Jacob E. Shabason

Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif.

The relationship between the binding affinity and specificity of modular interaction domains is potentially important in determining biological signaling responses. In signaling from the T‐cell receptor (TCR), the Gads C‐terminal SH3 domain binds a core RxxK sequence motif in the SLP‐76 scaffold. We show that residues surrounding this motif are largely optimized for binding the Gads C‐SH3 domain resulting in a high‐affinity interaction (KD=8–20 nM) that is essential for efficient TCR signaling in Jurkat T cells, since Gads‐mediated signaling declines with decreasing affinity. Furthermore, the SLP‐76 RxxK motif has evolved a very high specificity for the Gads C‐SH3 domain. However, TCR signaling in Jurkat cells is tolerant of potential SLP‐76 crossreactivity, provided that very high‐affinity binding to the Gads C‐SH3 domain is maintained. These data provide a quantitative argument that the affinity of the Gads C‐SH3 domain for SLP‐76 is physiologically important and suggest that the integrity of TCR signaling in vivo is sustained both by strong selection of SLP‐76 for the Gads C‐SH3 domain and by a capacity to buffer intrinsic crossreactivity.

In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

Multi‐molecular complexes nucleated by adaptor proteins play a central role in signal transduction. In T cells, one central axis consists of the assembly of several signaling proteins linked together by the adaptors linker of activated T cells (LAT), Src homology 2 domain‐containing leukocyte‐specific phosphoprotein of 76 kDa (SLP‐76), and Grb2‐related adaptor downstream of Shc (Gads). Each of these adaptors has been shown to be important for normal T cell development, and their proper sub‐cellular localization is critical for optimal function in cell lines. We previously demonstrated in Jurkat T cells and a rat basophilic leukemic cell line that expression of a 50‐amino acid polypeptide identical to the site on SLP‐76 that binds to Gads blocks proper localization of SLP‐76 and SLP‐76‐dependent signaling events. Here we extend these studies to investigate the ability of this polypeptide to inhibit TCR‐induced integrin activity in Jurkat cells and to inhibit in vivo thymocyte development and primary T cell function. These data provide evidence for the in vivo function of a dominant‐negative peptide based upon the biology of SLP‐76 action and suggest the possibility of therapeutic potential of targeting the SLP‐76/Gads interaction.

National Cancer Database Report on Pneumonectomy Versus Lung-Sparing Surgery for Malignant Pleural Mesothelioma

Introduction: Controversy exists regarding the optimal surgical technique for malignant pleural mesothelioma (MPM). We evaluated national practice patterns and outcomes of MPM treated with extrapleural pneumonectomy (EPP) versus lung‐sparing extended pleurectomy/decortication (P/D). Methods: The National Cancer Database was queried for patients with newly diagnosed MPM undergoing EPP or P/D. Multivariable logistic regression ascertained clinical factors independently associated with P/D receipt. Kaplan‐Meier analysis was used to evaluate overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Survival was then evaluated between propensity‐matched populations. Results: Overall, 1307 patients (271 undergoing EPP [21%] and 1036 undergoing P/D [79%]) met the criteria. Patients receiving P/D were older (p = 0.028), whereas those undergoing EPP were more likely to live in a rural area (p = 0.044), live farther from the treating facility (p = 0.039), and receive treatment at an academic center (p = 0.050). There were no differences between cohorts in 30‐day readmission or mortality (all p > 0.05). The median OS times in the EPP and P/D groups were 19 versus 16 months, respectively (p = 0.120); no differences were observed after propensity matching (p = 0.540). Conclusions: In this largest analysis of its kind to date, findings from this contemporary cohort demonstrate that P/D comprised most surgical procedures for MPM. Procedure type was influenced by sociodemographic and geographical factors, without observed differences in survival or postoperative mortality and readmission rates between techniques.

Radiation and Immune Checkpoint Blockade: From Bench to Clinic

Immune escape of malignant cells is an important hallmark of cancer, necessary for tumor formation and progression. Accordingly, in recent years, therapies that enhance the immune system have had remarkable success in treating a myriad of malignancies. Particularly successful has been immune checkpoint blockade (ICB), which is a therapy that targets T-cell inhibitory receptors, or immune checkpoints. Despite these encouraging clinical results, most patients do not respond to such agents. Therefore, determining methods to better target and enhance the therapeutic efficacy of ICB is of paramount importance. One appealing approach is to use standard anticancer therapies, such as radiation, chemotherapy, and targeted biologics, to favorably modulate the immune system and enhance the anticancer immune response. For example, although radiation therapy has classically been thought of as a local therapy, there is significant potential for combining radiation therapy with ICB to both optimize local control and to treat metastatic disease. This concept is supported by numerous preclinical studies and clinical case reports and has since led to many early and ongoing clinical trials. However, it is still unclear how to optimally combine radiation and ICB to maximize the therapeutic effect. In this review, we highlight relevant preclinical and clinical studies in the field of radiation and ICB and discuss optimal strategies for combination therapies moving forward.

Effect of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small-Cell Lung Cancer: A Propensity Score-Matched Analysis

Micro‐Abstract The role of prophylactic cranial irradiation (PCI) in metastatic small‐cell lung cancer (SCLC) is controversial. Using the National Cancer Database we show that patients treated with PCI have improved survival outcomes. In light of conflicting randomized trials, this study adds information to help guide physician and patient decision‐making about the utility of PCI in metastatic SCLC. Introduction Patients with small‐cell lung cancer (SCLC) have a high incidence of occult brain metastases and are often treated with prophylactic cranial irradiation (PCI). Despite a small survival advantage in some studies, the role of PCI in extensive stage SCLC remains controversial. We used the National Cancer Database to assess survival of patients with metastatic SCLC treated with PCI. Patients and Methods Metastatic SCLC patients without brain metastases were identified. To minimize treatment selection bias, patients with an overall survival (OS) < 6 months were excluded. Cox regression identified variables associated with OS. Patients were propensity score‐matched on factors associated with receipt of PCI or OS. The effect of PCI on OS was examined using Kaplan–Meier estimates. Results In the overall cohort (n = 4257), treatment with PCI (n = 473) was associated with improved survival (hazard ratio, 0.66; 95% confidence interval, 0.60‐0.74; P < .0001). Comparisons of propensity score‐matched cohorts revealed a significant survival benefit for patients who received PCI in median OS (13.9 vs. 11.1 months; P < .0001), as well as 1‐ and 2‐year OS (61.2% vs. 44.0% and 19.8% vs. 11.5%, respectively; P < .0001). This survival benefit persisted even after excluding patients who survived < 9 months (median: 15.3 vs. 12.9 months; P < .0001). In multivariable analysis, predictors of receipt of PCI were Caucasian race, younger age, and lower Charlson–Deyo score. Conclusion Using a modern population‐based data set, we showed that metastatic SCLC patients treated with PCI have significantly improved OS. This large retrospective study helps address the conflicting prospective data.

Impact of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small Cell Lung Cancer: A Propensity Score Matched Analysis of Patients in the National Cancer Database

to receive surgery and more likely to succumb to their cancer compared to their Caucasian (C) counterparts. Recent advancements in surgery (such as minimally invasive techniques) and radiation therapy (such as stereotactic body therapy) have resulted in improved short and long-term outcomes in early stage NSCLC. Herein, we designed a population-based study that sought to understand how racial disparities in the treatment and outcome of stage I NSCLC have changed in the past decade. Materials/Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to retrieve a case list of biopsy-proven stage I NSCLC patients above the age of 60. Patients who were diagnosed between the years of 2004-2012 were selected, excluding any patients without definitive records for local therapy. Patients were divided into one of four racial cohorts: C, AA, American Indian (AI), Asian/Pacific Islander (API), or Unknown (U). Demographics, local therapy, and survival metrics were compared using the following statistical analyses: chi-squared test, Kaplan-Meier method, and Cox multivariate analysis. Survival at 23 months was used as a proxy for 2-year survival to include the 2011 data in the final analysis. Results: There were 62,312 patients who met criteria for analysis. AA and AI were less likely to receive surgery than the typical stage I NSCLC patient (55.9% and 57.6% compared to 66.7% overall, P<.05). Two-year OS for C was 70%, AAwas 65%, AI was 60%, API was 76%, and U was 89% (P<.05). Two-year CSS for C was 79%, AA was 76%, AI was 73%, API was 84%, and U was 91% (P<.05). The median CSS for AI and AA was less than that of the typical stage I NSCLC patient (49 months and 80 months, respectively, compared to 107 months, P<.05). This difference in CSS disappeared on multivariate analysis, largely accounted for by sex (using female as reference, male HR Z 1.17), age (unit RR Z 1.01), treatment (using observation as reference, surgery HR Z 0.44, radiation HR Z 0.70, both surgery and radiation HR Z 0.48), and T stage (using T1 as reference, T2 HR Z 1.25) (all P<.05). Conclusion: Despite advancements in surgery and radiation in the last decade, both AA and AI continue to have higher rates of overall and cancer-specific mortality from early stage NSCLC compared to Caucasians. The poor outcomes in stage I NSCLC in AAs and AIs may be due to the association of these populations with more adverse risk factors, such as older age of diagnosis, male sex, T2 stage, and tendency to forgo surgery and receive no treatment. Author Disclosure: S.M. Dalwadi: None. G. Lewis: None. E. Butler: None. B.S. Teh: None. A. Farach: None.

Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy

Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Childrens Hospital of Philadelphia from 2007 to 2015. With a median follow‐up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in‐field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high‐dose RT, indicating the need for improvements in local therapy.

Trends and Patterns of Utilization of Hypofractionated Postmastectomy Radiotherapy: A National Cancer Database Analysis

Background The acceptance of hypofractionated radiotherapy in treating breast cancer in the breast conservation therapy setting has stimulated interest in hypofractionated postmastectomy radiotherapy (PMRT). We assessed national trends and patterns of utilization of hypofractionated PMRT. Patients and Methods Women 18 years of age or older with breast cancer treated with mastectomy and PMRT to the chest wall with or without regional lymph nodes from 2004 to 2014 were identified from the National Cancer Database. A standard fractionation cohort was defined as patients receiving 180 to 200 cGy per fraction to a total dose of 4500 to 7000 cGy over 5 to 7 weeks, and a hypofractionation cohort was defined as those receiving 250 to 400 cGy per fraction to a total dose of 3000 to 6000 cGy over 2 to 5 weeks. Multivariable logistic regression was used to determine factors associated with hypofractionated PMRT use. Results We identified 113,981 patients who met study criteria. Overall, hypofractionated PMRT use was low (1.1%) although utilization increased over time (P ≤ .001). Older age, greater comorbidity, further distance from treatment facility, treatment at academic facilities, less extensive disease, and recent treatment year were statistically significant predictors of hypofractionation use compared with standard fractionation. Conversely, breast reconstruction and receipt of chemotherapy were negative predictors. Conclusion Because of the absence of high‐level evidence to support its use, hypofractionated PMRT was uncommonly utilized in the United States from 2004 to 2014, although a small increase in use was noted over time. Findings from this study might be useful in designing future studies, and might serve as a baseline for evaluation of future changes in practice patterns. Micro‐Abstract There is growing interest in treating breast cancer with hypofractionated postmastectomy radiotherapy (PMRT). National patterns of hypofractionated PMRT utilization were assessed using the National Cancer Database. Overall, hypofractionated PMRT use was uncommon although it increased over time. Hypofractionated PMRT was used in patients more likely to gain convenience from shorter treatment schedules.

Predictors of Wound Complications following Radiation and Surgical Resection of Soft Tissue Sarcomas

Wound complications represent a major source of morbidity in patients undergoing radiation therapy (RT) and surgical resection of soft tissue sarcomas (STS). We investigated whether factors related to RT, surgery, patient comorbidities, and tumor histopathology predict the development of wound complications. An observational study of patients who underwent STS resection and RT was performed. The primary outcome was the occurrence of any wound complication up to four months postoperatively. Significant predictors of wound complications were identified using multivariable logistic regression. Sixty-five patients representing 67 cases of STS were identified. Median age was 59 years (range 22–90) and 34 (52%) patients were female. The rates of major wound complications and any wound complications were 21% and 33%, respectively. After adjusting for radiation timing, diabetes (OR 9.6; 95% CI 1.4–64.8; P = 0.02), grade ≥2 radiation dermatitis (OR 4.8; 95% CI 1.2–19.2; P = 0.03), and the use of 3D conformal RT (OR 4.6; 95% CI 1.1–20.0; P = 0.04) were associated with an increased risk of any wound complication on multivariable analysis. These data suggest that radiation dermatitis and radiation modality are predictors of wound complications in patients with STS.

Definitive local therapy is associated with improved overall survival in metastatic cervical cancer

PURPOSE Definitive local therapy is often used in metastatic cervical cancer to reduce morbidity associated with local tumor progression. However, the potential benefit of this therapeutic approach has not been rigorously investigated. We hypothesized that definitive local therapy is associated with improved overall survival (OS) in metastatic cervical cancer. METHODS AND MATERIALS Patients aged ≥18 years with newly diagnosed metastatic cervical cancer who were treated with chemotherapy were identified from the National Cancer Database. Patients were dichotomized into the following cohorts: definitive local therapy (defined as either concurrent chemoradiation therapy or definitive surgery) or conservative therapy (defined as systemic therapy with or without palliative radiation therapy). The association between definitive local therapy and OS was assessed using propensity score-weighted Cox proportional hazards models. Potential unmeasured confounding was assessed through sensitivity analyses. Factors associated with the receipt of definitive local therapy were identified with multivariable logistic regression. RESULTS A total of 2838 patients were identified, of whom 1194 (42%) and 1644 (58%) were treated with definitive local and conservative therapy, respectively. Receipt of definitive local therapy was statistically significant, associated with less comorbidity, lower clinical T stage, and node negative disease. Compared with conservative therapy, definitive local therapy was associated with improved OS (hazard ratio: 0.57; 95% confidence interval, 0.52-0.62; P ≤ .001). The median OS rate was 19.2 months in the definitive local therapy cohort and 10.1 months in the conservative therapy cohort. These findings were robust to potential unmeasured confounding in sensitivity analyses and on landmark analyses of patients who survived at least 12 months (hazard ratio: 0.71; 95% confidence interval, 0.62-0.82; P ≤ .001). CONCLUSIONS Definitive local therapy is associated with improved OS in patients with metastatic cervical cancer. These findings suggest a novel setting for the use of definitive local therapy in the metastatic setting.