Proteomics in orthopedic research: Recent studies and their translational implications.

Proteomics is a growing field that offers insights into various aspects of disease processes and therapy responses. Within the field of orthopedics, there are a variety of diseases that have a poor prognosis due to a lack of targeted curative therapy or disease modifying therapy. Other diseases have been difficult to manage in part due to lack of clinical biomarkers that offer meaningful insight into disease progression or severity. As an emerging technology, proteomics has been increasingly applied in studying bone biology and an assortment of orthopedics related diseases, such as osteoarthritis, osteosarcoma and bone tumors, osteoporosis, traumatic bone injury, spinal cord injury, hip and knee arthroplasty, and fragile healing. These efforts range from mechanistic studies for elucidating novel insights in tissue activity and metabolism to identification of candidate biomarkers for diagnosis, prognosis, and targeted treatment. The knowledge gained from these proteomic and functional studies has provided unique perspectives in studying orthopedic diseases. In this review, we seek to report on the current state of the proteomic study in the field of orthopedics, overview the advances in clinically applicable discoveries, and discuss the opportunities that may guide us for future research.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in the paraventricular nucleus of the thalamus: Influence on binge-type eating in male and female mice.

Binge eating disorder, characterized by the overconsumption of food in a discrete time period, is the most common eating disorder in the United States, but its neurological basis is not fully understood. The paraventricular nucleus of the thalamus (PVT) is a limbic brain region implicated in eating, and the anorexigenic neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is densely expressed in the PVT. This study sought to examine the possible involvement of PACAP in the PVT in binge-type eating. First, a model of binge-type eating was established in mice. Male and female C57BL/6J mice were given limited access to Milk Chocolate Ensure Plus® or had access only to chow and water. Under this model, while males and females both engaged in binge-type eating with Ensure, females engaged in this behavior to a greater degree than males. Next, the role of PACAP in the PVT was defined in relation to binge-type eating. Using quantitative real-time PCR, females were found to have higher baseline levels of PVT PACAP mRNA than males, but only males showed an increase in levels of PACAP after a history of binge-type eating, and only males showed a reduction in levels of PACAP immediately prior to a binge session. Using chemogenetics in PACAP-Cre transgenic mice on a C57BL/6J background, activation of PVT PACAP+ cells with a Cre-dependent Gq-DREADD was found to reduce binge-type eating, significantly in male but not female mice. These results indicate that PVT PACAP is involved in binge-type eating in a sex-dependent manner, with a decrease in PVT PACAP levels preceding binge-type eating in male mice, and enhanced PVT PACAP+ cell activity suppressing binge-type eating in male mice. Together, these results suggest that the PACAP system could be targeted in specific patient populations to help treat binge eating disorder.

Safety and Efficacy of Stereotactic Body Radiation Therapy for Ultra-central Thoracic Tumors: A Single Center Retrospective Review.

PURPOSE: We sought to evaluate the toxicity and efficacy of stereotactic body radiation therapy (SBRT) for ultracentral thoracic tumors at our institution. METHODS AND MATERIALS: Patients with ultracentral lung tumors or nodes, defined as having the planning target volume (PTV) overlapping or abutting the central bronchial tree and/or esophagus, treated at our institution with SBRT between 2009 and 2019 were retrospectively reviewed. All SBRT plans were generated with the goal of creating homogenous dose distributions. The primary endpoint was incidence of SBRT-related grade ≥3 toxicity, defined using the Common Terminology Criteria for Adverse Events (V5.0). Secondary endpoints included local failure (LF), progression-free survival (PFS), and overall survival. Competing risk analysis was used to estimate incidence and identify predictors of severe toxicity and LF, while the Kaplan-Meier method was used to estimate PFS and OS. RESULTS: A total of 154 patients receiving 162 ultracentral courses of SBRT were included. The most common prescription was 50 Gy in 5 fractions (42%), with doses ranging from 30 to 55 Gy in 5 fractions (BED10 range, 48-115 Gy). The incidence of severe toxicity was 9.4% at 3 years. The most common severe toxicity was pneumonitis (n = 4). There was 1 possible treatment-related death from pneumonitis/pneumonia. Predictors of severe toxicity included increased PTV size, decreased PTV V95%, lung V5 Gy, and lung V20 Gy. The incidence of LF was 14% at 3 years. Predictors of LF included younger age and greater volume of overlap between the PTV and esophagus. The median PFS was 8.8 months, while the median overall survival was 44.0 months. CONCLUSIONS: In the largest case series of ultracentral thoracic SBRT to date, homogenously prescribed SBRT was associated with relatively low rates of severe toxicity and LF. Predictors of toxicity should be interpreted in the context of the heterogeneity in toxicities observed.

Network Pharmacology and Transcriptomic Sequencing Analyses Reveal the Molecular Mechanism of Sanguisorba officinalis Against Colorectal Cancer.

Background: Colorectal cancer (CRC) is the most common malignant cancer worldwide. Sanguisorba officinalis has been shown to have anti-inflammatory, anti-bacterial, antioxidant, and anti-tumor effects, while its molecular mechanism against CRC remains unclear. The aim of this study is to explore the underlying mechanism of S. officinalis against CRC cell lines using network pharmacology and transcriptomic sequencing methods. Method: Firstly, the active ingredients and potential targets of S. officinalis against CRC were screened from databases. Secondly, the networks of ingredient-target, ingredient-target-CRC and protein-protein interaction were constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of network pharmacology and transcriptomic sequencing were performed. Finally, the effect of S. officinalis against CRC was verified by in vitro experiments. Results: In total, 14 active ingredients and 273 potential targets against CRC were identified in S. officinalis by network pharmacology. PI3K-Akt, HIF-1, and MAPK signaling pathways related to cell proliferation were regulated by S. officinalis in enrichment analyses and transcriptomic sequencing. In vitro, S. officinalis inhibited the proliferation and migration of CRC cells and arrested the cell cycle at the G0-G1 phase. The western blot showed that S. officinalis downregulated the expression of p-PI3K, p-Akt, HIF-1A, VEGFA, cyclin D1, c-Myc, and p-MAPK proteins in CRC cells. Conclusion: In conclusion, network pharmacology and transcriptomic sequencing analyses, in combination with in vitro studies, have been successfully applied to study the underlying mechanism of S. officinalis against CRC cells. Our results demonstrate that S. officinalis suppresses the proliferation, survival, and migration of CRC cells through regulating the PI3K-Akt, HIF-1, and MAPK signaling pathways.

Use of Neoadjuvant Imatinib to Facilitate Minimally Invasive Resection of Gastric Gastrointestinal Stromal Tumors.

BACKGROUND: Neoadjuvant imatinib is used to downstage surgery for large and/or unfavorably located gastric gastrointestinal stromal tumors (GISTs), but data regarding minimally invasive surgery (MIS) after neoadjuvant imatinib are limited. PATIENTS AND METHODS: We analyzed patients undergoing resection of nonmetastatic primary gastric GISTs larger than or equal to 4.5 cm in diameter at our institution between 2009 and 2020, as no tumors below this size received neoadjuvant imatinib. RESULTS: We identified 71 patients, 43 of whom (61%) received neoadjuvant imatinib. Patients receiving neoadjuvant imatinib had larger tumors at diagnosis [median diameter 8.6 cm (range 4.5-25 cm) versus 5.9 cm (range 4.5-11 cm), p < 0.01]. After a median 7.2 months of imatinib, tumors shrank by a median 34% in diameter, such that there was no longer a significant size difference at time of surgery between groups (median 6.3 cm versus 5.9 cm, p = 0.69). Of 29 patients for whom neoadjuvant imatinib was used to facilitate MIS, 21 (72%) underwent successful MIS, which accounted for 49% of the entire neoadjuvant cohort. In a multivariable regression model, smaller tumor size at time of surgery was predictive of successful MIS, but tumor location was not. CONCLUSIONS: Neoadjuvant imatinib caused significant tumor shrinkage, and MIS was successful in 72% of cases for which neoadjuvant imatinib was intended to facilitate it. Smaller tumor size at time of surgery, but not tumor location, was associated with successful MIS, which may help inform patient selection for neoadjuvant imatinib.

Surgical Management of Gastric Cancer: A Review.

Importance: Surgery plays a critical role in the management of all stages of gastric cancer. Observations: For patients with early gastric cancer and low risk of lymph node metastasis, endoscopic therapy or surgery alone is potentially curative. Novel techniques, such as sentinel lymph node biopsy, may allow for greater use of stomach-sparing procedures that could improve quality of life without compromising oncologic outcomes; however, experience with these techniques is rare outside of East Asia, and studies of long-term outcomes are still ongoing. Patients with later-stage localized gastric cancer benefit from more extensive lymphadenectomy and multimodality therapy, as they are at risk for nodal and distant metastases. There have been recent advances in chemotherapy that have led to improved survival, but the optimal sequencing of multimodality therapy is still being investigated. Better systemic therapy may also increase the role of surgery for patients with oligometastatic disease. There are ongoing studies examining the efficacy of peritoneal-directed therapies in both patients with low-volume peritoneal disease and patients at high risk of peritoneal recurrence. Conclusions and Relevance: The management of gastric cancer continues to evolve. Surgeons should be aware of novel surgical approaches currently under investigation as well as how surgery fits into the contemporary multidisciplinary approach to this disease.

Mapping the Current State of Canadian Medical School Oncology Interest Groups.

Cancer is the leading cause of mortality in Canada. Undergraduate medical education therefore must ensure adequate oncology education for all physicians and inspire some to make oncology their career specialty, in an effort to ensure public care needs are met in the future. Medical student-led oncology interest groups (OIGs) are a subset of specialty interest groups that supplement formal didactic and clinical learning to increase exposure to oncology and access to mentors. We conducted a survey of OIG leaders to ascertain their goals, activities, barriers, future directions, and perceptions about employment prospects. OIG leaders from 12/17 Canadian medical schools responded. Medical oncology was the most represented specialty in OIGs. Half of OIGs had faculty mentors. Self-reported goals were to increase exposure to oncology disciplines (n = 12), assist students with career selection (n = 11) and finding mentors (n = 7), and enhance oncology education (n = 10). OIGs held on average 5 events per year (range 1-12). Reported barriers were finding time to plan events, declining student interest over academic year, and limited funding. Many OIGs showed interest in more standardized resources about oncology disciplines (n = 9), access to presentations (n = 10), more funding (n = 7), and collaboration (n = 7). Employment in many oncology specialties was perceived poorly, and the most important career selection considerations were ease of employment, practice location, and partner/family preference. Our survey highlights common goals, barriers, and perceptions in OIG medical student leaders across Canada and provides guidance for future interventions.

Ceramide Regulates Anti-Tumor Mechanisms of Erianin in Androgen-Sensitive and Castration-Resistant Prostate Cancers.

Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.

Establishment of a Fast-Track Gastrectomy Pathway for Patients With Gastric Adenocarcinoma at a U.S. Academic Cancer Center.

INTRODUCTION: Implementation of fast-track perioperative care pathways for gastric cancer patients in the U.S. has been challenging due to low disease incidence and limited safety and efficacy data. Our institution recently implemented such a pathway for gastric cancer patients undergoing gastrectomy, and we sought to study its effects. METHODS: We analyzed data from consecutive patients who underwent gastrectomy for gastric adenocarcinoma from January 2014 to August 2020. Patients who had surgery for recurrence, urgent surgery for obstruction, bleeding, or perforation, or an intrathoracic anastomosis were excluded. The primary predictor was whether the patient had surgery before or after implementation of a perioperative fast-track gastrectomy pathway in July 2018, and the primary outcome was length of stay. RESULTS: One hundred sixty patients were identified, 109 pre-pathway implementation and 51 post-pathway implementation. Following pathway implementation, length of stay was significantly shorter (median 6 days versus 9 days, p < 0.001), and there was no significant difference in 30-day complication rates (29% pre versus 24% post, P = 0.56) or readmission rates (18% pre versus 16% post, P = 0.85). Using linear segmented regression analysis adjusting for age, body mass index, tumor stage (early versus late), type of surgery (distal/subtotal versus total gastrectomy), and approach (open versus minimally invasive), pathway implementation was found to be associated with a 31% decreased length of stay (effect size 0.69, 95% confidence interval 0.49 - 0.98, P = 0.04). CONCLUSIONS: Fast-track gastrectomy care pathways are safe and feasible for U.S. gastric cancer patients undergoing gastrectomy and are associated with decreased length of stay.

Organ at Risk Dose Constraints in SABR: A Systematic Review of Active Clinical Trials.

PURPOSE: Organ at risk (OAR) dose constraints are a critical aspect of SABR treatment planning. There is limited evidence supporting preferred dose constraints for many OARs. We sought to evaluate OAR dose constraints used in ongoing clinical trials of SABR for oligometastatic disease. METHODS AND MATERIALS: Clinicaltrials.gov was searched from inception to February 2020 to capture actively accruing clinical trials using SABR in oligometastatic disease. Dose constraints were obtained by contacting principal investigators and abstracted by 2 authors. Variability of constraints was assessed by comparing the width of the interquartile range and difference between the maximum and minimum dose to a volume. RESULTS: Fifty-three of 85 eligible clinical trials contributed OAR constraints used in analysis. Dose constraints for 1 to 8 fractions of SABR were collected for 33 OARs. Variability was found in the absolute allowable OAR doses, use of planning OAR volumes, and whether constraints were optional versus mandatory. For many OARs, modal dose constraints often matched a pre-existing publication, but no single pre-existing publication matched the modes of all OAR dose constraints. Organs displaying the most variability were the rectum, penile bulb, and chest wall and ribs. The esophagus, stomach, duodenum, and small bowel also indicated high variability for at least 1 constraint. OARs previously evaluated by HyTEC appeared to have less variability among study protocols. CONCLUSIONS: We found substantial variability in OAR dose constraints used in current clinical trials evaluating SABR in oligometastatic disease. We are unable to comment on toxicity rates or acceptability of dose constraints used. Future research and recommendations for standardized OAR dose constraints, as well as consistency in implementing planning OAR volume margins, should be priorities for the field of radiation oncology.

Breast Sarcomas, Phyllodes Tumors, and Desmoid Tumors: Epidemiology, Diagnosis, Staging, and Histology-Specific Management Considerations.

Breast sarcomas arise from connective tissues of the breast and account for fewer than 1% of all breast malignancies. They can be subclassified as primary breast sarcomas, which arise de novo and are histologically diverse, and secondary breast sarcomas, which arise as a result of radiation or lymphedema and are most commonly angiosarcomas. Two other connective tissue neoplasms that occur within the breast include phyllodes tumors and desmoid tumors, which exhibit a spectrum of behaviors. Malignant phyllodes tumors are biologically similar to primary breast sarcomas, whereas desmoid tumors are technically benign but often locally aggressive. Patients with breast sarcomas often present with a rapidly growing mass or, in cases of radiation-associated angiosarcoma, violaceous cutaneous lesions. Core needle biopsy is generally required to confirm the diagnosis of sarcomas. Staging workup includes MRI and chest imaging, although these are not required in the case of benign phyllodes or desmoid tumors. In general, localized breast sarcomas should be resected, with the extent of resection tailored to histologic subtype. Radiation and chemotherapy can be used in the neoadjuvant or adjuvant setting, but data are limited, so treatment decisions should be made on an individualized basis. Systemic therapy options for metastatic disease and refractory breast desmoids mimic those used for the same histologies when present in other sites. Given the rarity and heterogeneity of breast sarcoma, as well as limited literature describing these entities, expert multidisciplinary evaluation is crucial for optimal decision making.

Broad-spectrum pharmacological activity of Australian propolis and metabolomic-driven identification of marker metabolites of propolis samples from three continents.

Propolis is a by-product of honeybee farming known for its broad therapeutic benefits around the world and is extensively used in the health food and beverage industry. Despite Australia being one of the world's megadiverse countries with rich flora and fauna, Australian propolis samples have not been explored adequately with most in vitro and in vivo studies centred on their Brazilian and Chinese counterparts. In view of this, our study was designed to investigate the chemical composition and anti-proliferative, antibacterial, antifungal, anti-inflammatory and antioxidant properties of Australian propolis (AP-1) extract to draw a comparison with Brazilian (BP-1) and Chinese propolis (CP-1) extracts. The AP-1 extract displayed significantly greater anti-proliferative activity against the MCF7 and the MDA-MB-231 metastatic breast adenocarcinoma cell lines compared to BP-1 and CP-1 (p < 0.05). Similar trends were also observed in the antibacterial (Escherichia coli and Staphylococcus aureus), anti-inflammatory (lipopolysaccharide-induced RAW264.7 macrophages) and antioxidant assays (ABTS, DPPH and CUPRAC) with AP-1 exhibiting more potent activity than BP-1 and CP-1. The ultra-high performance liquid chromatography (UPLC) coupled with quadrupole high-resolution time of flight mass spectrometry (qTOF-MS) and chemometrics implementing unsupervised PCA and supervised OPLS-DA analyses of the propolis samples from Australia, China and Brazil revealed 67 key discriminatory metabolites belonging to seven main chemical classes including flavonoids, triterpenes, acid derivatives, stilbenes, steroid derivatives, diterpenes and miscellaneous compounds. Additionally, seven common phenolic compounds were quantified in the samples. Further mechanistic studies are necessary to elucidate the modes of action of Australian propolis for its prospective use in the food, nutraceutical and pharmaceutical industries.

A review of ongoing trials of stereotactic ablative radiotherapy for oligometastatic disease in the context of new consensus definitions.

The characterization and treatment of oligometastatic disease (OMD) are rapidly growing areas of research. Consensus statements have recently been developed by European Society for Radiotherapy and Oncology (ESTRO)/American Society for Radiation Oncology (ASTRO) and ESTRO/European Organization for Research and Treatment of Cancer (EORTC) in an effort to harmonize terminology describing OMD. The purpose of this study was to assess patient populations eligible for ongoing clinical trials evaluating stereotactic ablative radiotherapy (SABR) in OMD in the context of key definitions from both statements. Using the clinicaltrials.gov database, a search of ongoing OMD clinical trials evaluating the use of SABR was performed from inception to January 2020, using the keywords "oligometastasis", "stereotactic radiotherapy", and related terms. Results were independently reviewed by two investigators, with discrepancies settled by a third. Information from these trials including study design, population criteria, and primary endpoints were extracted. OMD was defined in general as a limited number of metastases that could be safely treated with metastasis-directed therapy. States of OMD were broadly categorized into de novo, repeat, and induced, with synchronous and metachronous being subsets of de novo. The initial search strategy identified 293 trials, of which 85 met our eligibility criteria. Phase II trials were by far the most common (n=46, 52%). Most trials had a single treatment arm (n=43, 51%), and 31 (36%) were randomized. The majority of trials (n=65, 76%) had populations that included all three subsets of OMD. Notably, 70 trials (82%) also included oligoprogressive disease, which is debatably a distinct entity from OMD. Progression-free survival was the most common primary endpoint (n=31, 36%), followed by local control (n=17, 20%), toxicity (n=14, 16%) and overall survival (n=7, 8%). Although the use of SABR for OMD is an active area of prospective clinical trial research, ongoing studies include mixed populations as defined by new consensus statements. Therefore, the applicability of results from these trials should be considered within relevant OMD scenarios.

Current Management and Progress in Radiotherapy for Small Cell Lung Cancer.

Radiotherapy (RT) and chemotherapy continue to be widely utilized in small cell lung cancer (SCLC) management. In most limited stage (LS)-SCLC cases, the standard initial therapy remains concurrent chemoradiotherapy (CRT), typically with an etoposide and platinum-based regimen. Hyperfractionated twice daily (BID) RT remains the standard of care, though conventional daily (QD) RT is now a viable alternative supported by randomized evidence. In LS-SCLC patients who experienced good response to CRT, prophylactic cranial irradiation (PCI) remains the standard of care. Brain imaging, ideally with MRI, should be performed prior to PCI to screen for clinically apparent brain metastases that may require a higher dose of cranial irradiation. Platinum doublet chemotherapy alone is the historic standard initial therapy in extensive stage (ES)-SCLC. Addition of immunotherapy such as atezolizumab and durvalumab to chemotherapy is now recommended after their benefits were demonstrated in recent trials. In patients with response to chemotherapy, consolidation thoracic RT and PCI could be considered, though with caveats. Emergence of hippocampal avoidance cranial irradiation and SRS in SCLC patients may supplant whole cranial irradiation as future standards of care. Incorporation of novel systemic therapies such as immunotherapies has changed the treatment paradigm and overall outlook of patients with SCLC. This narrative review summarizes the current state, ongoing trials, and future directions of radiotherapy in management of SCLC.

Chinese Propolis Inhibits the Proliferation of Human Gastric Cancer Cells by Inducing Apoptosis and Cell Cycle Arrest.

Special Chinese propolis sourced from the Changbai Mountains (CBMP) in Northeast China is rich in specific flavonoids and phenolic acids and its bioactivity has not been reported. This study aimed to investigate the antiproliferative effect of CBMP on cancer cells and its molecular mechanisms. Different cancer cell lines were treated with the ethanol extracts of CBMP for 24 hours before the cell viability and mechanism measurements. The results showed CBMP had weak activities against human pancreatic cancer cell PANC1, human lung cancer cell A549, human colon cancer cell HCT116, human liver cancer cell HepG2, human bladder cancer cell T24, and human breast cancer cell MDA-MB-231, but it significantly inhibited the growth of human gastric cancer SGC-7901 cells, caused cell apoptosis and cell cycle arrest in S phase, with increased production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential (MMP). The results indicate that Chinese propolis sourced from the Changbai Mountains selectively inhibits the proliferation of human gastric cancer SGC-7901 cells by inducing both death receptor-induced apoptosis and mitochondria-mediated apoptosis, and cell cycle arrest in S phase. These activities and mechanisms help understand the anticancer action of propolis and its active compounds.

Stereotactic ablative radiotherapy for malignant mediastinal and hilar lymphadenopathy: a systematic review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) safety and efficacy for mediastinal and hilar lymphadenopathy (MHL) is not yet established, given its potential for toxicity due to the proximity to esophagus and proximal bronchial tree (PBT). This review summarized current reported outcomes of MHL SABR. METHODS: This systematic review, based on the PRISMA guidelines, was performed using MEDLINE® (PubMed®), EMBASE and Cochrane Library databases from inception until December 2018. Studies reporting outcomes from SABR specifically for MHL from all primary malignancies were included. Non- English studies, guidelines, reviews, non-peer reviewed correspondences were excluded. Only the most recent publication and/or largest cohort from a single institution would be included for analysis. RESULTS: From the 222 studies identified, 4 retrospective studies totaling 196 patients were included in the analysis. One study included a small number of patients receiving non-ablative doses of stereotactic radiotherapy (RT). Non-small cell lung cancer (NSCLC) was the most common primary (65%), followed by breast (8%). Median follow-up ranged between 12 and 32 months. Reported dose and fractionation ranged from 21 to 60 Gy in 3-11 fractions, with median BED10 ranged from 46-106 Gy10. Three studies reported local control (LC) rates: study 1, 97% (1-year) and 77% (5-year); study 4, 88% (2-year); and study 2, 69% (6-month) and 66% (16-month). Pooled grade 3-5 toxicity rate according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 was 6% (n=11). Pooled SABR-related mortality (grade 5 toxicity) rate was 2% (n=4). Three SABR-related deaths from esophageal fistulae (2 to trachea, 1 to mediastinum) were reported, with all 3 having prior RT to the subcarinal nodes. CONCLUSIONS: Our review suggested SABR for MHL to be feasible and effective, though there is a potential for serious toxicity especially in the re-irradiation scenario. Multi-institutional and/or prospective studies will help determine the therapeutic benefit of SABR in this high-risk treatment scenario.