at a single institution were reviewed. Actuarial rates for LC and development of treatment-related radiographic edema (TRE) were determined by the Kaplan-Meier method. Results There were 211 patients who received radiation therapy for 223 lesions. Median follow-up was 5.7 years. Eleven patients experienced a local failure; of these, 2 were ultimately found to have pathologically proven metastatic carcinoma. Two- and 5-year LC was 97.8% and 94.6%, respectively, with no significant difference based on modality of therapy. Actuarial rate for development of TRE at 1 and 2 years was 30.1% and 34.6% for the SRS group and 1.6% and 2.5% for the FRT group, respectively (P < 0.001). Conclusions RT alone using a limited margin is an effective treatment option for MRI-defined meningiomas and should be considered even without biopsy if surgery will present significant morbidity. Although LC with SRS versus FRT was comparable, FRT was associated with a significantly decreased risk of TRE. Highlights • Radiation therapy has become one of the standards of care for patients with intracranial meningioma. • Radiation alone using a limited margin is an effective treatment option for MRI-defined meningiomas. • Radiation should be considered even without biopsy if surgery will present significant risks to the patient. • Both SRS and FRT techniques are used for treatment of intracranial meningiomas with excellent local control rates. • Although LC with SRS versus FRT was comparable, FRT was associated with a significantly decreased risk of TRE. [ABSTRACT FROM AUTHOR]