Citations

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Background: Prepectoral implant-based breast reconstruction has gained popularity because of advantages over the subpectoral technique. Acellular dermal matrix use with implant-based breast reconstruction has become common because of its perceived superior aesthetic outcome. Matrices are expensive, however, and recent evidence has pointed to several potential complications. This article reports a series of prepectoral implant-based breast reconstructions with and without acellular dermal matrix and compared their outcomes. Methods: This is a single-surgeon retrospective review of patients who underwent staged prepectoral implant-based breast reconstruction following nipple-sparing mastectomy over two periods. Patients with well-perfused mastectomy skin flaps with a homogeneous thickness underwent reconstruction with acellular dermal matrix initially. On evolution of the practice, it was not used. Patient demographics, operative data, and complications were analyzed. Aesthetic outcome was measured by the BREAST-Q survey and the Aesthetic Item Scale. A cost analysis was also performed. Results: Forty patients were included (acellular dermal matrix group, n = 19; non–acellular dermal matrix group, n = 21). The nonmatrix group had one case (5 percent) of seroma and one case (5 percent) with hematoma; there were none in the acellular dermal matrix group. Average BREAST-Q and Aesthetic Item Scale scores were 82.3 versus 81.6 (p = 0.954) and 20.98 versus 20.43 (p = 0.640) for the matrix and nonmatrix groups, respectively. The direct cost savings for the authors’ institution over 1 year if matrix was not used in all cases of implant-based breast reconstruction would be estimated at $3,105,960 to $6,211,920 for unilateral and bilateral cases, respectively, for Medicare reimbursement. Conclusions: With adequate patient selection, acellular dermal matrix is not always required during two-stage prepectoral implant-based breast reconstruction for good aesthetic outcomes. The economic burden on patients and the health care system could be lessened with selective matrix use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Background: Intrathoracic fistulas pose unique challenges for thoracic and reconstructive surgeons. To decrease the incidence of fistula recurrence, pedicled flaps have been suggested to buttress the repair site. The authors aimed to report their experience with muscle flap transposition for the management of intrathoracic fistulas. Methods: A retrospective review of all patients who underwent intrathoracic muscle flap transposition for the management of intrathoracic fistulas from 1990 to 2010 was conducted. Patient demographics, surgical characteristics, and complication rates were abstracted and analyzed. Results: A total of 198 patients were identified. Bronchopleural fistula was present in 156 of the patients (79 percent), and 48 had esophageal fistula (24 percent). A total of 238 flaps were used, constituting an average of 1.2 flaps per patient. After the initial fistula repair, bronchopleural fistula complicated the course of 34 patients (17 percent), and esophageal fistula occurred in 13 patients (7 percent). Partial flap loss was identified in 11 flaps (6 percent), and total flap loss occurred in four flaps (2 percent). Median follow-up was 27 months. At the last follow-up, 182 of the patients (92 percent) had no evidence of fistula, 175 (89 percent) achieved successful chest closure, and 164 (83 percent) had successful treatment. Preoperative radiation therapy and American Society of Anesthesiologists score of 4 or greater were identified as risk factors for unsuccessful treatment. Conclusions: Intrathoracic fistulas remain a source of major morbidity and mortality. Reinforcement of the fistula closure with vascularized muscle flaps is a viable option for preventing dehiscence of the repair site and can be potentially life-saving. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Abstract Background The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. Methods Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial. Results At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). Conclusions The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

AbstractGlaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from animal models. To assess the structure–function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometre scale. In our datasets, retinal ganglion cell dendrites degenerate early in human glaucoma, with remodelling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure–function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma.

Study Design: Narrative review. Objective: This article seeks to provide a narrative review regarding the ability of opportunistic information available from computed tomography (CT) scans to guide decisions in spine surgery related to patient bone quality. Methods: A review of the literature (limited to human and English language) was performed via PubMed and Google Scholar using the search terms; “osteoporosis” AND “opportunistic” AND “computed tomography” AND “spine surgery.” The titles and then abstracts of all identified citations were reviewed for inclusion by 2 of the authors (MS, BAF). Relevant articles were then studied in full text. Results: A review of the literature found 25 articles that were selected for inclusion in this narrative review. These articles were broadly divided into 4 subcategories: (1) opportunistic CT (oCT) and osteoporosis detection, (2) oCT data and the quality of screw fixation, (3) utilization of Hounsfield units to assess clinical and/or radiographic outcomes following spine fusion, and (4) virtual stress testing in spine surgery. Conclusion: The literature on oCT, as well as associated virtual stress-testing techniques, demonstrate the potential to enhance spine surgery outcomes by preoperatively identifying at-risk patients in need of bone health optimization and informing best techniques for performing spinal fusion surgery on patients with diminished bone quality. While our narrative summary of the limited literature to date suggests a promising future for oCT data, significant additional research and/or radiographic workflow standardization is needed to validate these methods for clinical use.

We present a case report of a patient whose occipital neuralgia symptoms were substantially improved after a single acupuncture treatment with complete resolution after only a short course of care. The patient, a 78-year-old woman, presented to our institution’s neurology department with symptoms of posterior neck pain and electrical sensations in her head which had been present for more than 1 year. With a desire to avoid pharmacologic intervention or invasive procedures, the patient requested acupuncture treatment. The patient received 5 acupuncture treatments over the course of 8 days with substantial resolution of her head pain after a single treatment. This case is suggestive that acupuncture may be a beneficial treatment for patients with occipital neuralgia.