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Ensuring high quality, evidence-based radiation therapy for patients with cancer is of the upmost importance. To address this need, the Veterans Affairs (VA) Radiation Oncology Program partnered with the American Society for Radiation Oncology and established the VA Radiation Oncology Quality Surveillance program. As part of this ongoing effort to provide the highest quality of care for patients with rectal cancer, a blue-ribbon panel comprised of rectal cancer experts was formed to develop clinical quality measures.The Rectal Cancer Blue Ribbon panel developed quality, surveillance, and aspirational measures for (a) initial consultation and workup, (b) simulation, treatment planning, and treatment, and (c) follow-up. Twenty-two rectal cancer specific measures were developed (19 quality, 1 aspirational, and 2 surveillance). In addition, dose-volume histogram constraints for conventional and hypofractionated radiation therapy were created.The quality measures and dose-volume histogram for rectal cancer serves as a guideline to assess the quality of care for patients with rectal cancer receiving radiation therapy. These quality measures will be used for quality surveillance for veterans receiving care both inside and outside the VA system to improve the quality of care for these patients.

In 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).One 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.The 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 age50, 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.This 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.

We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT).We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival).Sixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27-84 years)]. Median posttreatment follow-up was 19.1 months (0.8-164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05-0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14-0.64) had significantly improved overall survival (P0.001). The 5-year local progression-free survival (50% nCRTOutcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.

Background A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. Methods In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. Results The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). Conclusions Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

Purpose To compare the dosimetric performances of small-spot three-dimensional (3D) and four-dimensional (4D) robustly optimized intensity-modulated proton (IMPT) plans in the presence of uncertainties and interplay effect simultaneously for distal esophageal carcinoma. Method and materials Thirteen (13) patients were selected and re-planned with small-spot ( σ ~ 2-6 mm) 3D and 4D robust optimization in IMPT, respectively. The internal clinical target volumes (CTVhigh3d , CTVlow3d ) were used in 3D robust optimization. Different CTVs (CTVhigh4d , CTVlow4d ) were generated by subtracting an inner margin of the motion amplitudes in three cardinal directions from the internal CTVs and used in 4D robust optimization. All patients were prescribed the same dose to CTVs (50 Gy[RBE] for CTVhigh3d /CTVhigh4d and 45 Gy[RBE] for CTVlow3d /CTVlow4d ). Dose-volume histogram (DVH) indices were calculated to assess plan quality. Comprehensive plan robustness evaluations that consisted of 300 perturbed scenarios (10 different motion patterns to consider irregular motion (sampled from a Gaussian distribution) and 30 different uncertainties scenarios (sampled from a 4D uniform distribution) combined), were performed to quantify robustness to uncertainties and interplay effect simultaneously. Wilcoxon signed-rank test was used for statistical analysis. Results Compared to 3D robustly optimized plans, 4D robustly optimized plans had statistically improved target coverage and better sparing of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) in the nominal scenario. 4D robustly optimized plans had better robustness in target dose coverage (CTVhigh4d V100% , P = 0.002) and the protection of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) when uncertainties and interplay effect were considered simultaneously. Conclusions Even with small spots in IMPT, 4D robust optimization outperformed 3D robust optimization in terms of normal tissue protection and robustness to uncertainties and interplay effect simultaneously. Our findings support the use of 4D robust optimization to treat distal esophageal carcinoma with small spots in IMPT.

Introduction Anorectal neuroendocrine carcinomas (NECs) are uncommon malignancies with poor prognosis. Consensus guidelines exist for treating extrapulmonary NEC. However, limited data is available to guide treatment for anorectal NEC. In this study, we sought to review the clinical characteristics and outcomes of patients with NEC of the rectum and/or anus at Mayo Clinic. Patients and Methods This is a retrospective study of all patients with the diagnosis of NEC of the anus and/or rectum treated across Mayo Clinic sites since 2000. Baseline patient characteristics, tumor pathology, imaging profiles, treatment strategies utilized, and survival outcomes were analyzed. Kaplan-Meier analysis was used with a significance level of P Results The study included a total of 38 patients with primary NEC of the anus and/or rectum. The median age at diagnosis was 55.5 years. The median follow-up was 18.8 months. Fifteen patients had locoregional disease (LRD) at diagnosis. The remaining 23 had metastatic disease. Overall survival was significantly shorter in patients with LRD compared with those with metastatic disease at diagnosis (18.1 vs. 13.8 months; P = .039). The majority (n = 11) of patients with LRD were treated with concurrent chemoradiation therapy, and 10 underwent surgical resection of the primary tumor. The majority (13/15) of patients with LRD progressed, with the majority (11/15) of progressions being distant. The median progression-free survival for patients with LRD was 5.7 months (1-year progression-free survival, 26.7%). Conclusion Anorectal NEC is an aggressive malignancy with poor prognosis requiring multidisciplinary discussion. In addition, the systemic nature of anorectal NEC with distant recurrences in LRD and poor outcomes in metastatic disease emphasizes the need to further develop better systemic treatment options that can potentially improve outcomes in NEC.

Stereotactic radiosurgery is an effective treatment option for trigeminal neuralgia (TN), with frameless stereotactic radiosurgery (fSRS) allowing for a less invasive experience. A single-institutional series and systematic review of the literature were performed for cases of TN treated with fSRS.Patients at our institution with TN that were treated with fSRS from the years 2012-2021 were included. Similarly, multiple databases were searched for studies regarding TN treated with fSRS where patient-level data was included from 2004-2020. Pain levels, via the Barrow Neurological Institute (BNI) scale, before and after treatment were analyzed. Pooled analysis was performed to compare treatment outcomes between studies using CyberKnife and LINAC modalities.Twenty-three patients at our institution were treated with LINAC fSRS (median treatment dose: 85 Gy). Most patients had TN refractory to previous procedural treatments. Eight (35%) patients had an excellent posttreatment response (BNI I-II), while 11 (48%) patients had a good result (BNI IIIa/b). Eight patients had recurrence of pain. A total of 30 articles were included in the systematic review, encompassing 1705 patients. At last follow-up, 63.1% (774/1227) of patients endorsed an excellent response, while 16.1% (197/1227) had a good response, and 22.5% (215/957) of patients had recurrence. Pain response, facial numbness rates, and pain recurrence rates were not significantly different between CyberKnife and LINAC modalities.Frameless SRS for TN appears to be an efficacious noninvasive option for patients with substantial comorbidities, who have failed other treatment methods, although it can be limited by higher recurrence rates.

Lymphomatoid granulomatosis (LYG) is an uncommon angiocentric and angiodestructive T-cell rich, Epstein-Barr virus (EBV) positive B-cell multisystem lymphoproliferative disorder, predominately affecting the lungs. Since both clinical presentation and radiographic imaging findings, including X-ray and computed tomographic (CT), are nonspecific, the ultimate diagnosis of LYG relies on lung tissue sample diagnosis with its WHO grading based on the degree of cytologic atypia, necrosis and density of EBV positive B-cells. In addition, its histopathologic grading is correlated with clinical manifestation with high grade LYG mimicking aggressive B-cell lymphoma. Discordant grading between pulmonary and cutaneous LYG lesion has have been observed and might be a potential diagnostic and prognostic pitfall. F18-FDG PET/CT has been used to monitor disease progression and treatment response. In this study, we reviewed and summarized the clinical role of F18-FDG PET/CT in the surveillance of high grade pulmonary LYG, and examined its limitations in grading multisystem LYG.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Purpose Our purpose was to determine the effect of chemoradiotherapy (CRT) on patient-reported quality of life (QOL) for patients with intact pancreas cancer. Methods and Materials We reviewed a prospective QOL registry for patients with intact, clinically localized pancreatic ductal adenocarcinoma treated with CRT between June 2015 and November 2018. QOL was assessed pre-CRT (immediately before CRT, after neoadjuvant chemotherapy) and at the completion of CRT with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) and its component parts: FACT-General (FACT-G) and hepatobiliary cancer subscore (HCS). A minimally important difference from pre-CRT was defined as ≥ 6, 5, and 8 points for FACT-G, HCS, and FACT-Hep, respectively. Results Of 157 patients who underwent CRT, 100 completed both pre- and post-CRT surveys and were included in the primary analysis. Median age at diagnosis was 65 years (range, 23-90). National Comprehensive Cancer Network resectability status was resectable (3%), borderline resectable (40%), or locally advanced (57%). Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (75%) or gemcitabine and nab-paclitaxel (42%) were given for a median of 6 cycles (range, 0-42) before CRT. Radiation therapy techniques included 3-dimensional conformal (22%), intensity modulated photon (55%), and intensity modulated proton (23%) radiation therapy to a median dose of 50 Gy (range, 36-62.5). Concurrent chemotherapy was most commonly capecitabine (82%). Sixty-three patients (63%) had surgery after CRT. The mean decline in FACT-G, HCS subscale, and FACT-Hep from pre- to post-CRT was 3.5 (standard deviation [SD], 13.7), 1.7 (SD 7.8), and 5.2 (SD 19.4), respectively. Each of these changes were statistically significant, but did not meet the minimally important difference threshold. Pancreatic head tumor location was associated with decline in FACT-Hep. Nausea was the toxicity with the greatest increase from pre- to post-CRT by both physician-assessment and patient-reported QOL. Conclusions For patients with intact pancreatic adenocarcinoma, modern CRT is well tolerated with minimal decline in QOL during treatment.

Purpose To compare the dosimetric performances of intensity-modulated proton therapy (IMPT) plans generated with two different beam angle configurations (the Right-Left oblique posterior beams and the Superior-Inferior oblique posterior beams) for the treatment of distal esophageal carcinoma in the presence of uncertainties and interplay effect. Methods and materials Twenty patients' IMPT plans were retrospectively selected, with 10 patients treated with the R-L oblique posterior beams (Group R-L) and the other 10 patients treated with the S-I oblique posterior beams (Group S-I). Patients in both groups were matched by their clinical target volumes (CTVs-high and low dose levels) and respiratory motion amplitudes. Dose-volume-histogram (DVH) indices were used to assess plan quality. DVH bandwidth was calculated to evaluate plan robustness. Interplay effect was quantified using four-dimensional (4D) dynamic dose calculation with random respiratory starting phase of each fraction. Normal tissue complication probability (NTCP) for heart, liver, and lung was calculated, respectively, to estimate the clinical outcomes. Wilcoxon signed-rank test was used for statistical comparison between the two groups. Results Compared with plans in Group R-L, plans in Group S-I resulted in significantly lower liver Dmean and lung V30Gy[RBE] with slightly higher but clinically acceptable spinal cord Dmax . Similar plan robustness was observed between the two groups. When interplay effect was considered, plans in Group S-I performed statistically better for heart Dmean and V30Gy[RBE] , lung Dmean and V5Gy[RBE] , and liver Dmean , with slightly increased but clinically acceptable spinal cord Dmax . NTCP for liver was significantly better in Group S-I. Conclusions IMPT plans in Group S-I have better sparing of liver, heart, and lungs at the slight cost of spinal cord maximum dose protection, and are more interplay-effect resilient compared to IMPT plans in Group R-L. Our study supports the routine use of the S-I oblique posterior beams for the treatments of distal esophageal carcinoma.

Symptomatic vertebral hemangiomas (SVHs) are rare benign tumors that when symptomatic require procedural intervention or radiotherapy (RT). Although conventionally-fractionated RT has been an alternative to surgical resection, there is very little data on stereotactic body radiotherapy (SBRT) for SVHs. Six consecutively treated patients with SVHs underwent definitive single-fraction SBRT from 2010 to 2018 at our institution. The RT planning parameters, treatment, outcome, and toxicities are reported for 6 patients with 6 total SVHs treated with single-fraction SBRT. Each patient presented with back pain and received single-fraction SBRT to a thoracic vertebral body hemangioma. One patient had received radiofrequency ablation prior to SBRT. The median SBRT dose was 18 Gy (range, 13–20). Following SBRT, 4 (67%) patients reported improvement in presenting symptoms and 2 patients (33%) were refractory. There were no acute or chronic toxicities associated with SBRT including esophagitis, vertebral compression fractures, or myelopathy. To date, this is the largest series of single-fraction SBRT for SVHs. Single fraction SBRT appears to be a feasible option for SVHs. Further studies are needed to confirm our preliminary findings and optimize dose fractionation.

Purpose For treatment of rectal cancer, pencil beam scanning proton therapy (PBS-PT) may reduce radiation exposure to normal tissues compared with 3-dimensional conformal photon radiation therapy (3DCRT) or volumetric modulated arc photon radiation therapy (VMAT). The purpose of this study was to report the clinical implementation and dosimetric analysis of preoperative short-course PBS-PT for rectal cancer. Methods and Materials Eleven patients with stage IIA-IVB rectal cancer received preoperative short-course (25 Gy in 5 fx) PBS-PT between 2018 and 2019 preceding curative-intent total mesorectal excision. PBS-PT plans were generated using single-field optimization with 2 posterior-oblique fields. Verification computed tomography scans were performed on the first 3 days of treatment. Each patient had a backup 3DCRT and VMAT plan. Results Clinical target volume coverage was similar between PBS-PT, 3DCRT, and VMAT. PBS-PT had statistically significant reductions in dose to the small bowel, large bowel, bladder, and femoral heads across multiple dosimetric parameters. All patients completed PBS-PT as planned without need for replanning. All computed tomography verification scans demonstrated good target coverage with clinical target volume V100 > 95%. Conclusions Preoperative short-course PBS-PT has been successfully implemented and offers a significant reduction of dose to normal tissues. Prospective studies are warranted to evaluate if dosimetric advantages translate into clinical benefit.

Purpose Optimal clinical target volume (CTV) for inguinal lymph node irradiation in anal cancer remains uncertain. This study documents the location of radiographically involved inguinal lymph nodes and proposes guidelines for CTV delineation. Materials and Methods Patients with anal canal squamous cell carcinoma with inguinal lymph node metastases were identified. Criteria for lymph node involvement included: >15 mm short axis or suspicious morphology on CT or MRI, increased avidity on 18-FDG-PET, or positive biopsy. Distances from center of involved nodes to femoral vessels and inferior pubic symphysis were measured. Results Forty patients with 79 inguinal lymph nodes were included. Relative to right femoral vessels, nodes were located: 12:00 (n = 6); 1:00 (n = 28); 2:00 (n = 35), 3:00 (n = 5); 4:00 (n = 1); 10:00 (n = 1); 11:00 (n = 3). No nodes were identified lateral or posterior to vessels. Published AGITG guidelines covered 68% of nodes anteriorly and 85% medially. Margins from nearest femoral vessel to cover 95% of nodes were 30 mm anteriorly and 26 mm medially. Inferior margin to cover 95% of nodes was 14 mm below inferior pubic symphysis. Proposed borders include cranial, where external iliac vessels leave bony pelvis; caudal, 14 mm below inferior pubic symphysis; posterior, posterior border of femoral vessels; lateral, lateral border of femoral vessels; anterior, 30 mm margin on femoral vessels and medial, 26 mm margin on femoral vessels, including radiographically suspicious nodes. Conclusions Published guidelines for inguinal CTV in anal cancer may result in inadequate coverage of high risk areas. Updated guidelines based on this study ensure coverage of at-risk areas.

Purpose: There are very little data available comparing outcomes of intensity-modulated proton therapy (IMPT) to intensity-modulated radiation therapy (IMRT) in patients with locally advanced NSCLC (LA-NSCLC). Methods: Seventy-nine consecutively treated patients with LA-NSCLC underwent definitive IMPT (n = 33 [42%]) or IMRT (n = 46 [58%]) from 2016 to 2018 at our institution. Survival rates were calculated using the Kaplan-Meier method and compared with the log-rank test. Acute and subacute toxicities were graded based on Common Terminology Criteria for Adverse Events, version 4.03. Results: Median follow-up was 10.5 months (range, 1-27) for all surviving patients. Most were stage III (80%), received median radiation therapy (RT) dose of 60 Gy (range, 45-72), and had concurrent chemotherapy (65%). At baseline, the IMPT cohort was older (76 vs 69 years, P

ImportanceLong-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases.ObjectiveTo determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases.Design, Setting, and ParticipantsThis secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017.InterventionsStereotactic radiosurgery or WBRT.Main Outcomes and MeasuresIntracranial tumor control, toxic effects, cognitive deterioration, and QOL.ResultsFifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, −40.7; 95% CI, −68.1% to −13.4%), respectively. Data were first analyzed in February 2017.Conclusions and RelevanceThe use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group)

Purpose Proton beam therapy (PBT) may provide an advantage when planning well-selected patients with extremity soft tissue sarcoma (eSTS), specifically for large, anatomically challenging cases. We analyzed our early experience with PBT on toxicity and outcomes. Materials and Methods A retrospective study was performed for eSTS treated between June 2016 and October 2020 with pencil beam scanning PBT at 2 institutions. Diagnostic, treatment, and toxicity characteristics were gathered from baseline to last follow-up or death. Wound complications were defined as secondary operations for wound repair (debridement, drainage, skin graft, and muscle flap) or nonoperative management requiring hospitalization. Statistical analysis was performed with R software. Results Twenty consecutive patients with a median age 51.5 years (range, 19–78 years) were included. Median follow-up was 13.7 months (range, 1.7–48.1 months). Tumor presentation was primary (n = 17) or recurrent after prior combined modality therapy (n = 3). Tumor location was either lower extremity (n = 16) or upper extremity (n = 4). Radiation was delivered preoperatively in most patients (n = 18). Median pretreatment tumor size was 7.9 cm (range, 1.3 –30.0 cm). The 1-year locoregional control was 100%. Four patients (20%) had developed metastatic disease by end of follow-up. Maximum toxicity for acute dermatitis was grade 2 in 8 patients (40%) and grade 3 in 3 patients (15%). After preoperative radiation and surgical resection, acute wound complications occurred in 6 patients (35%). Tumor size was larger in patients with acute wound complications compared with those without (medians 16 cm, range [12–30.0 cm] vs 6.3 cm, [1.3–14.4 cm], P = .003). Conclusion PBT for well selected eSTS cases demonstrated excellent local control and similar acute wound complication rate comparable to historic controls. Long-term follow-up and further dosimetric analyses will provide further insight into potential advantages of PBT in this patient population.

Objective Radiation therapy (RT) is the primary treatment of intracranial metastasis (ICM) from lung cancer (LC). Radiation necrosis (RN) has been reported post-RT with an incidence of 5% to 24%. We reviewed the spectrum of imaging changes in patients treated with RT for ICM from LC in an effort to identify potential risk factors for RN. Methods We reviewed 63 patients with LC and ICM who received RT (radiosurgery [stereotactic radiosurgery] with/without whole brain radiation therapy) at our institution between 2013 and 2018. Data evaluated included demographics, tumor type, ICM burden and location, chemotherapy, surgery, and RT details as well as treatment choices and outcomes. Results Of the 63 patients, clinical and radiographic criteria for RN were noted in 24 (38%) as early as 2 months and as late as 5 years posttreatment. Six patients required surgical resection due to refractory symptoms revealing pathology-proven RN and occasionally tumor. Patients were significantly more likely to develop RN if they had surgical resection of an ICM (45.8% vs. 20.5%, P=0.05). No differences were found in location, size, or genetic profile of lesions. In total, 80% of patients received treatment for symptoms and/or radiographic change. This was generally a combination of steroids, bevacizumab, laser interstitial thermal treatment, or surgical resection. Most patients required >1 treatment modality. Conclusions This review of outcomes of RT for ICM in LC demonstrates a higher rate of RN than previously reported in the literature in those having had a surgical resection plus stereotactic radiosurgery. Our observation of RN as late as 5 years post-RT for ICM necessitates clinician awareness.

Background Guidelines to provide recommendations about driving restrictions for patients with brain metastases are lacking. We aim to determine whether clinical neurologic examination is sufficient to predict suitability to drive in these patients by comparison with an occupational therapy driving assessment (OTDA). Methods We prospectively evaluated the concordance between neurology assessment of suitability to drive (pass/fail) and OTDA in 41 individuals with brain metastases. Neuro-oncology evaluation included an interview and neurological examination. Participants subsequently underwent OTDA during which a battery of objective measures of visual, cognitive, and motor skills related to driving was administered. Results The mean age of patients who failed OTDA was age 68.9 years vs 59.3 years in the group members who passed (P = .0046). The sensitivity of the neurology assessment to predict driving fitness compared with OTDA was 16.1% and the specificity 90%. The 31 patients who failed OTDA were more likely to fail Vision Coach, Montreal Cognitive Assessment, and Trail Making B tests. Conclusions There was poor association between the assessment of suitability to drive by neurologists and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The positive predictive value was high to predict OTDA failure. Age could be a factor affecting OTDA performance. The results raise questions about the choice of assessments in making recommendations about driving fitness in people with brain metastases. OTDA should be strongly considered in patients with brain metastases who wish to continue driving.

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric-modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small-spot intensity-modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small-spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small-spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase-averaged 4D-CT's. The dose-volume-histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank-sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small-spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE] , lung Dmean , heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE] , liver V30Gy[RBE] , stomach V45Gy[RBE] , lung Dmean , V5Gy[RBE] , and V20Gy[RBE] , cord Dmax and D 0.03 c m 3 , liver Dmean , heart V20Gy[RBE] , and V30Gy[RBE] , but IMPT was significantly worse for CTVhigh D95% , D 2 c m 3 , and D5% -D95% , CTVlow D95% , heart Dmean , and V40Gy[RBE] , requiring careful and experienced adjustments during the planning process and robustness considerations. The small-spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small-spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small-spot IMPT for the treatment of distal esophageal carcinoma.

Purpose To quantitatively assess volumetric changes after hypofractionated stereotactic radiation therapy (HFSRT) in patients treated for vestibular schwannomas and meningiomas. Methods and materials We retrospectively reviewed records of patients treated with HFSRT at our institution from 2002 to 2014. Patients received a median dose of 25 Gy in 5 fractions. After treatment, they underwent clinical and radiologic follow-up with magnetic resonance imaging (MRI) at 3- to 12-month intervals. Gross tumor volume was outlined on each thin slice of contrast-enhanced T1 series before and on each scan after HFSRT. Volumetric changes were calculated and compared with neuroradiologist interpretations. Results Forty-three patients underwent 182 MRI scans. Tumor types included vestibular schwannoma (n = 34) and meningioma (n = 9). Median follow-up time was 29 months. Median gross tumor volume was 3.1 cm3. Local control was 81.4% for the entire cohort at the time of last follow-up. Transient volume expansion was noted in 17 patients (50%) with vestibular schwannoma and 2 (22%) with meningioma. For all patients, transient volume expansion and subsequent regression occurred at a median time of 5.5 and 12 months, respectively. Neuroradiologist agreement with regard to tumor regression, progression, or stability occurred in 155 of 182 total reports (85%). The largest discordance identified was a stable finding on the MRI interpretation when the measured volumetric change exceeded 20% (n = 24 [13%]). Conclusions HFSRT is associated with excellent local control and a low incidence of toxicity. With volumetric MRI measurement, transient volume expansion was a common finding and was associated with temporary adverse effects. Although the neuroradiologist’s interpretation generally agreed with the volumetric MRI measurement, the overall 15% discordance rate emphasizes the potential benefit of considering volumetric measurements, which may help clinicians correlate posttreatment symptoms with MRI findings.

BACKGROUND: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. METHODS: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. RESULTS: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P

The majority of esophageal cancer patients are diagnosed with locoregionally confined disease, which is often amenable to curative intent therapy. Chemoradiotherapy (CRT) improves overall survival (OS) in stage II and III esophagus cancer in the neoadjuvant and definitive settings. Due to the close proximity of organs at risk (OARs), including lungs, heart, stomach, bowel, kidneys, and spinal cord, esophageal CRT can result in profound acute and late toxicities. Acute toxicities can include esophagitis, nausea, vomiting, fatigue, and cytopenias. Late complications may also occur months or years after completion of thoracic radiotherapy, including significant cardiac, pulmonary, liver, kidney, or bowel toxicities, which can be life-threatening or fatal. Photon-based radiotherapy exposes OARs to significant doses of radiation, whereas proton beam therapy (PBT) has unique physical properties, as it lacks an exit dose. This allows PBT to deliver, a more conformal dose to the target and minimize the volume of OARs exposed to radiation. This dosimetric advantage may portend an increased therapeutic ratio of CRT for esophagus cancer. The objective of this review is to discuss the evolution of photon and proton-based radiotherapy techniques, rationale, dosimetric and clinical studies comparing outcomes of photon- and proton-based techniques, ongoing prospective trials, and future directions of PBT as a means of reducing toxicity and improving oncologic outcomes for patients with esophagus cancer.

Background Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton beam radiotherapy (PBT) provides the means to escalate radiation dose to the target volume while sparing the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated PBT for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods We evaluated the prospective registry of the Proton Collaborative Group for patients undergoing definitive PBT for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. Results To date, 63 patients have been treated at 9 institutions between 2013 and 2019. Thirty (48%) had HCC and 25 (40%) had ICC. The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range 32.5–75) and 80.5 GyE (range 53.6–100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ≥ 3 toxicity. With median follow-up of 5.1 months (range 0.1–40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. Conclusions Hypofractionated PBT results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlates with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease.

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Candida species are ubiquitous opportunistic pathogens, causing significant morbidity and mortality in humans. C. albicans can asymptomatically colonise the skin and mucosal surfaces in healthy and immunologically competent individuals without causing disease. Impairment of normal host defence mechanisms can result in the conversion of C. albicans from a harmless commensal to an opportunistic pathogen that can initiate mucocutaneous forms of infections, such as oral candidiasis, vulvovaginal candidiasis (VVC), and even invasive systemic infections of the bloodstream and deep organs.In vitro and in vivo studies have revealed distinct patterns of strain-dependent tissue invasion and surface colonisation. Yeast strain differences markedly influence the nature and magnitude of both innate and adaptive immune responses against C. albicans infection. The following studies set out to delineate adherence properties and functional differences between two clinical isolates of C. albicans (one, 3630, cutaneous and one, 3683 oral). It was anticipated that the differences observed in mouse studies in vivo would be reflected in their interactions with human phagocytic cells in vitro.The oral isolate, 3683, was significantly more adherent than 3630 to human monocyte-derived macrophages (MDM), and epithelial cells, but not to mouse cells. A survey of six other oral isolates identified one that was like 3683 in its ability to adhere to both phagocytic and non-phagocytic human cells. The addition of homologous cell-free culture supernatant (SN) (termed the secretome) to yeast cells from the same isolate significantly increased adherence of 3630 compared to 3683. In contrast, the addition of secretome to yeast cells of 3683 did not affect adherence to epithelial cells.The secretome of C. albicans consists of glycoproteins that respond to the availability of nutrients and mediate evasion of host immune responses. Mass spectroscopy was performed on lyophilised secretome from both clinical isolates and identified several potential candidates that could be involved in inducing or modulating the host responses to these distinct clinical isolates.Isolate 3683 consistently induced significantly higher IL-1β production from THP-1 derived MDM and peripheral blood mononuclear cells (PBMC), compared to 3630. When the secretome of 3630 and 3683 was added to MDM, IL-1β production was greater from the MDM activated with 3630 SN than from 3683, demonstrating that the secretome from the two strains induced different patterns of responsiveness. The interactions between homologous and heterologous SN co-cultured with yeast cells showed that 3630 induced significantly more IL-1β in the presence of both SNs, whereas the converse was true for 3683. Heat treatment of the yeast cells and SN abrogated the release of IL-1β for both isolates. This pattern of secretion was also seen in the production of IL-18. The secretion of mature IL-1β and IL-18 resulting from caspase-1 cleavage of the two precursor molecules, confirmed assembly of the nucleotide-binding oligomerisation domain (NOD)-like receptor (NLR) pyrin-domain containing protein 3 (NLRP3) inflammasome. Other pro-inflammatory cytokines were also considered. TNF-α production by MDM showed a similar pattern of cytokine expression to IL-1β. However, the isolate 3630 expressed significantly more IL-6 production than 3683, while the anti-inflammatory cytokine IL-10 was not detected. Similar patterns of pro-inflammatory cytokine production to MDM were confirmed using human-derived PBMC.Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to determine gene expression kinetics for IL-1β, IL-6 and TNF-α. mRNA expression relative to 18s (housekeeping gene) of IL-1β showed 3630 was significantly greater than 3683. Although IL-6 and TNF-α proteins were identified upon stimulation with the two isolates, there was no upregulation of mRNA expression.Filamentation is often considered as an initiator of pro-inflammatory cytokine responses. Diclofenac sodium, a nonsteroidal anti-inflammatory drug (NSAID), has been shown to inhibit hyphal formation and co-culture of isolates grown in diclofenac sodium showed no significant change in IL-1β production.The most widely studied mechanism of programmed cell death, apoptosis, involves activation of the initiator caspase, caspase-8, followed by the effector caspase, caspase-3 which cleaves cellular substrates and leads to non-lytic cell death. The formation of the NLRP3 inflammasome and activation of caspase-1 in response to extracellular or intracellular stimuli results in the secretion of mature IL-1β. It condemns the host cell to death via an inflammatory, lytic pathway (pyroptosis). Small molecule inhibitors for NLRP3 (MCC950) and caspase-8 (z-IETD-FMK) were used to investigate differential death mechanisms of MDM and PBMC in the presence of 3630 and 3683. The presence of inhibitors significantly reduced or abrogated the release of IL-1β in both MDM and PBMC.The studies presented here are the first to demonstrate that Candida yeasts and their secretomes from similar oral infections can be highly individual. This does not necessarily imply that there are no commonalities between them, but that a broader range of isolates would need to be evaluated before such relationships could be accurately evaluated. Furthermore, interactions with host phagocytic and non-phagocytic cells may induce cytokine responses that could actively modulate human immune responses.

Purpose Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. Methods and Materials NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher’s exact tests. Results Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). Conclusions This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.