Citations

Abstract Background: BRAF and MEK inhibitors are currently FDA approved for melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600+ colorectal cancer (CRC) has prevented its tissue-agnostic drug development. However, updated results from Vemurafenib-Basket study (Cancer Discov. 2020 May;10(5):657-663 ) and the NCI-match trial ( J Clin Oncol. 2020 Nov 20;38(33):3895-3904) reveal that BRAF pathway inhibition is active in > 20 unique cancer types. Objective: We aimed to describe the characteristics of BRAF V600 and study real-world outcomes using a clinico-genomic analysis using the AACR Genie database and the current medical literature. Methods: We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We conducted a literature search (using PubMed from 2012-2019) for case reports of clinical response and outcomes in patients with BRAF V600 mutation-positive non-melanoma cancers who received BRAF inhibitor therapy. Results: Among 96,324 samples, BRAF V600 mutations were seen in 43 different tumor types across 2,963 samples (3.07 %) in the AACR GENIE database. BRAF V600 was most commonly present in thyroid cancer (40.9%), parathyroid cancer (31.8%), melanoma (26.1%), histiocytosis (25.7%), and head and neck NOS (14.3%). Literature review revealed total of 178 cases across 69 tumor types. The most common cases included Erdheim-Chester disease (n = 30, 16.9%), papillary thyroid carcinoma (n=16, 8.9%), anaplastic thyroid carcinoma (n = 13, 7.3%), and hairy cell leukemia (n = 13, 7.3%). Furthermore, dabrafenib (BRAF), dabrafenib/trametinib (BRAF+MEK), trametinib(MEK), vemurafenib (BRAF), vemurafenib/trametinib (BRAF+MEK), vemurafenib/cobimetinib (BRAF+MEK) were used in 34% (n =56), 16% (n = 27), 4% (n = 6), 44% (n = 72), 1% (n = 1), 2% (n =3), respectively. Overall, median PFS was 6.5 months, and median OS was 28.5 months with a median duration of response (DOR) of 8 months. Conclusion: BRAF V600 mutations are prevalent across multiple non-melanoma cancers, lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers. Continued drug development is warranted beyond the current BRAF+/- MEK approved cancers. Citation Format: Jacob J. Adashek, Aakash P. Desai, Arjun K. Menta, Jason Roszik, Vivek Subbiah. Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1479.

Abstract Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown. Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC. Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics. Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1221.

Abstract Transfemoral access has long been the main access site for cerebral angiography and neurointerventional procedures. Radial access is accepted as an alternative to the traditional transfemoral approach. Ulnar access may be undertaken if the radial artery is occluded or small caliber, or when radial artery preservation is needed. The safety and feasibility of ulnar access for neuroangiographic procedures has been demonstrated. 1-3 In this operative video, we demonstrate ulnar artery access in a patient in whom radial artery preservation was desired. We further elaborate on the technical nuances of this access. This nontraditional access site offers the same advantages as radial access, avoiding the need to switch to femoral artery access. A preoperative Allen's test is not necessary. Ultrasound imaging is used to aid in the identification and successful puncture of the ulnar artery. A medial to lateral approach for ulnar artery puncture is advised to avoid injury to the ulnar nerve. Careful application of wrist closure bands avoids hematoma accumulation. The patient gave informed consent for the procedure and video recording. Institutional review board approval was deemed unnecessary. Video. © University at Buffalo, May 2021. Used with permission.

AbstractBackgroundAdult medulloblastoma (MB) is rare, and management guidelines are largely based on pediatric clinical trials and retrospective series. Limited data exist with respect to clinical characteristics, prognostic factors, and outcomes based on first-line treatments.MethodsTwo hundred adults with MB seen at a single institution from January 1978 to April 2017 were identified and followed for a median of 8.4 y (7.1, 10.3).ResultsPatient’s median age at diagnosis was 29 y (18, 63). One hundred eleven (55.5%) were standard-risk, 59 (29.5%) were high-risk, and 30 (15.0%) were indeterminate. Most received post-operative radiation (RT) (184 [92.0%]), and 105 (52.5%) received first-line chemotherapy. Median overall survival (OS) was 8.8 y (7.2, 12.2) and median progression-free survival (PFS) was 6.6 y (4.9, 11.2). High-risk patients had inferior OS (Hazard ratio [HR] = 2.5 [1.5, 4.2], P = .0006) and PFS (HR = 2.3 [1.3, 3.9], P = .002) compared to standard-risk patients. Age, sex, and metastatic disease were not associated with survival. After adjusting for risk status, those who received RT plus adjuvant chemotherapy had superior PFS compared to RT plus neoadjuvant chemotherapy [HR = 0.46 (0.22, 0.95), P = .0357]. Within a subgroup for whom detailed clinical data were available, those who received RT plus adjuvant chemotherapy had improved PFS compared to RT only [HR = 0.24 (0.074–0.76), P = .016]. The substitution of cisplatin for carboplatin and the elimination of vincristine did not negatively affect outcomes.ConclusionThis is the largest single-institution retrospective study of adult MB to our knowledge and identifies standard-risk status, first-line RT and adjuvant chemotherapy as factors associated with improved outcomes.

AbstractBackgroundPneumocystis jirovecii pneumonia (PJP) is a life‐threatening infection occurring in patients receiving bendamustine. The poorly defined incidence, particularly when utilizing polymerase chain reaction (PCR)‐based diagnostic techniques, precipitates unclear prophylaxis recommendations. Our objective was to determine the cumulative incidence of PJP diagnosed by single copy target, non‐nested PCR in patients receiving bendamustine.MethodsPatients were evaluated for PJP from initiation of bendamustine through 9 months after the last administration. The cumulative incidence of PJP was estimated using the Aalen–Johansen method. Cox proportional hazard models were used to demonstrate the strength of association between the independent variables and PJP risk.ResultsThis single‐center, retrospective cohort included 486 adult patients receiving bendamustine from 1 January 2006 through 1 August 2019. Most patients received bendamustine‐based combination therapy (n = 461, 94.9%), and 225 (46.3%) patients completed six cycles. Rituximab was the most common concurrent agent (n = 431, 88.7%). The cumulative incidence of PJP was 1.7% (95% CI 0.8%–3.3%, at maximum follow‐up of 2.5 years), after the start of bendamustine (n = 8 PJP events overall). Prior stem cell transplant, prior chemotherapy within 1 year of bendamustine, and lack of concurrent chemotherapy were associated with the development of PJP in univariate analyses. Anti‐Pneumocystis prophylaxis was not significantly associated with a reduction in PJP compared to no prophylaxis (HR 0.37, 95% CI (0.05, 3.04), p = 0.36).ConclusionsOur incidence of PJP below 3.5%, the conventional threshold for prophylaxis implementation, indicates routine anti‐Pneumocystis prophylaxis may not be necessary in this population. Factors indicating a high‐risk population for targeted prophylaxis require further investigation.

Background: Perfusion weighted imaging on MRI (MRP) and computerized tomography perfusion (CTP) are increasingly required to manage large vessel disease. Computerized algorithms can quantify perfusion data, but the programs are expensive and not widely used outside acute stroke evaluation. We aimed to determine how well human observers can identify asymmetries in cerebral perfusion images compared with an automated computer algorithm. Methods: Ten clinicians experienced in treating carotid artery disease (4 vascular neurologists, 3 neuroradiologists, 1 vascular surgeon, 1 neurosurgeon, 1 interventional radiologist) were given 28 post-processed, color-coded, axial-slice MRP scans from patients in the Carotid Revascularization Endovascular versus Stenting Trial - Hemodynamics (CREST-H) study. All patients had >70%, unilateral, asymptomatic carotid artery stenosis and had varying degrees of time-to-peak (TTP) delay on the side of stenosis, ranging from 0 to 2 secs, quantified by a semi-automated system that computes quantitative perfusion maps, using deconvolution of tissue and arterial signals (Olea, Cambridge, MA). A minimum volume of 10cc was required for a given TTP delay. Clinicians were asked to determine asymmetry (y/n) and side of occlusion for each case. Number of correct responses that matched the computer output were tallied. Results: We averaged correct responses by the 10 clinicians for cases at each increment of TTP delay; (Figure). At TTP delays ≥1.5 seconds, accuracy was ≥80%. At 1.25 sec accuracy fell to 60%, and at ≤ 1 sec, accuracy was ≤50%. For TTP=0 (no asymmetry), accuracy was 71%. Conclusions: Visual impression of hemodynamic asymmetry among experienced clinicians was reasonably accurate for TTP delays ≥1.5 seconds, but declined with more subtle asymmetries. Depending on the clinical impact of TTP delays (for CREST-H: correlation with cognitive decline), experienced clinicians may perform as well as an automated algorithm.

Background: Real world studies of silent brain infarction (SBI) and white matter disease (WMD) are impeded by challenges in cohort identification. Natural language processing (NLP) from imaging reports may facilitate future studies. However, electronic health records can be heterogeneous and the process of interpreting neuroimages and generating reports can vary. Understanding knowledge representation and relationships between neuroimages and imaging reports is crucial for using NLP to facilitate disease management and cohort identification. Methods: A balanced sample of head neuroimages (CT, MRI) of patients >50 years without clinical histories of symptomatic stroke, TIA, or dementia were obtained at Mayo Clinic and Tufts Medical Center. A team of 4 radiology residents performed report interpretation (RI) on 1000 reports according to a standardized protocol for the presence of SBIs, the presence of WMD, and WMD grade. A random subsample of 400 was doubly read for interrater reliability. For benchmarking, a team of 4 neuroradiologists directly reviewed and described findings on a subsample of 182 images, each doubly read. We assessed interrater reliability for direct review (DR) and RI, and agreement between these 2 information sources. An NLP algorithm was developed to review and extract findings from 1000 imaging reports. Results: For DR, interrater reliability was moderate for SBIs and WMD (k = 0.53, 95% CI 0.43-0.64 and k = 0.47, 95% CI 0.33-0.61) and good for WMD grade (Spearman 0.71, p<0.001). For RI, interrater reliability for SBIs, WMD and WMD grade was good (k = 0.88, 95% CI 0.80-0.97; k = 0.98, 95% CI 0.97-1.00; and Spearman = 0.985, p<0.001, respectively). Agreement between DR and RI was good for SBIs (k = 0.77, 95% CI 0.67-0.86) and WMD (k = 0.65, 95% CI 0.54-0.77). Spearman rank correlations comparing WMD grade interpretation DR to RI was 0.60 (p<0.001). In identifying the presence of SBIs and WMDs, the accuracy of the NLP algorithm was 0.991 and 0.994, respectively. Conclusion: For the presence of SBI and WMD, and WMD grade, agreement between RI and DR was similar to agreement between 2 neuroradiologists directly reviewing neuroimages. It is highly feasible to use NLP to identify patients with SBIs and WMDs for clinical studies.

Background and Purpose: Given the benign natural history of intracranial low-grade dural arteriovenous fistulas (dAVFs), their routine treatment remains controversial. The aim of this study is to compare the outcomes of low-grade dAVF treatment to conservative management. Methods: We performed a retrospective review of dAVF patients derived from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with low-grade (Borden I) dAVFs were included and categorized into treatment and observation cohorts. Primary outcome was defined as modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were rates of excellent (mRS 0-1) and good (mRS 0-2) functional outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. Results: The treatment and observation cohorts comprised 230 and 112 patients, respectively. At last follow up, no difference in primary or secondary outcomes was observed between the two cohorts, with the exception of obliteration, which was higher in the treatment cohort (79.3% vs. 28.2%, p<0.001; Table 1). The two cohorts were then matched in a 1:1 ratio, resulting in 64 patients in each matched cohort. No difference in primary or secondary outcomes was observed between the matched cohorts, with the exception of obliteration, which was higher in the matched treatment cohort (75.4% vs. 28.6%, p<0.001; Table 2). Subgroup analysis of symptomatic patients demonstrated higher obliteration rate in the treatment cohort, but no difference in primary or other secondary outcomes were found. Conclusions: Low-grade dAVF treatment was not associated with increased functional disability compared to conservative management. Although higher obliteration rates were achieved in the treatment cohort, rates of symptomatic improvement were similar between the two cohorts. This study did not provide evidence to support the routine treatment of low-grade dAVFs.

Objective The objective of this study was to introduce musculoskeletal physical examination skills in the gross anatomy course as a teaching tool and to evaluate medical students’ perceptions of this experience. Methods A list of 27 clinical examinations of the upper and lower limbs was generated from published core recommendations for undergraduate medical education. During gross anatomy laboratory sessions, teaching assistants (third year medical students) presented one or two of the clinical skills related to that day’s dissection to groups of 3–4 students at a time. The anatomic relationships tested by the clinical examinations were highlighted. One question on the laboratory examination at the end of the unit was an Objective Structured Clinical Examination (OSCE) station where students were given a clinical scenario and asked to demonstrate a physical examination that they would use in evaluating the patient. Following the upper and lower limb units, the students were given a Likert‐scale survey to evaluate their perceptions of the experience. Results Survey responses indicated that most students felt the physical examination demonstrations improved their understanding of the clinical significance of the related anatomy, increased their interest in and motivation to learn the material, and made the laboratory experience more enjoyable. Conclusions Introducing musculoskeletal physical examination skills in the gross anatomy course can be an effective way to emphasize the clinical significance of the anatomy, thereby enhancing students’ motivation to learn the material.