An optimized method for the isolation of urinary extracellular vesicles for molecular phenotyping: detection of biomarkers for radiation exposure.

BACKGROUND: Urinary extracellular vesicles (EVs) are a source of biomarkers with broad potential applications across clinical research, including monitoring radiation exposure. A key limitation to their implementation is minimal standardization in EV isolation and analytical methods. Further, most urinary EV isolation protocols necessitate large volumes of sample. This study aimed to compare and optimize isolation and analytical methods for EVs from small volumes of urine. METHODS: 3 EV isolation methods were compared: ultracentrifugation, magnetic bead-based, and size-exclusion chromatography from 0.5 mL or 1 mL of rat and human urine. EV yield and mass spectrometry signals (Q-ToF and Triple Quad) were evaluated from each method. Metabolomic profiling was performed on EVs isolated from the urine of rats exposed to ionizing radiation 1-, 14-, 30- or 90-days post-exposure, and human urine from patients receiving thoracic radiotherapy for the treatment of lung cancer pre- and post-treatment. RESULTS: Size-exclusion chromatography is the preferred method for EV isolation from 0.5 mL of urine. Mass spectrometry-based metabolomic analyses of EV cargo identified biochemical changes induced by radiation, including altered nucleotide, folate, and lipid metabolism. We have provided standard operating procedures for implementation of these methods in other laboratories. CONCLUSIONS: We demonstrate that EVs can be isolated from small volumes of urine and analytically investigated for their biochemical contents to detect radiation induced metabolomic changes. These findings lay a groundwork for future development of methods to monitor response to radiotherapy and can be extended to an array of molecular phenotyping studies aimed at characterizing EV cargo.

Management of Cardiovascular Disease in Women With Breast Cancer.

Cardio-oncology is a rapidly developing field which seeks to improve patient outcomes through enhanced clinical and research collaboration across the disciplines of oncology and cardiology. Breast cancer (BC) is the most common cancer diagnosis among women in the United States and, as decades of research have resulted in decreased mortality rates, there has been an increasing focus on reducing short- and long-term treatment toxicity and improving morbidity among survivors. Preexisting or emergent cardiovascular disease in a patient with BC requires a multidisciplinary, team-based approach to balance the need for curative cancer treatment while preventing increased cardiovascular disease morbidity and mortality. Given the overlap in risk factors for BC and cardiovascular disease, such as smoking, sedentary lifestyle, and obesity, there are opportunities for cardiovascular disease prevention and detection before, during, and after BC treatment. Cardiology providers also play an important role in preventing, diagnosing, and treating cardiac dysfunction and other cardiovascular complications that may develop as a result of BC treatment. A number of recent clinical practice guidelines address approaches to cardiotoxicity, however, they focus on specific agents or treatment modality, rather than on collaborative disease management. In this review we present cardiovascular concerns associated with contemporary, multimodality BC treatment and illustrate how current guideline recommendations apply to clinical cardiology and oncology questions. We provide a cardio-oncology team-based approach to cardiovascular assessment and management of patients with BC from diagnosis through treatment and in survivorship.

Incorporating Yttrium-90 trans-arterial radioembolization (TARE) in the treatment of metastatic pancreatic adenocarcioma: a single center experience.

BACKGROUND: The purpose of this retrospective study was to evaluate the efficacy of incorporating trans-arterial radioembolization (TARE) with systemic chemotherapy in the treatment of liver-dominant metastatic pancreatic ductal adenocarcinoma, with the aim of destroying liver metastases and improving patient outcomes. METHODS: We retrospectively evaluated 16 patients with liver-dominant metastatic pancreatic ductal adenocarcinoma who underwent TARE between February 2012 and August 2015; 15 of these patients also underwent concurrent systemic chemotherapy. Patient outcomes were assessed using Response Evaluation Criteria In Solid Tumors (RECIST), Version 1.1 and included disease response, median overall survival from the time of diagnosis of metastatic disease, and median overall survival following receipt of TARE. Treatment-related adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. RESULTS: The median overall survival from the time of diagnosis of metastatic disease and following receipt of TARE was 22.0 and 12.5 months, respectively. Overall and liver specific disease response were assessed for 13 patients with follow-up imaging available at the time of study (range 2-13 weeks post TARE). Four patients (31 %) demonstrated partial response and five patients (38 %) had stable disease in the liver at follow-up. One patient developed grade 3 elevation of total bilirubin three months post-treatment and another patient developed radiation cholecystitis directly following TARE. No treatment-related grade 4 or 5 toxicities were seen. CONCLUSION: TARE can be safely combined with systemic chemotherapy for the treatment of liver-dominant metastatic pancreatic cancer. Patient outcomes following this treatment strategy are promising but prospective evaluations are needed to validate these preliminary findings.

Neoadjuvant Combined-Modality Therapy for Locally Advanced Rectal Cancer and Its Future Direction.

Rectal cancer treatment presents a challenge, and its optimal management requires a multidisciplinary approach involving surgical, medical, and radiation oncologists. Advances in surgical techniques, radiotherapy, and medical imaging technology have transformed the therapeutic landscape and have led to substantial improvements in both local disease control and patient survival. The currently established standard of care for patients with locally advanced rectal cancer involves preoperative (neoadjuvant) concurrent radiotherapy and infusional fluorouracil-based or oral capecitabine-based chemotherapy, also known as chemoradiotherapy (CRT), followed by surgery. Surgery is often followed by adjuvant chemotherapy. Here we discuss the evolution of standard therapy for rectal cancer patients and the use of preoperative CRT for the treatment of locally advanced disease. Treatment schemes that have attempted to broaden the horizons of standard therapy include the use of induction chemotherapy and "watch-and-wait" approaches. We examine several novel trials using these and other treatment approaches, which may eventually lead to better patient selection and the avoidance of overtreatment and unnecessary adverse effects.

Comparative analysis of plan quality and delivery efficiency: ZAP-X vs. CyberKnife for brain metastases treatment.

Purpose/Objectives: ZAP-X, a novel and dedicated radiosurgery (SRS) system, has recently emerged, while CyberKnife has solidified its position as a versatile solution for SRS and stereotactic body radiation therapy over the past two decades. This study aims to compare the dosimetric performance and delivery efficiency of ZAP-X and CyberKnife in treating brain metastases of varying target sizes, employing circular collimation. Methods and materials: Twenty-three patients, encompassing a total of 47 brain metastases, were included in the creation of comparative plans of ZAP-X and CyberKnife for analysis. The comparative plans were generated to achieve identical prescription doses for the targets, while adhering to the same dose constraints for organs at risk (OAR). The prescription isodose percentage was optimized within the range of 97-100% for each plan to ensure effective target-volume coverage. To assess plan quality, indices such as conformity, homogeneity, and gradient (CI, HI, and GI) were computed, along with the reporting of total brain volumes receiving 12Gy and 10Gy. Estimated treatment time and monitor units (MUs) were compared between the two modalities in evaluating delivery efficiency. Results: Overall, CyberKnife achieved better CI and HI, while ZAP-X exhibited better GI and a smaller irradiated volume for the normal brain. The superiority of CyberKnife's plan conformity was more pronounced for target size less than 1 cc and greater than 10 cc. Conversely, the advantage of ZAP-X's plan dose gradient was more notable for target sizes under 10 cc. The homogeneity of ZAP-X plans, employing multiple isocenters, displayed a strong correlation with the target's shape and the planner's experience in placing isocenters. Generally, the estimated treatment time was similar between the two modalities, and the delivery efficiency was significantly impacted by the chosen collimation sizes for both modalities. Conclusion: This study demonstrates that, within the range of target sizes within the patient cohort, plans generated by ZAP-X and CyberKnife exhibit comparable plan quality and delivery efficiency. At present, with the current platform of the two modalities, CyberKnife outperforms ZAP-X in terms of conformity and homogeneity, while ZAP-X tends to produce plans with a more rapid dose falloff.

Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC).

PURPOSE: Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy. METHODS AND MATERIALS: Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy × 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2). RESULTS: The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%). CONCLUSIONS: PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial.

Patterns of Failure Following Preoperative Chemotherapy and Stereotactic Body Radiation Therapy and Resection for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer.

BACKGROUND: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in the treatment of pancreatic adenocarcinoma (PDAC) is controversial and the optimal target volumes and dose-fractionation are unclear. The aim of this study is to report on treatment outcomes and patterns of failure of patients with borderline resectable (BL) or locally advanced (LA) pancreatic cancer following preoperative chemotherapy and SBRT. METHODS: We conducted a single-institution, retrospective study of patients with BL or LA PDAC. Patients received neoadjuvant chemotherapy and SBRT was prescribed to 30 Gy over 5 fractions to the pancreas planning tumor volume (PTV). A subset of patients received a simultaneous integrated boost to the high risk vascular PTV and/or elective nodal irradiation (ENI). Following neoadjuvant chemoradiation, all patients underwent subsequent resection. Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMPFS), and locoregional control (LRC) estimates were obtained using Kaplan-Meier analysis. RESULTS: Twenty-two patients with BL (18) or LA (4) PDAC were treated with neoadjuvant chemotherapy and SBRT followed by resection from 2011-2022. Following neoadjuvant treatment, 5 patients (23%) achieved a pathologic complete response (pCR) and 16 patients (73%) had R0 resection. At 24 months, there were no isolated locoregional recurrences (LRRs), 9 isolated distant recurrences (DRs), and 5 combined LRRs and DRs. Two LRRs were in-field, 2 LRRs were marginal, and 1 LRR was both in-field and marginal. 2-year median LRC, LRRFS, DMPFS, PFS, and OS were 77.3%, 45.5%, 31.8%, 31.8%, and 59.1%, respectively. For BL and LA cancers, 2-year LRC, DMPFS, and OS were 83% vs. 75%, (p = 0.423), 39% vs. 0% (p = 0.006), and 61% vs. 50% (p = 0.202), respectively. ENI was associated with improved LRC (p = 0.032) and LRRFS (p = 0.033). Borderline resectability (p = 0.018) and lower tumor grade (p = 0.027) were associated with improved DMPFS. CONCLUSIONS: Following preoperative chemotherapy and SBRT, locoregional failure outside of the target volume occurred in 3 of 5 recurrences; ENI was associated with improved LRC and LRRFS. Further studies are necessary to define the optimal techniques for preoperative radiation therapy.

Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment.

Radiation therapy is an effective cancer treatment, although damage to healthy tissues is common. Here we analyzed cell-free, methylated DNA released from dying cells into the circulation to evaluate radiation-induced cellular damage in different tissues. To map the circulating DNA fragments to human and mouse tissues, we established sequencing-based, cell-type-specific reference DNA methylation atlases. We found that cell-type-specific DNA blocks were mostly hypomethylated and located within signature genes of cellular identity. Cell-free DNA fragments were captured from serum samples by hybridization to CpG-rich DNA panels and mapped to the DNA methylation atlases. In a mouse model, thoracic radiation-induced tissue damage was reflected by dose-dependent increases in lung endothelial and cardiomyocyte methylated DNA in serum. The analysis of serum samples from patients with breast cancer undergoing radiation treatment revealed distinct dose-dependent and tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation, indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type-specific effects of radiation and provide a readout of the biologically effective radiation dose received by healthy tissues.

National evaluation of patterns and predictors of underuse of multimodal therapy for high-risk extremity soft tissue sarcoma.

BACKGROUND: Treatment of high-risk extremity soft tissue sarcomas remains widely varied. Despite growing support for a multimodal approach for treatment of these rare and aggressive neoplasms, its dissemination remains underused. This national study aimed to evaluate variations in treatment patterns and uncover factors predictive of underuse of multimodal therapy in high-risk extremity soft tissue sarcomas. METHODS: The 2010 to 2015 National Cancer Database was used to evaluate trends in 3 common treatment patterns: surgery alone, surgery + adjuvant therapy, and neoadjuvant therapy + surgery. Demographic-, sarcoma-, hospital-, and treatment-level factors of 6,725 surgically treated patients with stage II or III intermediate- to high-grade extremity soft tissue sarcomas were evaluated by types of treatment modality. Stepwise multivariable logistic regression was performed to identify factors predictive of each treatment modality. RESULTS: When compared to surgery alone (34.6%) and adjuvant therapy (41.2%), use of neoadjuvant therapy + surgery for high-risk extremity soft tissue sarcomas remained low (25.3%). However, time trend analysis demonstrated that neoadjuvant therapy + surgery has significantly increased by 7% per year, whereas surgery alone decreased by 4% every year (P < .05 for both). Factors predictive of surgery alone were older age, nonprivate insurance, increasing travel distance, and multimorbidity (P < .05). Conversely, factors associated with neoadjuvant therapy + surgery were private insurance, higher education, and care at academic or high-volume institutions (for all, P < .05). Tumor-related factors predictive for neoadjuvant therapy + surgery included size <5 cm and higher-grade tumors (P < .05). CONCLUSION: Adoption of multimodality therapy for high-risk extremity soft tissue sarcomas remains low and gradual in the United States. Dissemination of multimodality therapy will require attention to access and hospital factors to maximize these therapies for high-risk extremity soft tissue sarcomas.

Impact of Clinician Linkage on Unequal Access to High-Volume Hospitals for Colorectal Cancer Surgery.

BACKGROUND: Understanding drivers of persistent surgical disparities remains an important area of cancer care delivery and policy. The degree to which clinician linkages contribute to disparities in access to quality colorectal cancer surgery is unknown. Using hospital surgical volume as a proxy for quality, the study team evaluated how clinician linkages impact access to colorectal cancer surgery at high-volume hospitals (HVHs). STUDY DESIGN: Maryland's Health Services Cost Review Commission was used to evaluate 6,909 patients who underwent colon or rectal cancer operations from 2013 to 2018. Two linkages based on patient sharing were examined separately for colon and rectal cancer surgery: (1) from primary care clinicians to specialists (gastroenterologist or medical oncologist) and (2) from specialists to surgeons (general or colorectal). A referral link was defined as 9 or more shared patients between 2 clinicians. Adjusted regression models examined associations between referral links and odds of receiving colon or rectal cancer operations at HVHs. RESULTS: The cohort included 5,645 colon and 1,264 rectal cancer patients across 52 hospitals. Every additional referral link between a primary care clinician and a specialist connected to a HVH was associated with a 12% and 14% increased likelihood of receiving colon (odds ratio [OR] 1.12, CI 1.07 to 1.17) and rectal (OR 1.14, CI 1.08 to 1.20]) cancer operations at a HVH, respectively. Every additional referral link between a specialist and a surgeon at a HVH was associated with at least a 25% increased likelihood of receiving colon (OR 1.28, CI 1.20 to 1.36) and rectal (OR 1.25, CI 1.15 to 1.36) cancer operation at a HVH. CONCLUSIONS: Patients of clinicians with linkages to HVHs are more likely to have their colorectal cancer operations at these hospitals. These findings suggest that policy interventions targeting clinician relationships are an important step in providing equitable surgical care.

Prostate Cancer Treatment with Pencil Beam Proton Therapy Using Rectal Spacers sans Endorectal Balloons.

Purpose: Proton beam radiotherapy (PBT) has been used for the definitive treatment of localized prostate cancer with low rates of high-grade toxicity and excellent patient-reported quality-of-life metrics. Technological advances such as pencil beam scanning (PBS), Monte Carlo dose calculations, and polyethylene glycol gel rectal spacers have optimized prostate proton therapy. Here, we report the early clinical outcomes of patients treated for localized prostate cancer using modern PBS-PBT with hydrogel rectal spacing and fiducial tracking without the use of endorectal balloons. Materials and Methods: This is a single institutional review of consecutive patients treated with histologically confirmed localized prostate cancer. Prior to treatment, all patients underwent placement of fiducials into the prostate and insertion of a hydrogel rectal spacer. Patients were typically given a prescription dose of 7920 cGy at 180 cGy per fraction using a Monte Carlo dose calculation algorithm. Acute and late toxicity were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Biochemical failure was defined using the Phoenix definition. Results: From July 2018 to April 2020, 33 patients were treated (median age, 75 years). No severe acute toxicities were observed. The most common acute toxicity was urinary frequency. With a median follow-up of 18 months, there were no high-grade genitourinary late toxicities; however, one grade 3 gastrointestinal toxicity was observed. Late erectile dysfunction was common. One treatment failure was observed at 21 months in a patient treated for high-risk prostate cancer. Conclusion: Early clinical outcomes of patients treated with PBS-PBT using Monte Carlo-based planning, fiducial placement, and rectal spacers sans endorectal balloons demonstrate minimal treatment-related toxicity with good oncologic outcomes. Rectal spacer stabilization without the use of endorectal balloons is feasible for the use of PBS-PBT.

Functional Imaging of Liver Cancer (FLIC): Study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma.

BACKGROUND: While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC. METHODS: This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy. DISCUSSION: This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC. CLINICAL TRIAL REGISTRATION: NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

Cardiomyocyte-specific circulating cell-free methylated DNA in esophageal cancer patients treated with chemoradiation.

Thoracic high dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4-6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of >35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.

TGFß Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFß Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFß), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFß-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFß treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype?

Immunotherapy represents the newest pillar in cancer care. Although there are increasing data showing the efficacy of immunotherapy there is a spectrum of response across unselected populations of cancer patients. In fact, response rates can be poor even among patients with immunogenic tumors for reasons that remain poorly understood. A promising clinical strategy to improve outcomes, which is supported by an abundance of preclinical data, is combining immunotherapy with radiation therapy. Here we review the existing evidence and future directions for combining immunotherapy and radiation therapy for patients with gastrointestinal cancers.

Radical excision for retroperitoneal soft tissue sarcoma: A national propensity-matched outcomes analysis.

BACKGROUND: Given the rarity of retroperitoneal soft tissue sarcoma, few studies have assessed if radical excision of retroperitoneal soft tissue sarcoma with adjacent organs improves survival outcomes. This propensity score-matched study aimed to evaluate the impact of radical excision versus resection of tumor alone. METHODS: The National Cancer Database 2004 to 2015 was used to assess short- and long-term outcomes of resection of tumor alone versus radical excision (tumor plus ≥1 adjacent organs) via 1:1 propensity-matched analyses. Subgroup analyses included low-grade, high-grade, liposarcoma, leiomyosarcoma, adjacent organ involvement alone, localized tumors alone, and high-volume hospitals (≥10 resections/y). Multivariable logistic regression models identified factors associated with radical excision. RESULTS: Comparison of propensity-matched groups (N = 1,139/group) revealed no significant differences in 30-day mortality, 90-day mortality, or overall survival (for all, P > .580). For all subgroup analyses comparing resection of tumor alone with radical excision, including localized tumors without organ invasion (N = 208/group), there were no identified differences in short- or long-term survival. Although it yielded lower R2 resection rates (P = .007), radical excision was associated with greater mean length of stay (P < .001). CONCLUSION: Radical excision was not associated with improved retroperitoneal soft tissue sarcoma survival irrespective of grade, histology, hospital volume, or adjacent organ involvement. Resection of ostensibly involved adjacent viscera may increase morbidity without survival benefit. These results inform ongoing discussion regarding histology-tailored, situation-specific extent of retroperitoneal soft tissue sarcoma resections.

A Prospective Study of Early Radiation Associated Cardiac Toxicity Following Neoadjuvant Chemoradiation for Distal Esophageal Cancer.

Purpose: This study aimed to prospectively evaluate the early effects of radiation on cardiac structure and function following neoadjuvant chemoradiation for distal esophageal cancer. Methods and Materials: Patients with non-metastatic esophageal cancer who were suitable for tri-modality therapy with concurrent chemoradiotherapy followed by esophagectomy were enrolled. Cardiac magnetic resonance imaging (CMR) was obtained at baseline and 3-5 months following completion of chemoradiation. Standardized myocardial segmentation was used to identify regions on post-treatment CMR with new T2 signal or late gadolinium enhancement (LGE). Pre and post-treatment cardiac function was assessed with quantitative end points including left ventricle end-systolic volume (LSESV). Serum biomarkers of cardiac damage including troponin I, CRP, and BNP were collected at baseline and time of follow-up CMR. Results: A total of 11 patients were enrolled from 2016 to 2018. Patients had clinical stage T2 (18%) and T3 (82%) disease with clinical N0 (27%) and N1 (73%) nodal stage. All patients completed baseline CMR and completed chemoradiotherapy. One patient did not complete follow-up CMR or serum biomarkers and was excluded from the analysis. The median time from completion of chemoradiation to follow-up CMR was 3.9 months. Three out of 10 patients (30%) developed new structural findings of myocardial fibrosis and/or reversible ischemia involving the basal and mid-inferior and inferoseptal walls. In these three patients, the LVESV was significantly increased from baseline following radiation. There were no differences in other quantitative end points or serum biomarkers between the patients with myocardial damage and those without. Conclusions: Our study is the first to our knowledge to prospectively demonstrate radiation associated structural and functional heart damage as early as 3 months following neoadjuvant chemoradiation for distal esophageal cancer. Given the early onset of this subclinical heart damage, strategies should be developed to identify patients at risk for future clinically significant heart toxicity.

Variations in Retroperitoneal Soft Tissue Sarcoma Outcomes by Hospital Type: A National Cancer Database Analysis.

PURPOSE: Surgical resection remains the cornerstone of retroperitoneal soft tissue sarcoma (RPS) treatment. Patient- and sarcoma-related factors are well known to influence survival outcomes. The effect of hospital-related factors on long-term survival, however, are not well understood. We sought to assess the relative contribution of hospital-level factors to mortality after surgical treatment of RPS. METHODS AND MATERIALS: The 2004-2015 National Cancer Database was used to identify 10,113 patients who underwent surgical treatment of RPS. Patient-, sarcoma-, hospital-, and treatment-level factors were compared by increasing survival times. Stepwise multivariable Cox regression was performed that controlled for covariates to measure the relative contributions of these factors on overall survival (OS). Effect modification analyses ascertained how hospital type modulates the volume relationship with respect to RPS mortality. RESULTS: Factors predictive of worsening OS were older age, nonprivate insurance, low income, presence of comorbidities, tumor histology, high grade or stage, and R2 resection (for all, P < .05). Increasing hospital surgical volume predicted decreasing risk of death across all survival times. However, analysis by hospital type demonstrated that compared with academic centers, the risk of death at community centers increased significantly as surgical volume increased (hazard ratio, 1.26; 95% CI, 1.03 to 1.53). CONCLUSION: Hospital factors affect mortality after surgical treatment of RPS. Specifically, hospital type alters the surgical volume-outcome relationship for RPS mortality such that community centers perform worse with increasing volumes. Recommendations that higher surgical volume improves outcomes cannot be applied universally and must be re-examined in other complex surgical cancers.

Plasma metabolite biomarkers predictive of radiation induced cardiotoxicity.

PURPOSE: Although advancements in cancer treatments using radiation therapy (RT) have led to improved outcomes, radiation-induced heart disease (RIHD) remains a significant source of morbidity and mortality in survivors of cancers in the chest. Currently, there are no diagnostic tests in clinical use due to a lack of understanding of the natural history and mechanisms of RIHD development. Few studies have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of developing cardiotoxicity. METHODS: We analyzed plasma and left ventricle heart tissue samples collected from a cohort of male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day × 5 days) of targeted X-ray radiation to the heart. Metabolomic and lipidomic analyses were utilized as a correlative approach for delineation of novel biomarkers associated with radiation-induced cardiac toxicity. Additionally, we used high-resolution mass spectrometry to examine the metabolomic profiles of plasma samples obtained from patients receiving high dose thoracic RT for esophageal cancer. RESULTS: Metabolic alterations in the rat model and patient plasma profiles, showed commonalities of radiation response that included steroid hormone biosynthesis and vitamin E metabolism. Alterations in patient plasma profiles were used to develop classification algorithms predictive of patients at risk of developing RIHD. CONCLUSION: Herein, we report the feasibility of developing a metabolomics-based biomarker panel that is associated with adverse outcomes of cardiac function in patients who received RT for the treatment of esophageal cancer.

Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.