Search

Purpose: Skin collimation is a useful tool in electron beam therapy (EBT) to decrease the penumbra at the field edge and minimize dose to nearby superficial organs at risk (OARs), but manually fabricating these collimation devices in the clinic to conform to the patient's anatomy can be a difficult and time intensive process. This work compares two types of patient-specific skin collimation (in-house 3D printed and vendor-provided machined brass) using clinically relevant metrics., Methods: Attenuation measurements were performed to determine the thickness of each material needed to adequately shield both 6 and 9 MeV electron beams. Relative and absolute dose planes at various depths were measured using radiochromic film to compare the surface dose, flatness, and penumbra of the different skin collimation materials., Results: Clinically acceptable thicknesses of each material were determined for both 6 and 9 MeV electron beams. Field width, flatness, and penumbra results between the two systems were very similar and significantly improved compared to measurements performed with no surface collimation., Conclusion: Both skin collimation methods investigated in this work generate sharp penumbras at the field edge and can minimize dose to superficial OARs compared to treatment fields with no surface collimation. The benefits of skin collimation are greatest for lower energy electron beams, and the benefits decrease as the measurement depth increases. Using bolus with skin collimation is recommended to avoid surface dose enhancement seen with collimators placed on the skin surface. Ultimately, the appropriate choice of material will depend on the desire to create these devices in-house or outsource the fabrication to a vendor., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy.

Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Head and neck and base of skull malignancies are challenging for surgical and radiotherapy treatment due to the density of sensitive tissues. Carbon ion radiotherapy (CIRT) is a form of heavy particle therapy that uses accelerated carbon ions to treat malignancies that may be radioresistant or in challenging anatomic locations. CIRT has an increased biological effectiveness (ie, increased cell killing) at the end of the range of the carbon beam (ie, within the target tissue) but not in the entrance dose. This increased biological effectiveness can overcome the effects of radioresistant tumors, tissue hypoxia, and the need for radiotherapy fractionation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery., Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected., Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube., Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity., Competing Interests: Conflicts of Interest: Bradford Hoppe, MD, MPH, and Perry Johnson, PhD, are Associate Editors of the International Journal of Particle Therapy. All other authors have no relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Background: Dose escalation for skull-based malignancies often presents risks to critical adjacent neural structures, including the brainstem. We report the incidence of brainstem toxicity following fractionated high-dose conformal proton therapy and associated dosimetric parameters., Material and Methods: We performed a single-institution review of patients with skull-base chordoma or chondrosarcoma who were treated with proton therapy between February 2007 and January 2020 on a prospective outcomes-tracking protocol. The primary endpoint was grade ≥2 brainstem toxicity. No patients received concurrent chemotherapy, and brainstem toxicity was censored for analysis if it coincided with local disease progression., Results: We analyzed 163 patients who received a minimum of 45 GyRBE to 0.03 cm 3 of the brainstem. Patients were treated to a median total dose of 73.8 (range 64.5-74.4) GyRBE at 1.8 GyRBE per fraction with 17 patients undergoing twice-daily treatment at 1.2 GyRBE per fraction. With a median follow-up of 4 years, the 5-year cumulative incidence of grade ≥2 brainstem injury was 1.3% (95% CI 0.25-4.3%). There was one grade 2, one grade 3, and no grade 4 or 5 events, with all patients recovering function with medical management., Conclusion: In delivering curative-intent radiotherapy for skull-base chordoma and chondrosarcoma in adults, small volumes of the brainstem can safely receive at least 64 GyRBE with minimal risk of serious brainstem injury.

Background: To report outcomes of a phase II single-institution trial of dose-escalated proton radiotherapy with elective nodal irradiation (ENI) and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma., Methods: Patients received 40.5 GyRBE in 18 fractions to the gross disease and elective nodal volumes followed by 22.5 GyRBE as a 10-fraction boost to the gross disease for a cumulative dose of 63 GyRBE over 28 fractions. Oral capecitabine (1,000 mg taken orally twice daily) was given on radiation treatment days. The primary objective of this study was to improve the proportion surviving to at least 1 year from the historical rate of 50% to 75%. Secondary objectives included assessing gastrointestinal (GI) toxicity and weight loss during treatment, and evaluating the safety of subsequent surgical resection. This single-institution study was closed to accrual early after the opening of the multicenter PAN009-18 trial by the Proton Collaborative Group (PCG), which follows a similar protocol., Results: At enrollment, 10 (67%) patients had unresectable disease, 3 (20%) had borderline-resectable disease, and 2 (13%) refused surgery. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved by treatment completion. The median percentage weight loss during treatment was -3.0% (range, -9.6% to +12.0%). Two (13%) initially borderline patients ultimately underwent R0 resection: their total operating room times were 267 and 410 minutes, and blood loss was 700 and 400 mL, respectively. Neither patient experienced intraoperative or postoperative complications. Both were discharged on postoperative day 6. The median follow-up was 0.93 years (range, 0.21 to 2.14 years). The 1-year overall survival (OS) rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease., Conclusions: The primary objective of 1-year OS of 75% was not reached. Proton therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications, suggesting that patients with borderline resectable or even resectable disease may benefit from neoadjuvant proton therapy. The PCG will test this premise as patients accrue to the multicenter PAN009-18 trial., Trial Registration: NCT02598349., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-593/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: To compare patterns-of-care and clinical outcomes among uninsured versus insured patients (IPs) with anorectal malignancies referred for radiotherapy at an urban safety-net hospital. This topic is important because uninsured patients (UPs) in the US often have limited access to health care, which can result in worse health outcomes., Methods: We reviewed the medical records of 59 patients with biopsy-proven, non-metastatic anal and rectal cancers who received curative-intent primary or neoadjuvant/adjuvant radiotherapy between May 2002 and August 2012. Data regarding patient and disease characteristics, weight loss, insurance status at symptom onset, date of first therapeutic intervention, and survival status at last follow-up, were collected and analyzed., Results: The percentage of IPs presenting with T4 tumors was 7% versus 40% among the uninsured (P=0.005). The median interval between first symptom onset and diagnosis date was 89 (range, 0-1,428) days for IPs and 221 (range, 0-1,576) days for UPs (P=0.01). The median interval between first symptom onset and treatment initiation was 172 (range, 9-1,498) days for IPs and 302 (range, 35-1,624 days) days for UPs (P=0.01). The 5-year overall survival rate was 59% for the entire cohort, 62% for the insured patients, and 55% for the uninsured patients (P=0.76)., Conclusions: Differences in health insurance status demonstrated various disparities in patterns-of-care, including significant delay in diagnosis, more advanced-stage disease at presentation, and treatment initiation delays among UPs. Nevertheless, overall survival at 5 years was not statistically significant between the insured and the uninsured., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-592/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Purpose: To report disease control and treatment-related side effects among adult patients with craniopharyngioma treated with radiotherapy., Methods: We performed a single-institution review of adult patients (> 21 years old) with craniopharyngioma treated with radiotherapy either definitively or postoperatively for gross residual disease. We report disease control, survival, and radiotherapy-related side effects., Results: A total of 49 adult patients with craniopharyngioma were included, 27 of whom were treated at initial presentation and 22 for recurrent disease following initial surgery and observation. Overall, 77% received radiotherapy postoperatively (either after primary surgery or surgery for recurrence). With a median clinical and radiographic follow-up of 4.2 (range, 0.4-21.6) years and 3.0 (range, 0-21.5) years, the 5- and 10-year local control rates were 100 and 94%, respectively. The 5- and 10-year overall survival rates were 80 and 66%, respectively. Eleven percent of patients experienced grade 2 vision deterioration and 18% suffered grade 2 endocrinopathies following radiotherapy., Conclusions: Radiotherapy provides excellent disease control with acceptable toxicity among adult patients with craniopharyngioma. These data support the use of fractionated radiotherapy in adult patients with recurrent or gross residual disease after surgery. For inoperable patients or those with moderate or high surgical risk to neurologic and/or vascular structures, we advocate for limited surgical resection and postoperative radiotherapy to balance optimal tumor control with tumor- and treatment-related morbidity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Radiation-associated angiosarcoma (RAAS) is a rare complication among patients treated with radiation therapy for breast cancer. Hyperfractionated-accelerated reirradiation (HART) improves local control after surgery. Proton therapy may further improve the therapeutic ratio by mitigating potential toxicity., Materials and Methods: Six patients enrolled in a prospective registry with localized RAAS received HART with proton therapy between 2015 and 2021. HART was delivered twice or thrice daily in fraction sizes of 1.5 or 1.0 Gy, respectively. All patients received 45 Gy to a large elective volume followed by boosts to a median dose of 65 (range, 60-75) Gy. Toxicity was recorded prospectively by using the Common Terminology Criteria for Adverse Events, version 4.0., Results: The median follow-up duration was 1.5 (range, 0.25-2.9) years. The median age at RAAS diagnosis was 73 (range, 60-83) years with a median latency of 8.9 (range, 5-14) years between radiation therapy completion and RAAS diagnosis. The median mean heart dose was 2.2 (range, 0.1-4.96) Gy. HART was delivered postoperatively (n = 1), preoperatively (n = 3), preoperatively for local recurrence after initial management with mastectomy (n = 1), and as definitive treatment (n = 1). All patients had local control of disease throughout follow-up. Three of 4 patients treated preoperatively had a pathologic complete response. The patient treated definitively had a complete metabolic response on her posttreatment PET/CT (positron emission tomography-computed tomography) scan. Two patients developed distant metastatic disease despite local control and died of their disease. Acute grade 3 toxicity occurred in 3 patients: 2 patients undergoing preoperative HART experienced wound dehiscence and 1 postoperatively developed grade 3 wound infection, which resolved., Conclusion: HART with proton therapy appears effective for local control of RAAS with a high rate of pathologic complete response and no local recurrences to date. However, vigilant surveillance for distant metastasis should occur. Toxicity is comparable to that in photon/electron series. Proton therapy for RAAS may maximize normal tissue sparing in this large-volume reirradiation setting., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, is Editor-in-Chief of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy., Methods: We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed., Results: Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively., Conclusions: Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To evaluate the effectiveness of external-beam proton therapy (PT) on local control and survival in patients with skull-base chordoma., Materials and Methods: We reviewed the medical records of patients with skull-base chordoma treated with definitive or adjuvant high-dose PT and updated their follow-up when feasible. We assessed overall survival, disease-specific survival, local control, and freedom from distant metastasis. Radiotherapy toxicities were scored using the Common Terminology Criteria for Adverse Events, version 4.0., Results: A total 112 patients were analyzed, of whom 105 (94%) received PT and 7 (6%) received combined proton-photon therapy between 2007 and 2019. Eighty-seven patients (78%) underwent a subtotal resection, 22 (20%) a gross total resection, and 3 (3%) a biopsy alone. The median radiotherapy dose was 73.8 Gy radiobiologic equivalent (GyRBE; range, 69.6-74.4). Ninety patients (80%) had gross disease at radiotherapy and 7 (6%) were treated for locally recurrent disease following surgery. Median follow-up was 4.4 years (range, 0.4-12.6); for living patients, it was 4.6 years (range, 0.4-12.6), and for deceased patients, 4.1 years (range, 1.2-11.2). At 5 years after radiotherapy, the actuarial overall survival, disease-specific survival, local control, and freedom from distant metastasis rates were 78% (n = 87), 83% (n = 93), 74% (n = 83), and 99% (n = 111), respectively. The median time to local progression was 2.4 years (range, 0.8-7). Local control and disease-specific survival by resection status was 95% versus 70% ( P  = 0.28) and 100% versus 80% ( P  = 0.06) for gross total, versus subtotal, resection or biopsy alone, respectively. There were no serious acute toxicities (grade ≥ 3) related to radiotherapy., Conclusion: High-dose PT alone or after surgical resection for skull-base chordoma reaffirms the favorable 5-year actuarial local control rate compared with conventional techniques with acceptable late-complication-free survival. Outcomes following gross total resection and adjuvant PT were excellent. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities., Competing Interests: Conflicts of Interest: Adam L. Holtzman, MD, has received a speaking honorarium from the American Academy of Insurance Medicine and the American Council of Life Insurers. William M. Mendenhall, MD, is Operating Editor of the International Journal of Particle Therapy., (©Copyright 2021 The Author(s).)

Background & Purpose: Dose escalation for skull-based chordoma and chondrosarcoma can put critical adjacent structures at risk, specifically the anterior optic pathway. We report the incidence of vision loss following high-dose conformal proton-based radiotherapy., Materials and Methods: We reviewed patients with skull-base chordoma or chondrosarcoma treated with proton-based therapy between 2007 and 2018. We analyzed 148 patients and 283 individual eyes with functional vision at baseline who received a minimum 30GyRBE to 0.1 cm 3 of the anterior optic pathway. Eyes were classified as "functionally blind" if visual acuity was 20/200 or worse. Kaplan-Meier and normal tissue complication probability modeling were used to establish the relationship between radiation dose and risk of functional vision loss., Results: At last follow-up, 110 of 148 patients were alive with no evidence of disease progression. With a median follow-up of 4.1 years (range, 0.5-12.8), 5 eyes in 3 patients developed functional blindness, with 2 patients developing bilateral blindness. Median time to blindness was 15.2 months. The 5-year incidence of vision loss was 2.1% (95% CI: 0.9-4.9%). On univariate analysis, development of blindness was associated with presence of multiple medical comorbidities (p = 0.0040). While there were no events with a maximum dose < 60GyRBE delivered to the anterior optic pathway, the crude rate was 3.6% over 60GyRBE, with all events occurring between 60-65GyRBE., Conclusions: Despite the high radiotherapy dose delivered to patients with skull-base chordoma and chondrosarcoma, the rate of vision loss is low and no events occurred in those who received a maximum dose under 60GyRBE., Competing Interests: Declaration of Competing Interest ALH has received honorariums for educational events from the American Academy of Insurance Medicine and the American Council of Life Insurers unrelated to this research., (Copyright © 2021. Published by Elsevier B.V.)

Introduction  In adults with skull base chordoma or chondrosarcoma, the impact of treatment center and access to care have not been well described in regard to perioperative mortality and survival. Methods  A query of the National Cancer Database (NCDB) and review of 1,102 adults-488 with chordomas and 614 with chondrosarcomas-was performed. The Kaplan-Meier's product limit method and chi-square analysis, respectively, assessed overall survival and 30-day (30D) and 90-day (90D) mortalities. Results  For 925 patients who had surgery and available mortality data, the 30D and 90D mortality rates were 0.9 and 1.5%. Lower education level ( p  = 0.0185) and treatment at a nonacademic facility ( p  = 0.016) were associated with increased risk of 90-day mortality. Median follow-up was 52 months and analysis was dichotomized by histology. For those with skull base chordoma, patients from a larger metro size ( p  = 0.002), age below the median 52 years ( p ≤ 0.001), and private insurance (<0.001) were associated with prolonged survival, whereas for skull base chondrosarcoma, the factors were treatment at an academic medical center ( p  = 0.001), high-volume center ( p  = 0.007), age below the median 52 years ( p ≤ 0.001), higher income ( p  = 0.043), higher education ( p  = 0.017), and private insurance ( p ≤ 0.001). Comparing high-, medium-, and low-volume centers, high-volume centers were most likely to be academic, deliver radiotherapy, escalate doses >70 Gy, and utilize proton radiotherapy consistent across both disease subsets. Conclusion  Higher educational attainment and treatment at an academic facility were associated with decreased 90D mortality for patients with skull base chordoma and chondrosarcoma. For those with skull base chordoma, larger metro size, younger age, and private insurance were associated with prolonged survival; for those with chondrosarcoma, it was treatment at a high-volume or academic medical center, younger age, higher income or education, and private insurance., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Opinion Statement: Desmoid tumors have a variable clinical course that ranges from indolence or spontaneous regression to an aggressive pattern marked by local invasion. Up to half may remain stable or regress; watchful waiting is the preferred approach in the initial management of desmoid tumors. Symptomatic or progressive tumors or those that may affect adjacent critical structures require surgery, radiotherapy, or systemic therapy. Although radiotherapy effectively controls desmoid tumors in most cases, concerns regarding late toxicity exist. Definitive radiotherapy for macroscopic disease is indicated when a non-morbid complete surgical resection cannot be accomplished and provides similar control rates to surgery plus radiotherapy but avoids toxicity from combined-modality treatment (surgery and radiotherapy). Adjuvant radiotherapy can be considered for microscopically involved margins, particularly for recurrent cases or when a future recurrence may be challenging to treat. Large size, extremity site, and younger age are poor prognostic factors after radiotherapy. In the extremity, radiotherapy may have superior outcomes to surgery. Younger patients, especially children, are challenging to manage as they are at particular risk for late toxicity due to the number of potential years at risk. For patients under 20 years old, for whom a non-morbid complete resection is not possible, we recommend systemic therapy as the first line of treatment. Although the long-term efficacy of systemic therapy is unproven, this strategy allows additional time for growth and development prior to radiotherapy. In younger patients and those with axial desmoid tumors adjacent to critical organs, consideration should be given to using proton therapy as the dosimetric advantages may mitigate some of the toxicity associated with conventional radiotherapy.

Background: Craniopharyngioma is a benign tumor that commonly develops within the suprasellar region. The tumor and treatment can have debilitating consequences for pediatric and adult patients, including vision loss and pituitary/hypothalamic dysfunction. Most craniopharyngioma series focus on treatment of the pediatric population. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using proton therapy to report outcomes for disease control, treatment-related toxicity, and tumor response., Methods: We analyzed 14 adult patients (≥ 22 years old). All patients had gross disease at the time of radiotherapy. Five were treated for de novo disease and 9 for recurrent disease. Patients received double-scattered conformal proton therapy to a mean dose of 54 GyRBE in 1.8 GyRBE/fraction (range 52.2-54 GyRBE). Weekly magnetic resonance imaging (MRI) helped to evaluate tumor changes during radiotherapy., Results: With median clinical and radiographic follow-up of 29 and 26 months, respectively, the 3-year local control and overall survival rates were both 100%. There were no grade 3 or greater acute or late radiotherapy-related side effects. There was no radiotherapy-related vision loss or optic neuropathy. No patients required intervention or treatment replanning due to tumor changes during radiotherapy. Two patients experienced transient cyst expansion at their first post-radiotherapy MRI. Both patients were followed closely clinically and radiographically and had subsequent dramatic tumor/cyst regression, requiring no interventions., Conclusions: Our data support the safety and efficacy of proton therapy in the treatment of adult craniopharyngioma as part of primary or salvage treatment. We recommend early consideration of radiotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03224767.

Pancreatic carcinoma is a challenging malignancy to manage with a very poor prognosis. Despite continued difficulties in its management, there have been incremental improvements in outcomes over the past several decades. Achieving the best oncologic outcomes requires a multimodality approach including surgery, chemotherapy, and radiotherapy. Proton radiotherapy enables the delivery of high-dose radiotherapy to the tumor or resection bed while sparing nearby critical organs. Due to their unique physical properties, protons can deliver radiotherapy dose distributions that are not achievable with photons (X-rays) even with advanced photon delivery techniques (e.g., intensity-modulated radiotherapy). Improved dose distributions can lead to reduced treatment toxicity and enable treatment intensification. As better chemotherapy regimens lead to better systemic disease control, it will become increasingly important that local-regional control is achieved. This will in part be accomplished by combining better radiotherapy with more active chemotherapies. Proton radiotherapy provides an excellent means for achieving this., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Gastrointestinal Oncology. All rights reserved.)

Purpose: We sought to assess clinical outcomes and toxicities of patients with recurrent lung cancer reirradiated with proton beam therapy (PBT) who were enrolled in 2 prospective registry trials., Methods and Materials: Seventy-nine consecutive patients were reirradiated with PBT at 8 institutions. Conventionally fractionated radiation therapy was used to treat the previous lung cancer in 68% of patients (median equivalent dose in 2 Gy fractions [EQD 2 ], 60.2 Gy) and hypofractionated/stereotactic body radiation therapy in 32% (median EQD 2 , 83.3 Gy). Nine patients (11%) received ≥2 courses of thoracic irradiation before PBT. Eastern Cooperative Oncology Group (ECOG) performance status was 2 to 3 in 13%. Median time from prior radiation therapy to PBT was 19.9 months. PBT was delivered with conventional fractionation in 58% (median EQD 2 , 60 Gy), hyperfractionation in 3% (median EQD 2 , 62.7 Gy), and hypofractionation in 39% (median EQD 2 , 60.4 Gy). Twenty-four patients (30%) received chemotherapy concurrently with PBT., Results: All patients completed PBT as planned. At a median follow-up of 10.7 months after PBT, median overall survival (OS) and progression-free survival (PFS) were 15.2 months and 10.5 months, respectively. Acute and late grade 3 toxicities occurred in 6% and 1%, respectively. Three patients died after PBT from possible radiation toxicity. On multivariate analysis, ECOG performance status ≤1 was associated with OS (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80; P = .014) and PFS (hazard ratio, 0.32; 95% confidence interval, 0.14-0.73; P = .007)., Conclusions: This is the largest series to date of PBT reirradiation for recurrent lung cancer and indicates that reirradiation with PBT is well tolerated with acceptable toxicity and encouraging efficacy. ECOG performance status was associated with OS and PFS., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: We sought to evaluate the effectiveness of definitive or adjuvant external-beam proton therapy on local control and survival in patients with skull-base chondrosarcoma., Methods: We reviewed the medical records of 43 patients with a median age of 49 years (range, 23-80 years) treated with double-scattered 3D conformal proton therapy for skull-base chondrosarcomas between January 2007 and February 2016. Proton therapy-related toxicities were scored using CTCAE v4.0., Results: The median radiotherapy dose was 73.8 Gy(RBE) (range, 64.5-74.4 Gy[RBE]). Thirty-six (84%) and 7 (16%) patients underwent surgical resection or biopsy alone. Tumor grade distribution included: grade 1, 19 (44%) patients; grade 2, 22 (51%); and grade 3, 2 (5%). Forty patients had gross disease at the time of radiotherapy and 7 patients were treated for locally recurrent disease following surgery. The median follow-up was 3.7 years (range, 0.7-10.1 years). There were no acute grade 3 toxicities related to RT. At 4 years following RT, actuarial rates of overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were 95%, 100%, 89%, and 95%., Conclusion: High-dose, double-scattered 3D conformal proton therapy alone or following surgical resection for skull-base chondrosarcoma is an effective treatment with a high rate of local control with no acute grade 3 radiation-related toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.

Background: Skull base chordomas and chondrosarcomas are rare tumors traditionally treated by surgical resection and adjuvant radiation therapy (RT). We will discuss data evaluating clinical outcomes of proton therapy in the treatment of skull base chordomas and chondrosarcomas., Methods: A literature review was performed using a MEDLINE search from January 1990 to January 2017., Results: The published data suggest that the dose intensification allowed by proton therapy has resulted in good clinical outcomes and a tolerable toxicity profile., Conclusion: Proton therapy is a modern RT technique that has demonstrated improved preliminary clinical outcomes in the treatment of skull base chordomas and chondrosarcomas compared to conventional radiotherapy, and comparable to other advanced photon-based RT techniques., (© 2018 Wiley Periodicals, Inc.)

To evaluate the benefit of adding CT imaging to the simulation process of clip-based proton therapy of ocular melanomas. For thirty ocular melanoma cases, the clip position in the eye model was determined based on orthogonal radiographs as well as on a CT image set. The geometrical shift of the clips between the standard simulation process and standard simulation process with addition of CT imaging (CT-guided) was determined. The dosimetric impact was evaluated by developing treatment plans based on both the standard-process model and the CT-guided model. In 40% of the studied cases, the difference in clip position between eye models created with and without CT was less than 0.5 mm. This difference was more than 1 mm in 17% of cases. The dosimetric impact of shifts below 1 mm was low because these shifts did not exceed the planning margins. For the four cases with a shift of more than 1 mm a reduction in target coverage (ΔV99%) of  -3% to  -6% was observed. Changes in macula and optic-disc mean dose of up to 16% and 35% of the prescribed dose were seen when these structures abutted the target. Adding CT imaging to the simulation process is beneficial in select cases where discrepancies between the eye model and ophthalmology measurements occur or where a critical structure is located close to the target and improved localization accuracy is wanted. For the majority of patients, addition of CT imaging does not result in quantifiable changes in dosimetry. Nevertheless, CT imaging is a valuable tool in the quality control of the modeling and treatment-planning process of clip-based eye treatments.

Objectives: The objective of this study is to evaluate long-term outcomes, specifically patterns of tumor recurrence, in patients with adult medulloblastoma treated with radiotherapy., Methods: We recorded outcomes of 28 (median age, 25 y) patients 18 years old or above with M0 to M3 medulloblastoma treated between 1971 and 2012. Among them, 61% had standard-risk disease. All received craniospinal irradiation with a posterior fossa boost. Median dose to the craniospinal axis was 36 Gy. Median total dose to the primary site was 55.9 Gy and 46% received chemotherapy., Results: Median follow-up among survivors was 14.2 years. At 5 and 10 years, local control was 80% and 73%, overall survival was 71% and 59%, cause-specific survival was 71% and 63%, and freedom from progression was 68% and 59%. Tumors recurred in 11 patients (39%); median time to recurrence was 2.4 years, and 82% of recurrences developed in patients with standard-risk disease. Of the recurrences, 55% involved the primary site; 36% were bone metastases without neural axis recurrence. There were no isolated recurrences in the spinal canal or ventricular system outside of the posterior fossa., Conclusion: The primary site is the main site of medulloblastoma recurrence, with isolated bone metastases more common in adults than children. Our results prompt us to consider 4 modifications to our treatment approach with adults who present with medulloblastoma: (1) initial staging to include PET or bone scan; (2) radiotherapy dose to the primary site of 59.4 Gy; (3) chemotherapy during and/or following radiotherapy in medically fit patients; (4) follow-up to include PET or bone scan twice a year for 3 years.

Purpose: Evaluate clinical outcomes in patients with vestibular schwannoma (VS) treated with fractionated proton therapy (PT) at a single institution., Materials and Methods: We retrospectively reviewed the medical records of patients treated with fractionated PT for definitive management of VS between November 2007 and December 2013 at our institution. No patient had received prior treatment for VS. Patients received 50.4 Gy in 28 fractions using passively scattered PT. Pretreatment and posttreatment hearing status, tumor dimensions, and cranial nerve V and VII function were evaluated. Hearing status was graded as nonserviceable or serviceable, defined as Gardner-Robertson grade I or II and the ability to use a telephone with the treated ear. Toxicities were prospectively evaluated using Common Terminology Criteria for Adverse Events, version 4.0., Results: Fourteen patients with 14 lesions (8 men, 6 women) were included in the analysis. Median age at treatment was 60 years (range, 24-74 years). Median clinical follow-up for living patients was 68 months (range, 36-106 months). Mean maximal tumor dimension was 2.1 cm (range, 0.5-3.8 cm). Mean tumor volume was 6.4 cm 3 (range, 0.3-16.0 cm 3 ). One patient died of unrelated causes 5 months after treatment, and 2 had subsequent surgical resections due to radiographic and/or clinical progression. The actuarial 3-year local control rate was 85%. There were no cranial nerve V or VII injuries. Two of 6 patients (33%) with serviceable hearing at the time of treatment retained serviceable hearing. Three patients (21%) demonstrated radiographic tumor regression on brain magnetic resonance imaging after a median of 26 months (range, 2-113 months). No acute toxicity of grade 3 or above was reported., Conclusion: Fractionated PT for VS is well tolerated and provides good local control. Improvements in proton delivery techniques and patient selection may enable improved outcomes., Competing Interests: Conflicts of interest: Dr William Mendenhall is operating editor of the International Journal of Particle Therapy. The authors have no other conflicts of interest to disclose., (© Copyright 2018 International Journal of Particle Therapy.)

Aim: To review surgical outcomes for patients undergoing pancreatectomy after proton therapy with concomitant capecitabine for initially unresectable pancreatic adenocarcinoma., Methods: From April 2010 to September 2013, 15 patients with initially unresectable pancreatic cancer were treated with proton therapy with concomitant capecitabine at 1000 mg orally twice daily. All patients received 59.40 Gy (RBE) to the gross disease and 1 patient received 50.40 Gy (RBE) to high-risk nodal targets. There were no treatment interruptions and no chemotherapy dose reductions. Six patients achieved a radiographic response sufficient to justify surgical exploration, of whom 1 was identified as having intraperitoneal dissemination at the time of surgery and the planned pancreatectomy was aborted. Five patients underwent resection. Procedures included: Laparoscopic standard pancreaticoduodenectomy ( n = 3), open pyloris-sparing pancreaticoduodenectomy ( n = 1), and open distal pancreatectomy with irreversible electroporation (IRE) of a pancreatic head mass ( n = 1)., Results: The median patient age was 60 years (range, 51-67). The median duration of surgery was 419 min (range, 290-484), with a median estimated blood loss of 850 cm 3 (range, 300-2000), median ICU stay of 1 d (range, 0-2), and median hospital stay of 10 d (range, 5-14). Three patients were re-admitted to a hospital within 30 d after discharge for wound infection ( n = 1), delayed gastric emptying ( n = 1), and ischemic gastritis ( n = 1). Two patients underwent R0 resections and demonstrated minimal residual disease in the final pathology specimen. One patient, after negative pancreatic head biopsies, underwent IRE followed by distal pancreatectomy with no tumor seen in the specimen. Two patients underwent R2 resections. Only 1 patient demonstrated ultimate local progression at the primary site. Median survival for the 5 resected patients was 24 mo (range, 10-30)., Conclusion: Pancreatic resection for patients with initially unresectable cancers is feasible after high-dose [59.4 Gy (RBE)] proton radiotherapy with a high rate of local control, acceptable surgical morbidity, and a median survival of 24 mo., Competing Interests: Conflict-of-interest statement: The authors of this current series have no conflicts of interested to disclose.

Purpose: Patients with locally recurrent prostate cancer after definitive prostate brachytherapy have few evidence-based salvage options. We evaluate the efficacy and treatment-related side-effects of salvage external-beam radiotherapy (EBRT) after definitive prostate brachytherapy (PBT)., Methods and Materials: Eleven patients previously treated with definitive PBT and with biopsy-proven local-only recurrence received salvage reirradiation with EBRT. Genitourinary (GU) function was assessed with International Prostate Symptom Scores. Treatment-related toxicities were graded using CTCAE v 4.03., Results: Median follow-up was 26.5 months (range, 1-53.6 months); median age at EBRT salvage was 67 years (range, 61-81 years). Salvage EBRT included the whole pelvis in 8 patients. Two patients were treated with 3D-CRT; 9 underwent IMRT. Five patients (45%) received androgen deprivation therapy concurrent with salvage EBRT as part of long- or short-course hormone therapy. The median prostate dose was 70.2 Gy (range, 64.8-75.6 Gy). Actuarial 3-year overall and biochemical failure-free survival were 77% and 69%, respectively. Five patients (45%) had worsening GU symptoms, and 9 (82%) experienced a decline in erectile function. One patient experienced acute grade 2 GU toxicity. Four patients (36%) experienced late grade ≥2 GI/GU toxicities, including 2 who experienced grade 3 toxicities (rectourethral fistula/incontinence, bladder outlet obstruction). No grade 4/5 toxicities were noted., Conclusions: Our data suggest that salvage EBRT can provide similar disease control and treatment-related toxicity to more established salvage therapies. This approach warrants further investigation on a larger scale., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Hodgkin lymphoma has gone from an incurable disease to one for which the majority of patients will be cured. Combined chemotherapy and radiotherapy achieves the best disease control rates and results in many long-term survivors. As a result, a majority of long-term Hodgkin lymphoma survivors live to experience severe late treatment-related complications, especially cardiovascular disease and second malignancies. The focus of research and treatment for Hodgkin lymphoma is to maintain the current high rates of disease control while reducing treatment-related morbidity and mortality. Efforts to reduce late treatment complications focus on improvements in both systemic therapies and radiotherapy. Herein we review the basis for the benefits of proton therapy over conventional X-ray therapy. We review outcomes of Hodgkin lymphoma treated with proton therapy, and discuss the ability of protons to reduce radiation dose to organs at risk and the impact on the most significant late complications related to the treatment.

Background: To report long-term outcomes following radiotherapy for desmoid tumors in children and young adults and identify variables impacting local-regional control and treatment complications., Procedure: From 1978 to 2008, 30 patients <30 years old were treated with radiotherapy for a pathologically confirmed desmoid tumor. The median age at radiotherapy was 23.7 years old (range, 10.3-29.9). Fifteen patients underwent definitive radiotherapy, 14 received radiotherapy after gross total resection, and 1 received preoperative radiotherapy. Sixteen patients received 1.8 Gy once daily and 14 received 1.2 Gy twice daily. Variables analyzed for prognostic value included gender, age at diagnosis, primary or recurrent presentation, age at radiotherapy, tumor site, tumor size, extent of resection, fractionation schedule, and radiotherapy dose., Results: The actuarial 15-year overall survival and local-regional control rates were 96% and 55%, respectively. Local-regional control in patients <18 years old at the time of radiotherapy was 20% versus 63% in those 18-30 years old (P = 0.08). Local-regional control rates for tumors receiving ≥ 55 Gy and < 55 Gy were 79% and 30%, respectively (P = 0.02). No other factors had a statistically significant association with local-regional control by univariate analysis. Twelve of 30 patients experienced grade 3-4 complications, including pathologic fractures, impaired range of motion, pain, and in-field skin cancers., Conclusions: The role of radiotherapy in managing young patients with desmoid tumors remains unclear. Younger patient age is associated with inferior local-regional control following RT. In children and young adults, doses ≥55 Gy were associated with improved tumor control, but also lead to increased risk of complications., (Copyright © 2010 Wiley-Liss, Inc.)

Ketogenic diets (KDs) are used for treatment of refractory epilepsy and metabolic disorders. The classic saturated fatty acid-enriched (SAT) KD has a fat:carbohydrate plus protein ratio of 4:1, in which the predominant fats are saturated. We hypothesized that a polyunsaturated fat-enriched (POLY) KD would induce a similar degree of ketosis with less detrimental effects on carbohydrate and lipid metabolism. Twenty healthy adults were randomized to two different weight-maintaining KDs for 5 d. Diets were 70% fat, 15% carbohydrate, and 15% protein. The fat contents were 60 or 15% saturated, 15 or 60% polyunsaturated, and 25% monounsaturated for SAT and POLY, respectively. Changes in serum beta-hydroxybutyrate, insulin sensitivity (S(I)), and lipid profiles were measured. Mean circulating beta-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group (P = 0.0004), compared with 3.1 mg/dl in the SAT group (P = 0.07). S(I) increased significantly in the POLY group (P = 0.02), whereas total and low-density lipoprotein cholesterol increased significantly in the SAT group (both P = 0.002). These data demonstrate that a short-term POLY KD induces a greater level of ketosis and improves S(I), without adversely affecting total and low-density lipoprotein cholesterol, compared with a traditional SAT KD. Thus, a POLY KD may be superior to a classical SAT KD for chronic administration.

Bone marrow-derived cells (BMDCs) can contribute to the regeneration of diverse adult tissues, including brain, liver and heart, following bone marrow transplantation. These unexpected events were initially considered a result of transdifferentiation of BMDCs, supporting the emerging idea of extended plasticity of adult stem cells. Although studies have now clearly demonstrated that spontaneous cell fusion, rather than transdifferentiation, was the primary cause for unexpected cell fate-switches of BMDCs into hepatocytes, Purkinje cells and cardiac myocytes in vivo.

Cell plasticity is a central issue in stem cell biology. Differentiated somatic nuclei have the flexibility to dedifferentiate when transferred into oocytes or when fused to pluripotent embryonic stem cells. Recent publications also claim that somatic stem cells can convert into developmentally unrelated cell types both in vivo and ex vivo without such drastic cell manipulations. Some of these claims are still controversial, making it difficult for us to determine the reality of somatic stem cell plasticity. Indeed, we have heard enough about the "potentials" of cell plasticity; how much do we know about mechanisms? A fundamental issue in current stem cell biology is to understand the mechanisms underlying cell plasticity. In this short review, we overview three research fields related to cell plasticity: nuclear transfer, transdifferentiation, and cell fusion, with an emphasis on studies of molecular mechanisms underlying cell plasticity.