Cavernous venous malformations in and around the central nervous system. Part 1: Dural and extradural.

Cavernous-type malformations are venous lesions that occur in multiple locations throughout the body, and when present in the CNS, they have canonically been referred to as cavernomas, cavernous angiomas, and cerebral cavernous malformations. Herein all these lesions are referred to as "cavernous venous malformations" (CavVMs), which is congruent with the current International Society for the Study of Vascular Anomalies classification system. Even though histologically similar, depending on their location relative to the dura mater, these malformations can have different features. In Part 1 of this review, the authors discuss and review pertinent clinical knowledge with regard to CavVMs as influenced by anatomical location, starting with the dural and extradural malformations. They particularly emphasize dural CavVMs (including those in the cavernous sinus), orbital CavVMs, and spinal CavVMs. The genetic and histopathological features of CavVMs in these locations are reviewed, and commonalities in their presumed mechanisms of pathogenesis support the authors' conceptualization of a spectrum of a single disease entity. Illustrative cases for each subtype are presented, and the pathophysiological and genetic features linking dural and extradural to intradural CavVMs are examined. A new classification is proposed to segregate CavVMs based on the location from which they arise, which guides their natural history and treatment.

Neurological Surgery Residency Programs in the United States: A National Cross-Sectional Survey.

BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education has approved 117 neurological surgery residency programs which develop and educate neurosurgical trainees. We present the current landscape of neurosurgical training in the United States by examining multiple aspects of neurological surgery residencies in the 2022-2023 academic year and investigate the impact of program structure on resident academic productivity. METHODS: Demographic data were collected from publicly available websites and reports from the National Resident Match Program. A 34-question survey was circulated by e-mail to program directors to assess multiple features of neurological surgery residency programs, including curricular structure, fellowship availability, recent program changes, graduation requirements, and resources supporting career development. Mean resident productivity by program was collected from the literature. RESULTS: Across all 117 programs, there was a median of 2.0 (range 1.0-4.0) resident positions per year and 1.0 (range 0.0-2.0) research/elective years. Programs offered a median of 1.0 (range 0.0-7.0) Committee on Advanced Subspecialty Training-accredited fellowships, with endovascular fellowships being most frequently offered (53.8%). The survey response rate was 75/117 (64.1%). Of survey respondents, the median number of clinical sites was 3.0 (range 1.0-6.0). Almost half of programs surveyed (46.7%) reported funding mechanisms for residents, including R25, T32, and other in-house grants. Residents received a median academic stipend of $1000 (range $0-$10 000) per year. Nearly all programs (93.3%) supported wellness activities for residents, which most frequently occurred quarterly (46.7%). Annual academic stipend size was the only significant predictor of resident academic productivity (R 2 = 0.17, P = .002). CONCLUSION: Neurological surgery residency programs successfully train the next generation of neurosurgeons focusing on education, clinical training, case numbers, and milestones. These programs offer trainees the chance to tailor their career trajectories within residency, creating a rewarding and personalized experience that aligns with their career aspirations.

Management of Combat Casualties during Aeromedical Evacuation from a Role 2 to a Role 3 Medical Facility.

INTRODUCTION: Emergent clinical care and patient movements through the military evacuation system improves survival. Patient management differs when transporting from the point-of-injury (POI) to the first medical treatment facility (MTF) versus transporting from the Role 2 to the Role 3 MTF secondary to care rendered within the MTF, including surgery and advanced resuscitation. The objective of this study was to describe care provided to patients during theater inter-facility transports and compare with pre-hospital transports (POI to first MTF). MATERIALS AND METHODS: We performed a retrospective chart review of patients with the Role 2 to the Role 3 transports in Afghanistan and Iraq from 2007 to 2016. Data collected included procedures and events at the MTF and during transport. We compared the intra-theater transport data (Role 2 to Role 3) to data from a previous study evaluating pre-hospiital transports (POI to first MTF). RESULTS: We reviewed the records of 869 Role 2 to Role 3 transport patients. Role 2 to Role 3 transports were longer in duration compared to POI transports (39 minutes vs. 23 minutes) and were more likely to be staffed by advanced personnel (nurses, physician assistants, and physicians) (57% vs. 3%). The sample primarily consisted of military-aged males (mean age 27 years) who suffered from explosive or blunt force injuries. Procedures performed during each phase of care reflected the capabilities of the teams and locations. Pain and cardiac events were more common in POI evacuations compared to the Role 2 to Role 3 transports, but documentation of respiratory events, hemodynamic events, neurologic events, and equipment failure was more common during the Role 2 to Role 3 transports. Survival rates were slightly higher among the Role 2 to Role 3 cohort (98% vs. 95%, difference 3% [95% confidence interval of the difference 1-5%]). CONCLUSIONS: Inter-facility transports (Role 2 to Role 3) are longer in duration, transport more complex patients, and are staffed by more advanced level provider types compared to transports from POI.

Intramuscular Administration of Tranexamic Acid in a Large Swine Model of Hemorrhage with Hyperfibrinolysis.

BACKGROUND: Traumatic injury with subsequent hemorrhage is one of the leading causes of mortality among military personnel and civilians alike. Post traumatic hemorrhage accounts for 40-50% of deaths in severe trauma patients occurring secondary to direct vessel injury or the development of trauma induced coagulopathy (TIC). Hyperfibrinolysis plays a major role in TIC and its presence increases a patient's risk of mortality. Early therapeutic intervention with intravenous (IV) tranexamic acid (TXA) prevents development of hyperfibrinolysis and subsequent TIC leading to decreased mortality. However, obtaining IV access in an austere environment can be challenging. In this study, we evaluated the efficacy of intramuscular (IM) versus IV TXA at preventing hyperfibrinolysis in a hemorrhaged swine. METHODS: Yorkshire cross swine were randomized on the day of study to receive IM or IV TXA or no treatment. Swine were sedated, intubated, and determined to be hemodynamically stable prior to experimentation. Controlled hemorrhaged was induced by the removal of 30% total blood volume. After hemorrhage, swine were treated with 1000 mg of IM or IV TXA. Control animals received no treatment. Thirty minutes post TXA treatment, fibrinolysis was induced with a 50 mg bolus of tissue plasminogen activator (tPA). Blood samples were collected to evaluate blood TXA concentrations, blood gases, blood chemistry, and fibrinolysis. RESULTS: Blood TXA concentrations were significantly different between administration routes at the early timepoints, but were equivalent by 20 minutes after injection, remaining consistently elevated for up to three hours post administration. Induction of fibrinolysis resulted in 87.18 ± 4.63% lysis in control animals, compared to swine treated with IM TXA 1.96 ± 2.66 % and 1.5 ± 0.42% lysis in the IV TXA group. CONCLUSION: In the large swine model of hemorrhage with hyperfibrinolysis, IM TXA is bioequivalent and equally efficacious in preventing hyperfibrinolysis as IV TXA administration.

Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

Price Transparency for Cervical Spinal Fusion Among High-Performing Spine Centers in the United States.

BACKGROUND AND OBJECTIVES: As of January 1, 2021, all US hospitals are required by the Hospital Price Transparency Final Rule (HPTFR) to publish standard charges for all items and services, yet the state of price transparency for cervical spinal fusion is unknown. Here, we assess the nationwide price transparency landscape for cervical spinal fusion among high-performing spine centers in the United States. METHODS: In this cross-sectional economic evaluation, we queried publicly available price transparency websites of 332 "high-performing" spine centers, as defined by the US News and World Report. We extracted variables including gross charges for cervical spinal fusion, payor options, price reporting methodology, and prices relevant to consumers including listed cash prices and minimum and maximum negotiated charges. RESULTS: While nearly all 332 high-performing spine surgery centers (99.4%) had an online cost estimation tool, the HPTFR compliance rate was only 8.4%. Gross charges for cervical spinal fusion were accessible for 68.1% of hospitals, discounted cash prices for 46.4% of hospitals, and minimum and maximum charges for 10.8% of hospitals. There were large IQRs for gross charges ($48 491.98-$99 293.37), discounted cash prices ($26 952.25-$66 806.63), minimum charges ($10 766.11-$21 248.36), and maximum charges ($39 280.49-$89 035.35). There was geographic variability in the gross charges of cervical spinal fusion among high-performing spine centers within and between states. There was a significant association between "excellent" discharge to home status and lower mean gross charges. CONCLUSION: Although online cost reporting has drastically increased since implementation of the HPTFR, data reported for cervical spinal fusion remain inadequate and difficult to interpret by both providers and patients.

The Role of FAS Receptor Methylation in Osteosarcoma Metastasis.

Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers.

Actionability classification of variants of unknown significance correlates with functional effect.

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional assays. Variants categorized by PODS as Potentially actionable (N = 204) were more likely to be oncogenic than those categorized as Unknown (N = 230) (37% vs 13%, p = 4.08e-09). Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.

An expanded role for surgery in grade 3 1p/19q co-deleted oligodendroglioma.

Background: Grade 3 1p/19q co-deleted oligodendroglioma is an uncommon primary CNS tumor with a high rate of progression and recurrence. This study examines the benefit of surgery after progression and identifies predictors of survival. Methods: This is a single-institution retrospective cohort study of consecutive adult patients with anaplastic or grade 3 1p/19q co-deleted oligodendroglioma diagnosed between 2001 and 2020. Results: Eighty patients with 1p/19q co-deleted grade 3 oligodendroglioma were included. The median age was 47 years (interquartile range 38-56) and 38.8% were women. All patients underwent surgery, including gross total resection (GTR) for 26.3% of patients, subtotal resection (STR) for 70.0% of patients, and biopsy for 3.8% of patients. Forty-three cases (53.8%) progressed at a median of 5.6 years, and the median overall survival (OS) was 14.1 years. Among 43 cases of progression or recurrence, 21 (48.8%) underwent another resection. Patients who underwent a second operation had improved OS (P = .041) and survival after progression/recurrence (P = .012), but similar time to subsequent progression as patients who did not have repeat surgery (P = .50). Predictors of mortality at initial diagnosis included a preoperative Karnofsky Performance Status (KPS) under 80 (hazard ratio [HR] 5.4; 95% CI 1.5-19.2), an STR or biopsy rather than GTR (HR 4.1; 95% CI 1.2-14.2), and a persistent postoperative neurologic deficit (HR 4.0; 95% CI 1.2-14.1). Conclusions: Repeat surgery is associated with increased survival, but not time to subsequent progression for progressing or recurrent 1p/19q co-deleted grade 3 oligodendrogliomas recur. Mortality is associated with a preoperative KPS under 80, lack of GTR, and persistent postoperative neurologic deficits after the initial surgery.

Development and Validation of Patient Education Tools for Deprescribing in Patients on Hemodialysis.

Background: Deprescribing is a patient-centered solution to reducing polypharmacy in patients on hemodialysis (HD). In a deprescribing pilot study, patients were hesitant to participate due to limited understanding of their own medications and their unfamiliarity with the concept of deprescribing. Therefore, patient education materials designed to address these knowledge gaps can overcome barriers to shared decision-making and reduce hesitancy regarding deprescribing. Objective: To develop and validate a medication-specific, patient education toolkit (bulletin and video) that will supplement an upcoming nationwide deprescribing program for patients on HD. Methods: Patient education tools were developed based on the content of previously validated deprescribing algorithms and literature searches for patients' preferences in education. A preliminary round of validation was completed by 5 clinicians to provide feedback on the accuracy and clarity of the education tools. Then, 3 validation rounds were completed by patients on HD across 3 sites in Vancouver, Winnipeg, and Toronto. Content and face validity were evaluated on a 4-point and 5-point Likert scale, respectively. The content validity index (CVI) score was calculated after each round, and revisions were made based on patient feedback. Results: A total of 105 patients participated in the validation. All 10 education tools achieved content and face validity after 3 rounds. The CVI score was 1.0 for most of the tools, with 0.95 being the lowest value. Face validity ranged from 72% to 100%, with majority scoring above 90%. Conclusion: Ten patient education tools on deprescribing were developed and validated by patients on HD. These validated, medication-specific education tools are the first of its kind for patients on HD and will be used in a nationwide implementation study alongside the validated deprescribing algorithms developed by our research group.

Contexte: La déprescription est une solution axée sur le patient pour réduire la polypharmacie chez les patients sous hémodialyse (HD). Dans une étude pilote sur la déprescription, les patients ont hésité à participer en raison de leur compréhension limitée de leurs propres médicaments et de leur manque de connaissance du concept de déprescription. Par conséquent, du matériel éducatif conçu pour combler ces lacunes dans les connaissances des patients pourrait surmonter les obstacles à la prise de décision partagée et réduire les hésitations à l'égard de la déprescription. Objectifs: Développer et valider une trousse d'information (bulletin et vidéo) pour les patients portant sur les médicaments. Cette trousse viendra compléter un futur programme national de déprescription pour les patients sous HD. Méthodologie: Des outils d'éducation pour les patients ont été développés à partir du contenu d'algorithmes de déprescription validés précédemment et de recherches documentaires sur les préférences des patients en matière d'éducation. Une ronde préliminaire de validation a été complétée par cinq cliniciens afin d'obtenir des commentaires sur l'exactitude et la clarté des outils d'éducation. Trois cycles de validation ont ensuite été réalisés par des patients sous HD dans trois sites: Vancouver, Winnipeg et Toronto. La validité du contenu et la validité apparente ont été évaluées à l'aide d'échelles de Likert à 4 et 5 points, respectivement. L'indice de validité du contenu (IVC) a été calculé après chaque ronde et des révisions ont été effectuées en fonction des commentaires des patients. Résultats: En tout, 105 patients ont participé à la validation. La validité du contenu et la validité apparente ont été atteintes pour les dix outils d'éducation après trois rondes auprès des patients. L'IVC s'établissait à 1,0 pour la plupart des outils évalués; 0,95 était la valeur d'indice la plus faible. La validité apparente variait entre 72% et 100%, la majorité des outils ayant obtenu un score supérieur à 90%. Conclusion: Dix outils d'éducation pour les patients portant sur la déprescription ont été développés et validés par des patients sous HD. Ces outils d'éducation validés portant spécifiquement sur les médicaments sont les premiers du genre conçus pour les patients sous HD. Ils seront utilisés dans le cadre d'une étude nationale de mise en œuvre, parallèlement aux algorithmes validés de déprescription qui ont été développés par notre groupe de recherche.

Hemodynamic events during en route critical care for patients with traumatic brain injury.

BACKGROUND: Exposure to stressors of flight may increase risk of secondary insults among critically injured combat casualties wounded with traumatic brain injury (TBI). The primary objective of this study was to describe the prevalence of hemodynamic events by phase of transport among patients with TBI transported by Critical Care Air Transport Teams (CCATT). METHODS: We performed a secondary analysis of a retrospective cohort of 477 adults with moderate to severe TBI, who required transport by CCATT to Germany from multiple hospitals in the Middle East between January 2007 and May 2014. We abstracted clinical data from handwritten CCATT medical records. Hemodynamic events included systolic blood pressure <100 mm Hg and cerebral perfusion pressure <60 mm Hg. We calculated the proportion of patients experiencing hemodynamic events for each phase of flight. RESULTS: We analyzed 404 subjects after exclusions for catastrophic brain injury (n = 39) and missing timestamps (n = 34). Subjects had high Injury Severity Scores (median, 29; interquartile range [IQR], 21-35) and a median flight time of 423 minutes (IQR, 392.5-442.5 minutes). The median of documented in-flight vital signs was 8 measurements (IQR, 6.5-8 measurements). Documented systolic blood pressure in-flight events occurred in 3% of subjects during ascent, 7.9% during early flight, 7.7% during late flight, and 2.2% during descent, with an overall in-flight prevalence of 13.9%. Among patients with intracranial pressure monitoring (n = 120), documented cerebral perfusion pressure events occurred in 5% of subjects during ascent, 23% during early flight, 17% during late flight, and 5.8% during descent, with an overall in-flight prevalence of 30.8%. CONCLUSION: Documented hemodynamic events occurred during each phase of flight in severely injured combat casualties wounded with TBI, and episodic documentation likely underestimated the actual in-flight frequency of secondary insults. LEVEL OF EVIDENCE: Prognostic and epidemiological; Level IV.

A functional genomic approach to actionable gene fusions for precision oncology.

Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.

Evaluation of aqueous dimethyl trisulfide as an antidote to a highly lethal cyanide poisoning in a large swine model.

BACKGROUND: Cyanide is a rapid acting, lethal, metabolic poison and remains a significant threat. Current FDA-approved antidotes are not amenable or efficient enough for a mass casualty incident. OBJECTIVE: The objective of this study is to evaluate short and long-term efficacy of intramuscular aqueous dimethyl trisulfide (DMTS) on survival and clinical outcomes in a swine model of cyanide exposure. METHODS: Anesthetized swine were instrumented and acclimated until breathing spontaneously. Potassium cyanide infusion was initiated and continued until 5 min after the onset of apnea. Subsequently, animals were treated with intramuscular DMTS (n = 11) or saline control (n = 10). Laboratory values and DMTS blood concentrations were assessed at various time points and physiological parameters were monitored continuously until the end of the experiment unless death occurred. A subset of animals treated with DMTS (n = 5) were survived for 7 days to evaluate muscle integrity by repeat biopsy and neurobehavioral outcomes. RESULTS: Physiological parameters and time to apnea were similar in both groups at baseline and at time of treatment. Survival in the DMTS-treated group was 90% and 30% in saline controls (p = 0.0034). DMTS-treated animals returned to breathing at 12.0 ± 10.4 min (mean ± SD) compared to 22.9 ± 7.0 min (mean ± SD) in the 3 surviving controls. Blood collected prior to euthanasia showed improved blood lactate concentrations in the DMTS treatment group; 5.47 ± 2.65 mmol/L vs. 9.39 ± 4.51 mmol/L (mean ± SD) in controls (p = 0.0310). Low concentrations of DMTS were detected in the blood, gradually increasing over time with no elimination phase observed. There was no mortality, histological evidence of muscle trauma, or observed adverse neurobehavioral outcomes, in DMTS-treated animals survived to 7 days. CONCLUSION: Intramuscular administration of aqueous DMTS improves survival following cyanide poisoning with no observed long-term effects on muscle integrity at the injection site or adverse neurobehavioral outcomes.

Surgical advances in the management of brain metastases.

As the epidemiological and clinical burden of brain metastases continues to grow, advances in neurosurgical care are imperative. From standard magnetic resonance imaging (MRI) sequences to functional neuroimaging, preoperative workups for metastatic disease allow high-resolution detection of lesions and at-risk structures, facilitating safe and effective surgical planning. Minimally invasive neurosurgical approaches, including keyhole craniotomies and tubular retractors, optimize the preservation of normal parenchyma without compromising extent of resection. Supramarginal surgery has pushed the boundaries of achieving complete removal of metastases without recurrence, especially in eloquent regions when paired with intraoperative neuromonitoring. Brachytherapy has highlighted the potential of locally delivering therapeutic agents to the resection cavity with high rates of local control. Neuronavigation has become a cornerstone of operative workflow, while intraoperative ultrasound (iUS) and intraoperative brain mapping generate real-time renderings of the brain unaffected by brain shift. Endoscopes, exoscopes, and fluorescent-guided surgery enable increasingly high-definition visualizations of metastatic lesions that were previously difficult to achieve. Pushed forward by these multidisciplinary innovations, neurosurgery has never been a safer, more effective treatment for patients with brain metastases.

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

RAC1 Alterations Induce Acquired Dabrafenib Resistance in Association with Anaplastic Transformation in a Papillary Thyroid Cancer Patient.

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that RAC1 mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments.

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.

Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations.

Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib's antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib's antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.

Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer.

PURPOSE: Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. EXPERIMENTAL DESIGN: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. RESULTS: KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. CONCLUSIONS: We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.