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Competing Interests: This study was supported by the Melvin Markey Scholars Program at the Cleveland Clinic.

Competing Interests: Dr Koyfman receives research support from Merck and Bristol-Myers Squibb, consults for Merck and Regeneron, and receives honoraria from Uptodate. Drs Ilori, Campbell, Smile, Keller, Joshi, and Woody have no conflicts of interest to declare.

Background/aim: Head and neck cancers are often treated with extended courses of radiotherapy (RT), which may prove excessively toxic for frail patients. Split course RT (SCRT) delivers two courses of RT separated by 4-6 weeks, personalizing treatment intensity based on response. In this study, we present our updated experience using this technique., Patients and Methods: From a single institution database, we identified patients considered for SCRT. For patients undergoing a second course of RT, cumulative incidence of locoregional recurrence (LRR) and overall survival (OS) are reported., Results: A total of 98 patients were included, of whom seventy-five percent underwent a second course of RT. The most common fractionation was 30 Gy in 10 fractions for each course, with a median cumulative dose of 60 Gy. In those undergoing a second course of RT, median OS was 9.7 months and cumulative incidence of LRR at 6, 12, and 24 months was 17.0%, 23.1%, and 29.4%, respectively., Conclusion: SCRT offers an attractive treatment paradigm to personalize radiation intensity based on patient tolerance, while maintaining reasonable safety and efficacy in those unfit for standard full course RT., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Adjuvant chemoradiation (CRT), with high-dose cisplatin remains standard treatment for oral cavity squamous cell carcinoma (OCSCC) with high-risk pathologic features. We evaluated outcomes associated with different cisplatin dosing and schedules, concurrent with radiation (RT), and the effect of cumulative dosing of cisplatin. An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I-IVB AJCC 7th edition) treated with primary surgical resection between January 2005 and January 2015, with or without adjuvant therapy, was established from six academic institutions. Patients were categorized by cisplatin dose and schedule, and resultant groups compared for demographic data, pathologic features, and outcomes by statistical analysis to determine disease free survival (DFS) and freedom from metastatic disease (DM). From a total sample size of 1282 pts, 196 pts were identified with high-risk features who were treated with adjuvant CRT. Administration schedule of cisplatin was not significantly associated with DFS. On multivariate (MVA), DFS was significantly better in patients without perineural invasion (PNI) and in those receiving ≥200 mg/m 2 cisplatin dose ( p < 0.001 and 0.007). Median DFS, by cisplatin dose, was 10.5 (<200 mg/m 2 ) vs. 20.8 months (≥200 mg/m 2 ). Our analysis demonstrated cumulative cisplatin dose ≥200 mg/m 2 was associated with improved DFS in high-risk resected OCSCC pts.

Purpose/objectives: Metastasis-directed therapy with stereotactic body radiotherapy (SBRT) in the setting of oligometastatic disease is a rapidly evolving paradigm given ongoing improvements in systemic therapies and diagnostic modalities. However, SBRT to targets in the abdomen and pelvis is historically associated with concerns about toxicity. The purpose of this study was to evaluate the safety and efficacy of SBRT to the abdomen and pelvis for women with oligometastases from primary gynecological tumors., Materials/methods: From our IRB-approved registry, all patients who were treated with SBRT between 2014 and 2020 were identified. Oligometastatic disease was defined as 1 to 5 discrete foci of clinical metastasis radiographically diagnosed by positron emission tomography (PET) and/or computerized tomography (CT) imaging. The primary endpoint was local control at 12 months. Local and distant control rates were estimated using the Kaplan-Meier method. Time intervals for development of local progression and distant progression were calculated based on follow up visits with re-staging imaging. Acute and late toxicity outcomes were determined based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: We identified 34 women with 43 treated lesions. Median age was 68 years (range 32-82), and median follow up time was 12 months (range 0.2-54.0). Most common primary tumor sites were ovarian (n=12), uterine (n=11), and cervical (n=7). Median number of previous lines of systemic therapy agents at time of SBRT was 2 (range 0-10). Overall, SBRT was delivered to 1 focus of oligometastasis in 29 cases, 2 foci in 2 cases, 3 foci in 2 cases, and 4 foci in 1 case. All patients were treated comprehensively with SBRT to all sites of oligometastasis. Median prescription dose was 24 Gy (range 18-54 Gy) in 3 fractions (range 3-6) to a median prescription isodose line of 83.5% (range 52-95). Local control by lesion at 12 and 24 months was 92.5% for both time points. Local failure was observed in three treated sites among two patients, two of which were at 11 months in one patient, and the other at 30 months. Systemic control rate was 60.2% at 12 months. Overall survival at 12 and 24 months was 85% and 70.2%, respectively. Acute grade 2 toxicities included nausea (n=3), and there were no grade > 3 acute toxicities. Late grade 1 toxicities included diarrhea (n=1) and fatigue (n=1), and there were no grade > 2 toxicities., Conclusion: SBRT to oligometastatic gynecologic malignancies in the abdomen and pelvis is feasible with encouraging preliminary safety and local control outcomes. This approach is associated with excellent local control and low rates of toxicity during our follow-up interval. Further investigations into technique, dose-escalation and utilization are warranted., Competing Interests: Authors’ disclosure of potential conflicts of interest The authors have nothing to disclose., (© 2021 Old City Publishing, Inc.)

Purpose: To report on the use of outpatient anesthesia (OPA) facilitating delivery of stereotactic body radiation therapy (SBRT) in patients with severe cognitive impairments (CI) diagnosed with inoperable early stage lung cancer., Methods and Materials: We surveyed our institutional review board-approved prospective lung SBRT data registry to document the feasibility of using anesthesia in CI patients and to determine their SBRT outcomes., Results: From 2004 to 2018, 8 from a total 2084 patients were identified for this analysis. The median age at treatment was 68 years (range, 44-78). Most patients were female (62.5%). CI diagnoses included Alzheimer-related dementia (3 patients), chronic schizophrenia (3 patients), severe anxiety disorder (1 patient), and severe developmental disability (1 patient). The median tumor size was 3.4 cm (range, 1.1-10.5), and 7 patients (87.5 %) had central lesions. The median follow-up time was 22.5 months. The most common (50%) SBRT schedule used was 50 Gy in 5 fractions. Intravenous propofol (10 mg/mL) was used for OPA in all cases at the time of simulation and with daily treatments. OPA was well tolerated and all patients completed SBRT as prescribed. There was one grade 5 but no other grade 3 or higher SBRT-related toxicities. One patient died with local failure and one of distant failure., Conclusions: OPA made lung SBRT feasible for patients with CIs. SBRT outcomes were in keeping with those reported in the literature. CI should not be considered a contraindication per se to SBRT delivery in patients otherwise appropriate for this modality., (© 2019 The Author(s).)

Background/aim: There are limited data regarding survival, failure patterns, and factors associated with disease recurrence in patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) with nodal metastases., Patients and Methods: A retrospective analysis of patients with cSCC-HN metastatic to cervical and/or parotid lymph nodes treated with surgery and post-operative radiation therapy was performed., Results: This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years was 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p<0.0001)., Conclusion: Patients with nodal metastases from cSCC-HN have suboptimal outcomes. ECE and immunosuppression were significantly associated with DR., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Definitive chemoradiation (CRT) is a common approach for locally advanced hypopharyngeal squamous cell carcinoma (SCC) with the goal of organ preservation. Reports on long-term oncologic and functional outcomes have been limited. This study reports on outcomes utilizing this approach at a single institution over 30 years., Materials and Methods: Medical records for patients with stage III-IVB SCC of the hypopharynx were retrospectively reviewed. Patient and disease-related factors were identified and analyzed for impact on overall survival (OS), cancer-specific survival (CSS), disease-free survival, distant failure, and locoregional failure., Results: A total of 54 patients were identified who were treated with definitive CRT to a mean dose of 72 Gy. With a median follow-up period of 49.8 months, 5- and 10-year OS was 62% and 43% respectively. Five and 10-year CSS were 74% and 72% respectively. Ten-year local control was 78%. Of the 37 patients with no treatment failure, 29% experienced a grade 3 or higher late toxicity, with the majority resolving during continued long-term follow-up., Conclusion: This study demonstrates good outcomes with long-term follow-up with acceptable rates of late toxicities. The findings here represent the longest published median follow-up in this population and validate the strategy of organ preservation., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is the standard of care for medically inoperable patients with early-stage NSCLC. However, NSCLC is composed of several histological subtypes and the impact of this heterogeneity on SBRT treatments has yet to be established., Methods: We analyzed 740 patients with early-stage NSCLC treated definitively with SBRT from 2003 through 2015. We calculated cumulative incidence curves using the competing risk method and identified predictors of local failure using Fine and Gray regression., Results: Overall, 72 patients had a local failure, with a cumulative incidence of local failure at 3 years of 11.8%. On univariate analysis, squamous histological subtype, younger age, fewer medical comorbidities, higher body mass index, higher positron emission tomography standardized uptake value, central tumors, and lower radiation dose were associated with an increased risk for local failure. On multivariable analysis, squamous histological subtype (hazard ratio = 2.4 p = 0.008) was the strongest predictor of local failure. Patients with squamous cancers fail SBRT at a significantly higher rate than do those with adenocarcinomas or NSCLC not otherwise specified, with 3-year cumulative rates of local failure of 18.9% (95% confidence interval [CI]: 12.7-25.1), 8.7% (95% CI: 4.6-12.8), and 4.1% (95% CI: 0-9.6), respectively., Conclusion: Our results demonstrate an increased rate of local failure in patients with squamous cell carcinoma. Standard approaches for radiotherapy that demonstrate efficacy for a population may not achieve optimal results for individual patients. Establishing the differential dose effect of SBRT across histological groups is likely to improve efficacy and inform ongoing and future studies that aim to expand indications for SBRT., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Isolated nodal failure (INF) without synchronous local or distant failure is an uncommon occurrence after stereotactic body radiation therapy (SBRT) for lung cancer. Here we review the natural history and patterns of failure after post-SBRT INF with or without salvage mediastinal radiotherapy (SvRT)., Methods: Patients treated with SBRT for non-small cell lung cancer with definitive intent were identified. Patients who experienced hilar or mediastinal INF without synchronous distant, lobar, or local failure were included and grouped according to the use of SvRT. The rates of subsequent locoregional control, distant metastases, progression-free survival (PFS), and overall survival were assessed., Results: Of 797 patients treated with definitive SBRT, 24 (3%) experienced INF and 15 (63%) received SvRT. The most common SvRT regimen (53%) was 45 Gy in 15 fractions. The median follow-up after INF was 11.3 months for survivors. There were no grade 3 or higher toxicities after SvRT. The 1-year Kaplan-Meier PFS and overall survival estimates were 33% and 56% for patients not receiving radiotherapy and 75% and 73% with SvRT. After SvRT, the rate of locoregional control at 1 year was 84.4%. Crude rates of distant failure were 20.0% with SvRT and 22.2% with no radiotherapy. Of the 13 deaths observed, five (38%) were related to distant progression of lung cancer, four (31%) to comorbidities, three (23%) to mediastinal progression, and one (8%) to an unknown cause., Conclusions: INF is uncommon after SBRT. Despite the significant comorbidities of this population, intrathoracic progression remains a contributor to morbidity and mortality. SVRT for INF is well tolerated and may improve PFS., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We present the case of a patient undergoing reirradiation for a T4 nasopharyngeal tumor 1 year after his initial radiation, treated with SBRT to a moderate dose with twice weekly fractionation. Despite the measures of caution employed, the patient had a fatal carotid blowout at 7 months following SBRT. This suggests that spacing apart fractions of SBRT alone may not be sufficient to obviate the risk of carotid blowout syndrome and other risk factors and interventions should be considered.

Introduction: To examine regional nodal failure patterns with respect to lesion size in medically inoperable early-stage non-small cell lung cancer (NSCLC) patients treated with definitive lung stereotactic body radiation therapy (SBRT)., Methods: Between 2004 and 2012, 342 medically inoperable early-stage NSCLC patients treated with definitive SBRT were identified in our institutional review board-approved prospective registry. All patients were treated on a Novalis/BrainLAB system using ExacTrac for image guidance. Kaplan-Meier analysis was performed with the log-rank test used to detect differences between lesion size and nodal failure patterns. Cox-proportional hazard regression analysis was performed to identify predictors of nodal failure., Results: Median follow-up was 17.6 months (range, 0-84 months). Median tumor size, positron emission tomography maximum standardized uptake value, and dose/fractionation were 2.2 cm (range, 0.8-7.2 cm), 6.7 (range, 1-59), and 50 Gray (Gy)/five fractions, respectively. Of the 342 lesions evaluated, 14.6% (50 of 342) experienced nodal failure. Nodal failure rates were 17.45% (26 of 149), 10.3% (11 of 107), 14.1% (10 of 71), and 20% (3 of 15) for lesions less than or equal to 2 cm, 2.1 to 3 cm, 3.1 to 5 cm, and greater than 5 cm, respectively. Rates of nodal failure were not significantly different between the four different size groups (p = 0.15). On univariate analysis, 2.1 to 3 cm lesions versus less than or equal to 2 cm exhibited less nodal failure after SBRT (hazard ratio = 0.406; 95% confidence interval = 0.189-0.87; p = 0.0205). No other patient, tumor, or treatment factor significantly affected nodal failure., Conclusion: For early-stage NSCLC treated with SBRT, tumor size does not influence the rates of regional nodal failure. This finding warrants further investigation on the possible mechanisms of SBRT by which loco-regional control is improved.

Background and Purpose: We compare our institutional outcomes of synchronous primary (SP) lung lesion patients with non-SP patients.Materials and Methods: From an IRB approved prospective registry of 445 NSCLC patients treated with SBRT (8/2005 8/2012), 26 (5.8%) had SPs by biopsy or PET/CT. SBRT was delivered on a Novalis/BrainLAB platform with daily Exactrac set-up., Results: There were no significant differences comparing SP vs non-SP groups for age, Charlson score, smoking pack years, and PET SUV (p=ns). 18 (69%) SP patients had at least one lesion biopsied. Ipsilateral and bilateral SPs were seen in 10 (38.4%) and 16 (61.6%) respectively. 77% received 50 Gy / 5 fx. SP vs non-SP median follow up was 12 (range 1.5-49.8) vs 15.2 months. Median survival for SP vs non-SP groups was 20.7 vs 28.4 months (p=0.3). In SP vs non-SP groups, local failure was 4% vs 7.6% (p=ns) and nodal/distant failure was 23% vs 24.6% (p=ns). Patients with ipsilateral and bilateral SPs had a 50% vs 14% distant failure respectively (p=0.037)., Conclusions: After SBRT, there were no differences in survival and patterns of failure for SP vs non-SP patients. Ipsilateral SPs had significantly worse distant failure compared to bilateral SPs.

Leukocyte-derived microparticles (MPs) are markers of cardiovascular diseases and contribute to pathogenesis by their interaction with various cell types. The presence and activation state of a multifunctional leukocyte receptor, integrin alpha(M)beta(2) (CD11b/18), on MPs derived from human neutrophils (PMNs) were examined. alpha(M)beta(2) expression was significantly enhanced on MPs derived from stimulated compared with resting PMNs. Furthermore, alpha(M)beta(2) on MPs from stimulated but not resting PMNs was in an activated conformation because it was capable of binding activation-specific monoclonal antibodies (CBRM1/5 and mAb24) and soluble fibrinogen. MPs expressing active alpha(M)beta(2) interacted with and were potent activators of resting platelets as assessed by induction of P-selectin expression and activation of alpha(IIb)beta(3). With the use of function-blocking antibodies and MPs obtained from alpha(M)(-/-)-deficient mice, we found that engagement of GPIbalpha on platelets by alpha(M)beta(2) on MPs plays a pivotal role in MP binding. Platelet activation by MPs occurs by a pathway dependent on Akt phosphorylation. PSGL-1/P-selectin interaction also is involved in the conjugation of MPs to platelets, and the combination of blocking reagents to both alpha(M)beta(2)/GPIbalpha and to PSGL-1/P-selectin completely abrogates MP-induced platelet activation. Thus, cooperation of these 2 receptor/counterreceptor systems regulates the prothrombotic properties of PMN-derived MPs.

Shc family proteins serve as phosphotyrosine adaptor molecules in various receptor-mediated signaling pathways. In mammals, three distinct Shc genes have been described that encode proteins characterized by two phosphotyrosine-interaction modules, an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Here, we report the analysis of an uncharacterized fourth Shc family protein, ShcD/Shc4, that is expressed in adult brain and skeletal muscle. Consistent with this expression pattern, we find that ShcD can associate via its PTB domain with the phosphorylated muscle-specific kinase (MuSK) receptor tyrosine kinase and undergo tyrosine phosphorylation downstream of activated MuSK. Interestingly, additional sites of tyrosine phosphorylation, including a novel Grb2 binding site, are present on ShcD that are not found in other Shc family proteins. Activation of MuSK upon agrin binding at the neuromuscular junction (NMJ) induces clustering and tyrosine phosphorylation of acetylcholine receptors (AChRs) required for synaptic transmission. ShcD is coexpressed with MuSK in the postsynaptic region of the NMJ, and in cultured myotubes stimulated with agrin, expression of ShcD appears to be important for early tyrosine phosphorylation of the AChR. Thus, we have characterized a new member of the Shc family of docking proteins, which may mediate a specific aspect of signaling downstream of the MuSK receptor.