Exploring Novel Therapeutic Avenues for Chemotherapy-Related Cognitive Impairment.

Many patients with cancer are at risk of developing cognitive symptoms that often become evident during or after cancer-directed therapy and may have difficulties with attention, concentration, multitasking, executive function, and memory. Despite recent advances in identifying potential molecular and cellular mechanisms underlying cancer and chemotherapy-related cognitive impairment, there is generally a lack of effective treatment strategies, and the development of novel therapeutic interventions represents a major unmet medical need in clinical practice. A recent study by Kim and colleagues suggests that multisensory 40-Hz gamma entrainment using sensory stimuli with combined visual and auditory stimuli is associated with powerful neuroprotective effects in mouse models of cisplatin- or methotrexate-induced "chemobrain." Although the study has some limitations and successful interventions in animal models have often failed to translate into clinical practice, this noninvasive treatment modality has shown promise in preserving brain structure and function and could be tested in patients with cancer who are at risk of cognitive decline.

Same day discharge colon surgery: is it financially worth it?

AIM: Same day discharge (SDD) for colorectal surgery shows increasing promise in the era of enhanced recovery after surgery protocols and minimally invasive surgery. It has become increasingly relevant due to the constraints posed by the COVID-19 pandemic. The aim of this study was to compare SDD and postoperative day 1 (POD1) discharge to understand the clinical outcomes and financial impact on factors such as cost, charge, revenue, contribution margin and readmission. METHOD: A retrospective review of colectomies was performed at a single institution over a 2-year period (n = 143). Two populations were identified: SDD (n = 51) and POD1 (n = 92). Patients were selected by International Statistical Classification of Diseases and Related Health Problems-10 (ICD-10) and Diagnosis Related Grouper (DRG) codes. RESULTS: There was a statistically significant difference favouring SDD in total hospital cost (p < 0.0001), average direct costs (p < 0.0001) and average charges (p < 0.0016). SDD average hospital costs were $8699 (values in USD throughout) compared with $11 652 for POD 1 (p < 0.0001), and average SDD hospital charges were $85 506 compared with $97 008 for POD1 (p < 0.0016). The net revenue for SDD was $22 319 while for POD1 it was $26 173 (p = 0.14). Upon comparison of contribution margins (SDD $13 620 vs. POD1 $14 522), the difference was not statistically significant (p = 0.73). There were no identified statistically significant differences in operating room time, robotic console time, readmission rates or surgical complications. CONCLUSIONS: Amidst the pandemic-related constraints, we found that SDD was associated with lower hospital costs and comparable contribution margins compared with POD1. Additionally, the study was unable to identify any significant difference between operating time, readmissions, and surgical complications when performing SDD.

Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.

BACKGROUND: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. METHODS: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. RESULTS: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. CONCLUSIONS: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.

Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2.

BACKGROUND: BRCA1/2 testing is crucial to guide clinical decisions in patients with hereditary breast/ovarian cancer, but detection of variants of uncertain significance (VUSs) prevents proper management of carriers. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) BRCA1/2 Variant Curation Expert Panel (VCEP) has recently developed BRCA1/2 variant classification guidelines consistent with ClinGen processes, specified against the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular-Pathology) classification framework. METHODS: The ClinGen-approved BRCA1/2-specified ACMG/AMP classification guidelines were applied to BRCA1/2 VUSs identified from 2011 to 2022 in a series of patients, retrieving information from the VCEP documentation, public databases, literature and ENIGMA unpublished data. Then, we critically re-evaluated carrier families based on new results and checked consistency of updated classification with main sources for clinical interpretation of BRCA1/2 variants. RESULTS: Among 166 VUSs detected in 231 index cases, 135 (81.3%) found in 197 index cases were classified by applying BRCA1/2-specified ACMG/AMP criteria: 128 (94.8%) as Benign/Likely Benign and 7 (5.2%) as Pathogenic/Likely Pathogenic. The average time from the first report as 'VUS' to classification using this approach was 49.4 months. Considering that 15 of these variants found in 64 families had already been internally reclassified prior to this work, this study provided 121 new reclassifications among the 151 (80.1%) remaining VUSs, relevant to 133/167 (79.6%) families. CONCLUSIONS: These results demonstrated the effectiveness of new BRCA1/2 ACMG/AMP classification guidelines for VUS classification within a clinical cohort, and their important clinical impact. Furthermore, they suggested a cadence of no more than 3 years for regular review of VUSs, which however requires time, expertise and resources.

Differential DNA damage repair and PARP inhibitor vulnerability of the mammary epithelial lineages.

It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial cell lineage identity. Bioinformatics, post-irradiation DNA damage repair kinetics, and clonogenic assays demonstrated luminal lineage exhibiting a more pronounced DDR and HR repair compared to the basal lineage. Consequently, basal progenitors were far more sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis) in both mouse and human mammary epithelium. Furthermore, PARPi sensitivity of murine and human breast cancer cell lines as well as patient-derived xenografts correlated with their molecular resemblance to the mammary progenitor lineages. Thus, mammary epithelial cells are intrinsically divergent in their DNA damage repair capacity and PARPi vulnerability, potentially influencing the clinical utility of this targeted therapy.

The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study.

BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Mitigating Radiotoxicity in the Central Nervous System: Role of Proton Therapy.

OPINION STATEMENT: Central nervous system (CNS) radiotoxicity remains a challenge in neuro-oncology. Dose distribution advantages of protons over photons have prompted increased use of brain-directed proton therapy. While well-recognized among pediatric populations, the benefit of proton therapy among adults with CNS malignancies remains controversial. We herein discuss the role of protons in mitigating late CNS radiotoxicities in adult patients. Despite limited clinical trials, evidence suggests toxicity profile advantages of protons over conventional radiotherapy, including retention of neurocognitive function and brain volume. Modelling studies predict superior dose conformality of protons versus state-of-the-art photon techniques reduces late radiogenic vasculopathies, endocrinopathies, and malignancies. Conversely, potentially higher brain tissue necrosis rates following proton therapy highlight a need to resolve uncertainties surrounding the impact of variable biological effectiveness of protons on dose distribution. Clinical trials comparing best photon and particle-based therapy are underway to establish whether protons substantially improve long-term treatment-related outcomes in adults with CNS malignancies.

PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants.

We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.

Sources of geogenic arsenic in well water associated with granitic bedrock from Nova Scotia, Canada.

Arsenic toxicity in drinking water is a global issue, with chronic exposure causing cancer and other health concerns. Groundwater from geochemically similar granites from mainland Nova Scotia, Canada, can have high and low levels of arsenic. The origin of this variation is uncertain, but different mineral hosts for arsenic could explain the disparity. The lability of arsenic from different minerals was assessed using laser ablation inductively coupled plasma mass spectrometry combined with calculations based upon well water data. Pyrite has the highest arsenic concentration (mean: 2300 µg/g, n = 9), is unstable in the groundwater system, and can release arsenic during oxidation. However, oxidation products replacing pyrite can adsorb arsenic, modifying the amount released. Cordierite has low arsenic concentrations (mean: 7.3 µg/g, n = 5) but is abundant and relatively soluble. Thus, cordierite could be a previously unrecognized source of arsenic in metapelitic rocks from metamorphic terranes. Pyrite from one of the granites studied was not oxidized, which in addition to the absence of cordierite in these same granites could account for the lower arsenic levels observed in associated well water. The results of this study can be used to identify potential geogenic sources of arsenic in other granitic terranes and reduce the risk of exposure through drinking water.

Pectin based biologic Velcro effectively seals traumatic solid organ and small bowel injuries.

INTRODUCTION: Injuries to the liver and small bowel are common in multiple injuries. While there are currently a variety of accepted damage-control techniques to expeditiously manage such injuries, morbidity and mortality remain high. Pectin polymers have previously been shown to effectively seal visceral organ injuries ex vivo through physiochemical entanglement with the glycocalyx. We sought to compare the standard of care for the management of penetrating liver and small bowel injuries with a pectin-based bioadhesive patch in a live animal model. METHODS: Fifteen adult male swine underwent a laparotomy with standardized laceration to the liver. Animals were randomized to one of three treatment arms: packing with laparotomy pads (n = 5), suture repair (n = 5), or pectin patch repair (n = 5). Following 2 hours of observation, fluid was evacuated from the abdominal cavity and weighed. Next, a full-thickness small bowel injury was created, and animals were randomized to either a sutured repair (n = 7) or pectin patch repair (n = 8). The segment of bowel was then pressurized with saline, and the burst pressure was recorded. RESULTS: All animals survived the protocol to completion. There were no clinically significant differences between groups regarding baseline vitals or laboratory studies. On one-way analysis of variance, there was a statistically significant difference between groups regarding blood loss after liver repair (26 mL suture vs. 33 mL pectin vs. 142 mL packing, p < 0.01). On post hoc analysis, there was no statistically significant difference between suture and pectin ( p = 0.9). After repair, small bowel burst pressures were similar between pectin and suture repair (234 vs. 224 mm Hg, p = 0.7). CONCLUSION: Pectin-based bioadhesive patches performed similarly to the standard of care for the management of liver lacerations and full-thickness bowel injuries. Further testing is warranted to assess the biodurability of a pectin patch repair, as it may offer a simple option to effectively temporize traumatic intra-abdominal injuries.

Bioadhesive patch as a parenchymal sparing treatment of acute traumatic pulmonary air leaks.

INTRODUCTION: Traumatic pulmonary injuries are common in chest trauma. Persistent air leaks occur in up to 46% of patients depending on injury severity. Prolonged leaks are associated with increased morbidity and cost. Prior work from our first-generation pectin patches successfully sealed pulmonary leaks in a cadaveric swine model. We now test the next-generation pectin patch against wedge resection in the management of air leaks in anesthetized swine. METHODS: A continuous air leak of 10% to 20% percent was created to the anterior surface of the lung in intubated and sedated swine. Animals were treated with a two-ply pectin patch or stapled wedge resection (SW). Tidal volumes (TVs) were recorded preinjury and postinjury. Following repair, TVs were recorded, a chest tube was placed, and animals were observed for presence air leak at closure and for an additional 90 minutes while on positive pressure ventilation. Mann-Whitney U test and Fisher's exact test used to compare continuous and categorical data between groups. RESULTS: Thirty-one animals underwent either SW (15) or pectin patch repair (PPR, 16). Baseline characteristics were similar between animals excepting baseline TV (SW, 10.3 mL/kg vs. PPR, 10.9 mL/kg; p = 0.03). There was no difference between groups for severity of injury based on percent of TV loss (SW, 15% vs. PPR, 14%; p = 0.5). There was no difference in TV between groups following repair (SW, 10.2 mL/kg vs. PPR, 10.2 mL/kg; p = 1) or at the end of observation (SW, 9.8 mL/kg vs. PPR, 10.2 mL/kg; p = 0.4). One-chamber intermittent air leaks were observed in three of the PPR animals, versus one in the SW group ( p = 0.6). CONCLUSION: Pectin patches effectively sealed the lung following injury and were noninferior when compared with wedge resection for the management of acute traumatic air leaks. Pectin patches may offer a parenchymal sparing option for managing such injuries, although studies evaluating biodurability are needed.

Cognitive issues in patients with IDH mutant gliomas: from neuroscience to clinical neuropsychology.

PURPOSE: The understanding of cognitive symptoms in patients with IDH-Mutant gliomas (IDH-Mut) is rapidly developing. In this article, we summarize the neuroscientific knowledge base regarding the influence of IDH-Mut tumors and their treatment on cognition and provide guidance regarding the management of these symptoms in patients. METHODS: We performed a review of peer reviewed publications relevant to IDH-Mut glioma and cognitive outcomes and provide an overview of the literature as well as a case example to clarify management strategies. RESULTS: At the time of presentation, patients with IDH-Mut gliomas have a favorable cognitive profile as compared with those with IDH-wild type (WT) tumors. The relatively low cognitive burden may reflect the slower growth rate of IDH-Mut tumors, which is less disruptive to both local and widespread neural networks. Human connectomic research using a variety of modalities has demonstrated relatively preserved network efficiency in patients with IDH-Mut gliomas as compared with IDH-WT tumors. Risk of cognitive decline from surgery can potentially be mitigated by careful integration of intra-operative mapping. Longer term cognitive risks of tumor treatment, including chemotherapy and radiation, are best managed by instituting neuropsychological assessment as part of the long-term care of patients with IDH-Mutant glioma. A specific timeline for such integrative care is provided. CONCLUSIONS: Given the relative recency of the IDH-mutation based classification of gliomas, as well as the long time course of this disease, a thoughtful and comprehensive strategy to studying patient outcomes and devising methods of cognitive risk reduction is required.

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2.

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Surgical Training for a Disaster: Preparation of Surgical Trainees for Victims of Conflict.

INTRODUCTION: With increasing global unrest and military physician shortages potentially leading to a surgeon draft, we sought to evaluate the readiness of graduating general surgery residents to care for casualties of war. MATERIALS AND METHODS: We evaluated the National Data Reports of Surgery Case Logs for general surgery residents from 2009 to 2018 to quantify experience with key procedures that provide critical skills required for wartime surgery. Reported cases from the Accreditation Council for Graduate Medical Education for graduating residents from civilian and military residency programs were analyzed for 28 individual procedures determined to be critical for the care of combat casualties. These included central and peripheral vascular procedures, as well as neck, thoracic, abdominal, and peripheral interventions. RESULTS: From 2009 to 2018, there has been a significant decrease in wartime-relevant cases by graduating residents. Notably, these include aorto-iliac/femoral bypasses (50% reduction; 7.1%/year; P < .001), femoral-popliteal bypasses (60% reduction; 6.9%/year; P < .001), femoral-femoral bypasses (30% reduction; 2.6%/year; P < .001), upper extremity amputations (50% reduction; 6.4%/year; P = .016), fasciotomies for trauma (50% reduction; 4.5%/year; P = .013), open repair of ruptured infrarenal aorto-iliac aneurysms (70% reduction; 5.8%/year; P < .001), repair of traumatic aorta or vena cava injuries (70% reduction; 7%/year; P = .007), carotid endarterectomies (40% reduction; 4%/year; P < .001), lung resections (40% reduction; 3.7%/year; P = .001), trauma splenectomies/splenorrhaphy (30% reduction; 2.9%/year; P < .001), and repair of traumatic liver lacerations (30% reduction; 2.5%/year; P = .036). CONCLUSIONS: Graduating general surgery residents has limited exposure to wartime critical skills due to a significant reduction in open vascular, head and neck, thoracic, and operative trauma cases. As the threat of global war persists and new graduates continue to deploy worldwide, residency training must be augmented to ensure adequate preparation in case a surgeon draft is required to fulfill demand for military surgeons.

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain.

BACKGROUND: Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease. AIMS: The primary objective of this trial is to assess the analgesic efficacy of subcutaneous tanezumab 10 mg in subjects with SWN who continue pre-existing pain therapy (excluding non-steroidal anti-inflammatory drugs). The secondary objective is to assess safety in this population. Exploratory objectives include assessment of pain features, quality of life, and predictive biomarkers. METHODS: The study is comprised of four periods (pre-treatment, double-blind treatment, single-arm treatment, safety follow-up) across 10 months with a delayed-start trial design to allow all participants to receive tanezumab. Forty-six participants will be enrolled and randomized 1:1 to receive either tanezumab or placebo subcutaneously in the double-blind treatment period; all participants receive tanezumab during the single-arm treatment period. CONCLUSIONS: This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases. CLINICAL TRIAL REGISTRATION: NCT04163419 on ClinicalTrials.gov.

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.

Brain metastases: A Society for Neuro-Oncology (SNO) consensus review on current management and future directions.

Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field.