Samuel Marcrom

Poly(ADP-ribose) polymerase activity and inhibition in cancer.

Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination. Five PARP inhibitors are now in late-stage development in clinical trials that are seeking to expand the understanding of targeted therapies and DNA repair defects in human cancer. This review examines the cell biology of PARP, the discovery of synthetic lethality with HR deficiency, the clinical development of PARP inhibitors, and the role of PARP inhibitors in ongoing clinical trials and clinical practice.

Fractionated stereotactic radiation therapy for intact brain metastases

Purpose Limited data exist on fractionated stereotactic radiation therapy (FSRT) for brain metastases. We sought to evaluate the safety and efficacy of FSRT and further define its role in brain metastasis management. Methods and materials A total of 72 patients were treated with linear accelerator–based FSRT to 182 previously untreated, intact brain metastases. Targets received 25 or 30 Gy in 5 fractions. All targets within the same course received the same prescription regardless of size. Toxicity was recorded per Radiation Therapy Oncology Group central nervous system toxicity criteria. Results The median follow-up was 5 months (range, 1-71 months). The Kaplan-Meier estimate of 12-month local control was 86%. Tumors <3 cm in diameter demonstrated improved 12-month local control of 95% compared with 61% in tumors ≥3 cm (P < .001). The Kaplan-Meier estimate of 12-month local control was 91% in tumors treated with 30 Gy and only 75% in tumors treated with 25 Gy (P = .015). Tumor diameter ≥3 cm resulted in increased local failure, and a 30 Gy prescription resulted in decreased local failure on multivariate analysis (hazard ratio [HR], 8.11 [range, 2.09-31.50; P = .003] and HR, 0.26 [range, 0.07-0.93; P = .038]). Grade 4 central nervous system toxicity occurred in 4 patients (6%) requiring surgery, and no patient experienced irreversible grade 3 or 5 toxicity. Increasing tumor diameter was associated with increased toxicity risk (HR, 2.45 [range, 1.04-5.742; P = .04]). Conclusions FSRT for brain metastases appears to demonstrate a high rate of local control with minimal risk of severe toxicity. Local control appears to be associated with smaller tumor sizeand a higher prescription dose. FSRT is a viable option for those who are poor single-fraction candidates.

Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy

BackgroundClear cell sarcoma (CCS) is a rare, aggressive soft tissue sarcoma thought to derive from neural crest and characterized by a 12;22 translocation. The resulting fusion protein directly activates expression of the melanocyte master transcription factor and drives the same down-stream pathways in CCS and melanoma leading to significant clinical parallels between these malignancies. Striking success of immune checkpoint blockade in melanoma has promoted interest in immunotherapy of CCS.Case presentationWe report the first complete clinical response of a bulky chest wall recurrence of mediastinal CCS in a young woman to anti-PD1 checkpoint blockade with pembrolizumab combined with standard fractionation radiotherapy to enhance regional control and potentially boost the systemic immune response. The treatment was well tolerated with grade 2 skin toxicity within the range expected with radiation alone. Significant reduction in tumor bulk occurred after only 2 radiation fractions and complete response was achieved at 50 Gray.ConclusionThe complete clinical response observed in our patient suggests synergy between concurrent radiotherapy and PD1 blockade in CCS. This case and the striking parallels between CCS and melanoma indicate the need for prospective trials of immune checkpoint blockade combined with radiotherapy in this rare malignancy.

Generation of a New Disease-specific Prognostic Score for Patients With Brain Metastases From Small-cell Lung Cancer Treated With Whole Brain Radiotherapy (BMS-Score) and Validation of Two Other Indices

&NA; The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT (BMS‐score). The new BMS score was more prognostic than the RPA and ds‐GPA score. BMS score and RPA showed the most significant differences between classes. Introduction: Patients with small‐cell lung cancer (SCLC) demonstrate an exception in the treatment of brain metastases (BM), because in patients with SCLC whole brain radiotherapy (WBRT) only is the preferred treatment modality. The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT. Patients and Methods: The present study was conducted utilizing a single‐institution, previously described, retrospective database of patients with SCLC who were treated with WBRT (n = 221). Univariate and multivariate analyses were performed to generate the “brain metastases from SCLC score” (BMS score) based on favorable prognostic factors: Karnofsky performance status (KPS > 70), extracerebral disease status (stable disease/controlled), and time of appearance of BM (synchronous). Furthermore, the disease‐specific graded prognostic assessment score as well as the recursive partitioning analysis (RPA) were performed and compared with the new BMS score by using the log‐rank (Mantel‐Cox) test. Results: BMS score and RPA showed the most significant differences between classes (P < .001). BMS score revealed a mean overall survival (OS) of 2.62 months in group I (0‐1 points), 6.61 months in group II (2‐3 points), and 12.31 months in group III (4 points). The BMS score also identified the group with the shortest survival (2.62 months in group I), and the numbers of patients in each group were most equally distributed with the BMS score. Conclusion: The new BMS score was more prognostic than the RPA and disease‐specific graded prognostic assessment scores. The BMS score is easy to use and reflects known prognostic factors in contemporary patients with SCLC treated with WBRT. Future studies are necessary to validate these findings.

Accessibility, availability, and quality of online information for US radiation oncology residencies

PURPOSE Radiation oncology (RO) residency applicants commonly use Internet resources for information on residency programs. The purpose of this study is to assess the accessibility, availability, and quality of online information for RO graduate medical education. METHODS AND MATERIALS Accessibility of online information was determined by surveying databases for RO residency programs within the Fellowship Residency Electronic Interactive Data Access System (FREIDA) of the American Medical Association, the Accreditation Council for Graduate Medical Education (ACGME), and Google search. As of June 30, 2015, websites were assessed for presence, accessibility, and overall content availability based on a 55-item list of desired features based on 13 program features important to previously surveyed applicants. Quality scoring of available content was performed based on previously published Likert scale variables deemed desirable to RO applicants. Quality score labels were given based on percentage of desired information presented. RESULTS FREIDA and ACGME databases listed 89% and 98% of program websites, respectively, but only 56% and 52% of links routed to a RO department-specific website, respectively. Google search obtained websites for 98% of programs and 95% of links routed to RO department-specific websites. The majority of websites had program descriptions (98%) and information on staff. However, resident information was more limited (total number [42%], education [47%], previous residents [28%], positions available [35%], contact information [13%]). Based on quality scoring, program websites contained only 47% of desired information on average. Only 13% of programs had superior websites containing 80% or more of desired information. CONCLUSIONS Compared with Google, the FREIDA and ACGME program databases provide limited access to RO residency websites. The overall information availability and quality of information within RO residency websites varies widely. Applicants and programs may benefit from improved content accessibility and quality from US RO program websites in the residency application process.

Focal Management of Large Brain Metastases and Risk of Leptomeningeal Disease

Purpose: Surgery is often used for large or symptomatic brain metastases but is associated with risk of developing leptomeningeal dissemination. Emerging data suggest that fractionated stereotactic radiation therapy (FSRT) is an effective management strategy in large brain metastases. We sought to retrospectively compare leptomeningeal disease (LMD) and local control (LC) rates for patients treated with surgical resection followed by radiosurgery (S þ SRS) versus FSRT alone. Methods and Materials: We identified all patients with a brain metastasis 3 cm in diameter treated from 2004 to 2017 with S þ SRS or FSRT alone (25 or 30 Gy in 5 fractions) who had follow-up imaging. LMD was defined as focal or diffuse leptomeningeal enhancement that was >5 mm from the index metastasis. Categorical baseline characteristics were compared with the c test. LMD and LC rates were evaluated by the Kaplan-Meier (KM) method, with the log-rank test used to compare subgroups. Results: A total of 125 patients were identified, including 82 and 43 in the S þ SRS and FSRT alone groups, respectively. Median pretreatment Graded Prognostic Assessment in the Sþ SRS and FSRT groups was 2.5 and 1.5, respectively (P< .001). Median follow-up was 7 months. The KM estimate of 12-month LMD rate in the Sþ SRS and FSRT groups was 45% and 19%, respectively (PZ .048). The KM estimate of 12-month local control in the Sþ SRS and FSRT groups was 70% and 69%, respectively (PZ .753). The 12-month KM estimate of grade 3 toxicity was 1.4% in S þ SRS group versus 6.3% in the FSRT alone group (P Z .248). After adjusting for graded prognostic assessment (GPA), no overall survival difference was observed between groups (PZ .257). Conclusions: Surgery is appropriate for certain brain metastases, but S þ SRS may increase LMD risk compared with FSRT alone. Because S þ SRS and FSRT seem to have similar LC, FSRT may be a viable alternative to S þ SRS in select patients with large brain metastases. Sources of support: This research did not receive any funding from agencies in the public, commercial, or not-for-profit sectors. Disclosures: J.B.F., R.A.P., and C.D.W. have unrelated contracts, personal fees, and grants with Varian Medical Systems. J.M.M. has disclosures unrelated to this project. The authors report no specific conflicts of interest concerning the findings specified in this article. * Corresponding author: Samuel R. Marcrom, MD; E-mail: smarcrom@uabmc.edu https://doi.org/10.1016/j.adro.2019.07.016 2452-1094/ 2019 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Advances in Radiation Oncology: JanuaryeFebruary 2020 Focal Brain Metastasis Management and LMD Risk 35 2019 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).