Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

BACKGROUND: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. RESULTS: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). CONCLUSION: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

The impact of county-level food access on the mortality and post-transplant survival among patients with steatotic liver disease.

BACKGROUND: The impact of county-level food access on mortality associated with steatotic liver disease, as well as post-liver transplant outcomes among individuals with steatotic liver disease, have not been characterized. METHODS: Data on steatotic liver disease-related mortality and outcomes of liver transplant recipients with steatotic liver disease between 2010 and 2020 were obtained from the Centers for Disease Control Prevention mortality as well as the Scientific Registry of Transplant Recipients databases. These data were linked to the food desert score, defined as the proportion of the total population in each county characterized as having both low income and limited access to grocery stores. RESULTS: Among 2,710 counties included in the analytic cohort, median steatotic liver disease-related mortality was 27.3 per 100,000 population (interquartile range 24.9-32.1). Of note, patients residing in counties with high steatotic liver disease death rates were more likely to have higher food desert scores (low: 5.0, interquartile range 3.1-7.8 vs moderate: 6.1, interquartile range, 3.8-9.3 vs high: 7.6, interquartile range 4.1-11.7). Among 28,710 patients who did undergo liver transplantation, 5,310 (18.4%) individuals lived in counties with a high food desert score. Liver transplant recipients who resided in counties with the worst food access were more likely to have a higher body mass index (>35 kg/m2: low food desert score, 17.3% vs highest food desert score, 20.1%). After transplantation, there was no difference in 2-year graft survival relative to county-level food access (food desert score: low: 88.4% vs high: 88.6%; P = .77). CONCLUSION: Poor food access was associated with a higher incidence rate of steatotic liver disease-related death, as well as lower utilization of liver transplants. On the other hand, among patients who did receive a liver transplant, there was no difference in 2-year graft survival regardless of food access strata. Policy initiatives should target the expansion of transplantation services to vulnerable communities in which there is a high mortality of steatotic liver disease.

Textbook outcome in liver surgery: open vs minimally invasive hepatectomy among patients with hepatocellular carcinoma.

BACKGROUND: We sought to investigate whether minimally invasive hepatectomy (MIH) was superior to open hepatectomy (OH) in terms of achieving textbook outcome in liver surgery (TOLS) after resection of hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. TOLS was defined by the absence of intraoperative grade ≥2 events, R1 resection margin, posthepatectomy liver failure, bile leakage, major complications, in-hospital mortality, and readmission. RESULTS: A total of 1039 patients who underwent HCC resection were included in the analysis. Although most patients underwent OH (n = 724 [69.7%]), 30.3% (n = 315) underwent MIH. Patients who underwent MIH had a lower tumor burden score (3.6 [IQR, 2.6-5.2] for MIH vs 6.1 [IQR, 3.9-10.1] for OH) and were more likely to undergo minor hepatectomy (84.1% [MIH] vs 53.6% [OH]) than patients who had an OH (both P < .001). After propensity score matching to control for baseline differences between the 2 cohorts, the incidence of TOLS was comparable among patients who had undergone MIH (56.6%) versus OH (64.8%) (P = .06). However, MIH was associated with a shorter length of hospital stay (6.0 days [IQR, 4.0-8.0] for MIH vs 9.0 days [IQR, 6.0-12.0] for OH). Among patients who had MIH, the odds ratio of achieving TOLS remained stable up to a tumor burden score of 4; after which the chance of TOLS with MIH markedly decreased. CONCLUSION: Patients with HCC who underwent resection with MIH versus OH had a comparable likelihood of TOLS, although MIH was associated with a short length of stay.

Effect of the opioid crisis on the liver transplantation donor pool: A national analysis.

BACKGROUND: Over the last decade there has been a surge in overdose deaths due to the opioid crisis. We sought to characterize the temporal change in overdose donor (OD) use in liver transplantation (LT), as well as associated post-LT outcomes, relative to the COVID-19 era. METHODS: LT candidates and donors listed between January 2016 and September 2022 were identified from the Scientific Registry of Transplant Recipients database. Trends in LT donors and changes related to OD were assessed pre- versus post-COVID-19 (February 2020). RESULTS: Between 2016 and 2022, most counties in the United States experienced an increase in overdose-related deaths (n = 1284, 92.3%) with many counties (n = 458, 32.9%) having more than a doubling in drug overdose deaths. Concurrently, there was an 11.2% increase in overall donors, including a 41.7% increase in the number of donors who died from drug overdose. In pre-COVID-19 overdose was the 4th top mechanism of donor death, while in the post-COVID-19 era, overdose was the 2nd most common cause of donor death. OD was younger (OD: 35 yrs, IQR 29-43 vs. non-OD: 43 yrs, IQR 31-56), had lower body mass index (≥35 kg/cm2, OD: 31.2% vs. non-OD: 33.5%), and was more likely to be HCV+ (OD: 28.9% vs. non-OD: 5.4%) with lower total bilirubin (≥1.1 mg/dL, OD: 12.9% vs. non-OD: 20.1%) (all p < .001). Receipt of an OD was not associated with worse graft survival (HR .94, 95% CI .88-1.01, p = .09). CONCLUSIONS: Opioid deaths markedly increased following the COVID-19 pandemic, substantially altering the LT donor pool in the United States.

Opportunities and Challenges for Machine Learning-Assisted Enzyme Engineering.

Enzymes can be engineered at the level of their amino acid sequences to optimize key properties such as expression, stability, substrate range, and catalytic efficiency-or even to unlock new catalytic activities not found in nature. Because the search space of possible proteins is vast, enzyme engineering usually involves discovering an enzyme starting point that has some level of the desired activity followed by directed evolution to improve its "fitness" for a desired application. Recently, machine learning (ML) has emerged as a powerful tool to complement this empirical process. ML models can contribute to (1) starting point discovery by functional annotation of known protein sequences or generating novel protein sequences with desired functions and (2) navigating protein fitness landscapes for fitness optimization by learning mappings between protein sequences and their associated fitness values. In this Outlook, we explain how ML complements enzyme engineering and discuss its future potential to unlock improved engineering outcomes.

Comparative outcomes after treatment of peri-implant, periprosthetic, and interprosthetic femur fractures: which factors increase mortality risk?

Objectives: To compare mortality rates between patients treated surgically for periprosthetic fractures (PPF) after total hip arthroplasty (THA), total knee arthroplasty (TKA), peri-implant (PI), and interprosthetic (IP) fractures while identifying risk factors associated with mortality following PPF. Design: Retrospective. Setting: Single, Level II Trauma Center. Patients/Participants: A retrospective review was conducted of 129 consecutive patients treated surgically for fractures around a pre-existing prosthesis or implant from 2013 to 2020. Patients were separated into 4 comparison groups: THA, TKA, PI, and IP fractures. Intervention: Revision implant or arthroplasty, open reduction and internal fixation (ORIF), intramedullary nailing (IMN), percutaneous screws, or a combination of techniques. Main Outcome Measurements: Primary outcome measures include mortality rates of different types of PPF, PI, and IP fractures at 1-month, 3-month, 6-month, 1-year, and 2-year postoperative. We analyzed risk factors associated with mortality aimed to determine whether treatment type affects mortality. Results: One hundred twenty-nine patients were included for final analysis. Average follow-up was similar between all groups. The overall 1-year mortality rate was 1 month (5%), 3 months (12%), 6 months (13%), 1 year (15%), and 2 years (22%). There were no differences in mortality rates between each group at 30 days, 90 days, 6 months, 1 year, and 2 years (P-value = 0.86). A Kaplan-Meier survival curve demonstrated no difference in survivorship up to 2 years. Older than 65 years, history of hypothyroidism and dementia, and discharge to a skilled nursing facility (SNF) led to increased mortality. There was no survival benefit in treating patients with PPFs with either revision, ORIF, IMN, or a combination of techniques. Conclusion: The overall mortality rates observed were 1 month (5%), 3 months (12%), 6 months (13%), 1 year (15%), and 2 years (22%), and no differences were found between each group at all follow-up time points. Patients aged 65 and older with a history of hypothyroidism and/or dementia discharged to an SNF are at increased risk for mortality. From a mortality perspective, surgeons should not hesitate to choose the surgical treatment they feel most comfortable performing. Level of Evidence: Level III.

First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .

Pulsatile microvascular cerebral blood flow waveforms change with intracranial compliance and age.

Significance: Diffuse correlation spectroscopy (DCS) is an optical method to measure relative changes in cerebral blood flow (rCBF) in the microvasculature. Each heartbeat generates a pulsatile signal with distinct morphological features that we hypothesized to be related to intracranial compliance (ICC). Aim: We aim to study how three features of the pulsatile rCBF waveforms: the augmentation index (AIx), the pulsatility index, and the area under the curve, change with respect to ICC. We describe ICC as a combination of vascular compliance and extravascular compliance. Approach: Since patients with Chiari malformations (CM) (n=30) have been shown to have altered extravascular compliance, we compare the morphology of rCBF waveforms in CM patients with age-matched healthy control (n=30). Results: AIx measured in the supine position was significantly less in patients with CM compared to healthy controls (p<0.05). Since physiologic aging also leads to changes in vessel stiffness and intravascular compliance, we evaluate how the rCBF waveform changes with respect to age and find that the AIx feature was strongly correlated with age (Rhealthy subjects=-0.63, Rpreoperative CM patient=-0.70, and Rpostoperative CM patients=-0.62, p<0.01). Conclusions: These results suggest that the AIx measured in the cerebral microvasculature using DCS may be correlated to changes in ICC.

Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2-88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

Postoperative morbidity after simultaneous versus staged resection of synchronous colorectal liver metastases: Impact of hepatic tumor burden.

BACKGROUND: We sought to characterize the risk of postoperative complications relative to the surgical approach and overall synchronous colorectal liver metastases tumor burden score. METHODS: Patients with synchronous colorectal liver metastases who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Propensity score matching was employed to control for heterogeneity between the 2 groups. A virtual twins analysis was performed to identify potential subgroups of patients who might benefit more from staged versus simultaneous resection. RESULTS: Among 976 patients who underwent liver resection for synchronous colorectal liver metastases, 589 patients (60.3%) had a staged approach, whereas 387 (39.7%) patients underwent simultaneous resection of the primary tumor and synchronous colorectal liver metastases. After propensity score matching, 295 patients who underwent each surgical approach were analyzed. Overall, the incidence of postoperative complications was 34.1% (n = 201). Among patients with high tumor burden scores, the surgical approach was associated with a higher incidence of postoperative complications; in contrast, among patients with low or medium tumor burden scores, the likelihood of complications did not differ based on the surgical approach. Virtual twins analysis demonstrated that preoperative tumor burden score was important to identify which subgroup of patients benefited most from staged versus simultaneous resection. Simultaneous resection was associated with better outcomes among patients with a tumor burden score <9 and a node-negative right-sided primary tumor; in contrast, staged resection was associated with better outcomes among patients with node-positive left-sided primary tumors and higher tumor burden score. CONCLUSION: Among patients with high tumor burden scores, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications.

A Prognostic Model To Predict Survival After Recurrence Among Patients With Recurrent Hepatocellular Carcinoma.

OBJECTIVE: We sought to develop and validate a preoperative model to predict survival after recurrence (SAR) in hepatocellular carcinoma (HCC). BACKGROUND: Although HCC is characterized by recurrence as high as 60%, models to predict outcomes after recurrence remain relatively unexplored. METHODS: Patients who developed recurrent HCC between 2000 and 2020 were identified from an international multi-institutional database. Clinicopathologic data on primary disease and laboratory and radiologic imaging data on recurrent disease were collected. Multivariable Cox regression analysis and internal bootstrap validation (5000 repetitions) were used to develop and validate the SARScore. Optimal Survival Tree analysis was used to characterize SAR among patients treated with various treatment modalities. RESULTS: Among 497 patients who developed recurrent HCC, median SAR was 41.2 months (95% CI 38.1-52.0). The presence of cirrhosis, number of primary tumors, primary macrovascular invasion, primary R1 resection margin, AFP>400 ng/mL on the diagnosis of recurrent disease, radiologic extrahepatic recurrence, radiologic size and number of recurrent lesions, radiologic recurrent bilobar disease, and early recurrence (≤24 months) were included in the model. The SARScore successfully stratified 1-, 3- and 5-year SAR and demonstrated strong discriminatory ability (3-year AUC: 0.75, 95% CI 0.70-0.79). While a subset of patients benefitted from resection/ablation, Optimal Survival Tree analysis revealed that patients with high SARScore disease had the worst outcomes (5-year AUC; training: 0.79 vs. testing: 0.71). The SARScore model was made available online for ease of use and clinical applicability ( https://yutaka-endo.shinyapps.io/SARScore/ ). CONCLUSION: The SARScore demonstrated strong discriminatory ability and may be a clinically useful tool to help stratify risk and guide treatment for patients with recurrent HCC.

Is surgical treatment of hepatocellular carcinoma at high-volume centers worth the additional cost?

BACKGROUND: Case volume has been associated with improved outcomes for patients undergoing treatment for hepatocellular carcinoma, often with higher hospital expenditures. We sought to define the cost-effectiveness of hepatocellular carcinoma treatment at high-volume centers. METHODS: Patients diagnosed with hepatocellular carcinoma from 2013 to 2017 were identified from Medicare Standard Analytic Files. High-volume centers were defined as the top decile of facilities performing hepatectomies in a year. A multivariable generalized linear model with gamma distribution and a restricted mean survival time model were used to estimate costs and survival differences relative to high-volume center status. The incremental cost-effectiveness ratio was used to define the additional cost incurred for a 1-year incremental gain in survival. RESULTS: Among 13,666 patients, 8,467 (62.0%) were treated at high-volume centers. Median expenditure was higher ($19,148, interquartile range $15,280-$29,128) among patients treated at high-volume centers versus low-volume centers ($18,209, interquartile range $14,959-$29,752). Despite similar median length-of-stay (6 days, interquartile range 4-9), a slightly higher proportion of patients were discharged to home from high-volume centers (n = 4,903, 57.9%) versus low-volume centers (n = 2,868, 55.2%) (P = .002). A 0.14-year (95% confidence interval 0.06-0.22) (1 month and 3 weeks) survival benefit was associated with an incremental cost of $1,070 (95% confidence interval $749-$1,392) among patients undergoing surgery at high-volume centers. The incremental cost-effectiveness ratio for treatment at a high-volume center was $7,951 (95% confidence interval $4,236-$21,217) for an additional year of survival, which was below the cost-effective threshold of $21,217. CONCLUSION: Surgical care at high-volume centers offers the potential to deliver cancer care in a more cost-effective and value-based manner.

Liver transplantation access and outcomes: Impact of variations in liver-specific specialty care.

BACKGROUND: We sought to characterize the impact access to gastroenterologists/hepatologists has on liver transplantation listing, as well as time on the liver transplantation waitlist and post-transplant outcomes. METHODS: Liver transplantation registrants aged >18 years between January 1, 2004 and December 31, 2019 were identified from the Scientific Registry of Transplant Recipients Standard Analytic Files. The liver transplantation registration ratio was defined as the ratio of liver transplant waitlist registrations in a given county per 1,000 liver-related deaths. RESULTS: A total of 150,679 liver transplantation registrants were included. Access to liver transplantation centers and liver-specific specialty physicians varied markedly throughout the United States. Of note, the liver transplantation registration ratio was lower in counties with poor access to liver-specific care versus counties with adequate access (poor access 137.2, interquartile range 117.8-163.2 vs adequate access 157.6, interquartile range 127.3-192.2, P < .001). Among patients referred for liver transplantation, the cumulative incidence of waitlist mortality and post-transplant graft survival was comparable among patients with poor versus adequate access to liver-specific care (both P > .05). Among liver transplantation recipients living in areas with poor access, after controlling for recipient and donor characteristics, cold ischemic time, and model for end-stage liver disease score, the area deprivation index predicted graft survival (referent, low area deprivation index; medium area deprivation index, hazard ratio 1.52, 95% confidence interval 1.03-12.23; high area deprivation index, 1.45, 95% confidence interval 1.01-12.09, both P < .05). CONCLUSION: Poor access to liver-specific care was associated with a reduction in liver transplantation registration, and individuals residing in counties with high social deprivation had worse graft survival among patients living in counties with poor access to liver-specific care.

Optimal policy tree to assist in adjuvant therapy decision-making after resection of colorectal liver metastases.

BACKGROUND: Although systemic postoperative therapy after surgery for colorectal liver metastases is generally recommended, the benefit of adjuvant chemotherapy has been debated. We used machine learning to develop a decision tree and define which patients may benefit from adjuvant chemotherapy after hepatectomy for colorectal liver metastases. METHODS: Patients who underwent curative-intent resection for colorectal liver metastases between 2000 and 2020 were identified from an international multi-institutional database. An optimal policy tree analysis was used to determine the optimal assignment of the adjuvant chemotherapy to subgroups of patients for overall survival and recurrence-free survival. RESULTS: Among 1,358 patients who underwent curative-intent resection of colorectal liver metastases, 1,032 (76.0%) received adjuvant chemotherapy. After a median follow-up of 28.7 months (interquartile range 13.7-52.0), 5-year overall survival was 67.5%, and 3-year recurrence-free survival was 52.6%, respectively. Adjuvant chemotherapy was associated with better recurrence-free survival (3-year recurrence-free survival: adjuvant chemotherapy, 54.4% vs no adjuvant chemotherapy, 46.8%; P < .001) but no overall survival significant improvement (5-year overall survival: adjuvant chemotherapy, 68.1% vs no adjuvant chemotherapy, 65.7%; P = .15). Patients were randomly allocated into 2 cohorts (training data set, n = 679, testing data set, n = 679). The random forest model demonstrated good performance in predicting counterfactual probabilities of death and recurrence relative to receipt of adjuvant chemotherapy. According to the optimal policy tree, patient demographics, secondary tumor characteristics, and primary tumor characteristics defined the subpopulation that would benefit from adjuvant chemotherapy. CONCLUSION: A novel artificial intelligence methodology based on patient, primary tumor, and treatment characteristics may help clinicians tailor adjuvant chemotherapy recommendations after colorectal liver metastases resection.

Association of persistent poverty and U.S. News and World Report hospital rankings among patients undergoing major surgery.

BACKGROUND: We sought to determine the association of persistent poverty on patient outcomes relative to US News World Report (USNWR) rankings among individuals undergoing common major surgical procedures. METHODS: Medicare beneficiaries who underwent AAA repair, CABG, colectomy, or lung resection were identified. Multivariable logistic regression was used to evaluate the relationship between care at USNWR hospitals, county-level duration of poverty (never-high poverty (NHP); intermittent high poverty (IHP): persistent-poverty (PP)) and 30-day mortality. RESULTS: Among 916,164 beneficiaries, individuals residing in PP neighborhoods who received surgical care at ranked hospitals had lower risk-adjusted 30-day mortality (5.89% vs 8.89%; p â€‹< â€‹0.001). On multivariable analysis, 30-day mortality was lower at ranked hospitals across all poverty categories with greatest decrease among patients from PP regions (NHP: OR-0.91, 95%CI0.87-0.95; IHP: OR-0.78, 95%CI0.69-0.88; PP: OR-0.69, 95%CI0.57-0.83; p â€‹< â€‹0.001). CONCLUSION: Receipt of surgical care at top-ranked hospitals was associated with improvement in postoperative mortality, especially among patients residing in persistent poverty..

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies.

PURPOSE: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.

Association of Neighborhood Deprivation and Transplant Center Quality with Liver Transplantation Outcomes.

BACKGROUND: Social determinants of health can impact the quality of liver transplantation (LT) care. We sought to assess whether the association between neighborhood deprivation and transplant outcomes can be mitigated by receiving care at high-quality transplant centers. STUDY DESIGN: In this population-based cohort study, patients who underwent LT between 2004 and 2019 were identified in the Scientific Registry of Transplant Recipients. LT-recipient neighborhoods were identified at the county level and stratified into quintiles relative to Area Deprivation Index (ADI). Transplant center quality was based on the Scientific Registry of Transplant Recipients 5-tier ranking using standardized transplant rate ratios. Multivariable Cox regression was used to assess the relationship between ADI, hospital quality, and posttransplant survival. RESULTS: A total of 41,333 recipients (median age, 57.0 [50.0 to 63.0] years; 27,112 [65.4%] male) met inclusion criteria. Patients residing in the most deprived areas were more likely to have nonalcoholic steatohepatitis, be Black, and travel further distances to reach a transplant center. On multivariable analysis, post-LT long-term mortality was associated with low- vs high-quality transplant centers (hazard ratio [HR] 1.19, 95% CI 1.07 to 1.32), as well as among patients residing in high- vs low-ADI neighborhoods (HR 1.25, 95% CI 1.16 to 1.34; both p ≤ 0.001). Of note, individuals residing in high- vs low-ADI neighborhoods had a higher risk of long-term mortality after treatment at a low-quality (HR 1.31, 95% CI 1.06 to 1.62, p = 0.011) vs high-quality (HR 1.12, 95% CI 0.83 to 1.52, p = 0.471) LT center. CONCLUSIONS: LT at high-quality centers may be able to mitigate the association between posttransplant survival and neighborhood deprivation. Investments and initiatives that increase access to referrals to high-quality centers for patients residing in higher deprivation may lead to better outcomes and help mitigate disparities in LT.

Erdheim-Chester disease: misdiagnosed as multiple sclerosis.

Erdheim-Chester disease is a rare histiocytic neoplasm with a wide range of clinical manifestations. Due to its rarity and protean characteristics, this condition often presents a diagnostic challenge. A Caucasian woman in her late 60s presented with unsteadiness, dysphagia and dysarthria. She was initially diagnosed with secondary progressive multiple sclerosis but deteriorated over 2 years with a potential lack of therapeutic response. Subsequent investigations resulted in the diagnosis of Erdheim-Chester disease. She received targeted therapy with BRAF and MAPK-pathway inhibitors. Her initial response to treatment has been positive with functional gains and reduced disease burden on MR brain imaging, and with no significant adverse effects.