Association between volume and cost in low-resection volume regions: a population-level study on pancreatoduodenectomy for pancreatic cancer patients.

BACKGROUND: Pancreatoduodenectomy (PD) is a highly complex, invasive, and costly surgical procedure. Limited evidence on the PD volume-cost relationship in countries with a low population density exists. This study aimed to investigate this issue in Australia. METHODS: This retrospective cohort study included pancreatic cancer patients who had a PD at any public hospital in New South Wales, Australia between 2016 and 2019. The primary outcome was the total hospital cost during PD admission (not including patient financial burden). Study hospitals were grouped into low-volume hospitals (LVHs; <10 PDs per annum) or high-volume hospitals (HVHs). Multivariable modelling was applied to examine the association between volume and cost. RESULTS: Of 443 PDs, the median total hospital cost per patient at HVHs was AU$55398; significantly lower than that at LVHs (AU$62859; P = 0.001). After adjusting for available patient and clinical factors, the total cost per patient at LVHs was 22% higher than that of HVHs (adjusted estimate: 1.22, 95% CI: 1.08-1.37; P = 0.002). Similar patterns were found in three main cost components: 24% higher employee cost at LVHs than at HVHs (1.24, 95% CI: 1.10-1.41; P < 0.001), 15% higher operating cost (1.15, 95% CI: 1.00-1.31; P = 0.047), and 31% higher other costs (1.31, 95% CI: 1.12-1.53; P < 0.001). CONCLUSION: Performance of PDs at HVHs was associated with substantially lower hospital costs. Our findings demonstrate the likely economic benefit of centralizing PDs in countries with a relatively low population density. Future studies should investigate related patient financial burdens.

Advocacy Skill Development in Public Health Education Curriculum: A Pilot Study.

The National Commission for Health Education Credentialing (NCHEC) released updated Responsibilities and Competencies for Health Education Specialists based on the 2020 HESPA II. For the first time, advocacy is a standalone area of responsibility (Area V: Advocacy) for health education specialists. Although this is exciting for the field of health education, there is limited consensus on how to effectively teach advocacy or what content and skills to include. Furthermore, while the HESPA II was updated, the Council on Education for Public Health (CEPH) criteria for advocacy have not been. This pilot study examined how CEPH-accredited programs in the United States are addressing the profession-wide advocacy competency in their health education curricula. A cross-sectional research design with single-point data collection was used to assess how CEPH-accredited university programs (including Standalone Baccalaureate Programs, Public Health Programs, and Schools of Public Health) are preparing health education students to meet the national advocacy responsibility. The survey included items from the Advocacy Area of Responsibility and potential barriers for faculty teaching advocacy. Results indicate that most programs are teaching something about advocacy, but there is no program teaching all listed sub-competencies. Barriers to including all components of the advocacy responsibility were largely related to faculty motivation, knowledge, and time. With a full responsibility area devoted to advocacy, it is reasonable to expect that programs will adjust with the profession. However, program administrators must be catalysts for these changes in their individual programs.

Prognostic utility of the modified Albumin-Bilirubin score among patients undergoing curative-intent surgery for gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) has been associated with high rates of recurrence and dismal prognosis even after curative-intent resection. The prognostic utility of the modified ALBI (mALBI) score among individuals undergoing curative-intent resection for GBC has not been determined. METHODS: Patients undergoing radical resection for GBC between 2000-2022 were identified from an international, multi-institutional database. Preoperative albumin and bilirubin levels were used to calculate the mALBI score. The relationship between mALBI, overall survival (OS), and recurrence-free survival (RFS) was examined. RESULTS: Among 269 patients undergoing radical resection for GBC, 59.9% of patients had mALBI grade 1, 17.8% had grade 2a, 17.5% had grade 2b, and 4.8% had mALBI grade 3. Following surgery, patients with high mALBI (Grade 2b/3) had worse 5-year OS (19.2% vs. 54.4%, p<0.001) and RFS (17.8% vs. 42.0%, p<0.001) compared with patients with a low mALBI (Grade 1/2a) score. On multivariable analysis, after controlling for relevant clinicopathologic variables, a high mALBI score remained independently associated with higher hazards of death and recurrence (OS: HR 2.38, 95%CI 1.50-3.79; RFS: HR 2.12, 95%CI 1.41-3.20) compared with individuals with a low mALBI score following curative-intent resection for GBC. Of note, mALBI was associated with incrementally worse survival within T2, T3, and N+ categories, whereas classic AJCC subclassifications failed to distinguish patients relative to long-term survival. CONCLUSION: The mALBI score presents a simple, objective measure of hepatic functional reserve and may be a useful prognostic tool as applied to patients undergoing curative-intent resection for GBC.

Development of an artificial intelligence-based model to predict early recurrence of neuroendocrine liver metastasis after resection.

PURPOSE: We sought to develop an artificial intelligence (AI)-based model to predict early recurrence (ER) after curative-intent resection of neuroendocrine liver metastases (NELMs). METHODS: Patients with NELM who underwent resection were identified from a multi-institutional database. ER was defined as recurrence within 12 months of surgery. Different AI-based models were developed to predict ER using 10 clinicopathologic factors. RESULTS: Overall, 473 patients with NELM were included. Among 284 patients with recurrence (60.0%), 118 patients (41.5%) developed an ER. An ensemble AI model demonstrated the highest area under receiver operating characteristic curves of 0.763 and 0.716 in the training and testing cohorts, respectively. Maximum diameter of the primary neuroendocrine tumor, NELM radiologic tumor burden score, and bilateral liver involvement were the factors most strongly associated with risk of NELM ER. Patients predicted to develop ER had worse 5-year recurrence-free survival and overall survival (21.4% vs 37.1% [P = .002] and 61.6% vs 90.3% [P = .03], respectively) than patients not predicted to recur. An easy-to-use tool was made available online: (https://altaf-pawlik-nelm-earlyrecurrence-calculator.streamlit.app/). CONCLUSION: An AI-based model demonstrated excellent discrimination to predict ER of NELM after resection. The model may help identify patients who can benefit the most from curative-intent resection, risk stratify patients according to prognosis, as well as guide tailored surveillance and treatment decisions including consideration of nonsurgical treatment options.

Landscape of racial and ethnic health disparities in the All of Us Research Program.

The All of Us Research Program ("All of Us") is an initiative led by the National Institutes of Health whose goal is to advance research on personalized medicine and health equity through the collection of genetic, environmental, demographic, and health data from volunteer participants who reside in the USA. The program's emphasis on recruiting a diverse participant cohort makes "All of Us" an effective platform for investigating health disparities. In this work, we analyzed participant electronic health record (EHR) data to identify the diseases and disease categories in the "All of Us" cohort for which racial and ethnic prevalence disparities can be observed. In conjunction with these analyses, we developed the US Health Disparities Browser as an interactive web application that enables users to visualize differences in race- and ethnic-group-specific prevalence estimates for 1755 different diseases: https://usdisparities.biosci.gatech.edu/. The web application features a catalog of all diseases represented in the browser, which can be sorted by overall prevalence as well as the variance in prevalence across racial and ethnic groups. The analyses outlined here provide details on the nature and extent of racial and ethnic health disparities in the "All of Us" participant cohort, and the accompanying browser can serve as a resource through which researchers can explore these disparities Database URL: https://usdisparities.biosci.gatech.edu.

Machine learning models including preoperative and postoperative albumin-bilirubin score: short-term outcomes among patients with hepatocellular carcinoma.

BACKGROUND: We sought to assess the impact of various perioperative factors on the risk of severe complications and post-surgical mortality using a novel maching learning technique. METHODS: Data on patients undergoing resection for HCC were obtained from an international, multi-institutional database between 2000 and 2020. Gradient boosted trees were utilized to construct predictive models. RESULTS: Among 962 patients who underwent HCC resection, the incidence of severe postoperative complications was 12.7% (n = 122); in-hospital mortality was 2.9% (n = 28). Models that exclusively used preoperative data achieved AUC values of 0.89 (95%CI 0.85 to 0.92) and 0.90 (95%CI 0.84 to 0.96) to predict severe complications and mortality, respectively. Models that combined preoperative and postoperative data achieved AUC values of 0.93 (95%CI 0.91 to 0.96) and 0.92 (95%CI 0.86 to 0.97) for severe morbidity and mortality, respectively. The SHAP algorithm demonstrated that the factor most strongly predictive of severe morbidity and mortality was postoperative day 1 and 3 albumin-bilirubin (ALBI) scores. CONCLUSION: Incorporation of perioperative data including ALBI scores using ML techniques can help risk-stratify patients undergoing resection of HCC.

Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations.

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.

Gelatin maleimide microgels for hematopoietic progenitor cell encapsulation.

Hematopoietic stem cells (HSCs) are the apical cells of the hematopoietic system, giving rise to cells of the blood and lymph lineages. HSCs reside primarily within bone marrow niches that contain matrix and cell-derived signals that help inform stem cell fate. Aspects of the bone marrow microenvironment have been captured in vitro by encapsulating cells within hydrogel matrices that mimic native mechanical and biochemical properties. Hydrogel microparticles, or microgels, are increasingly being used to assemble granular biomaterials for cell culture and noninvasive delivery applications. Here, we report the optimization of a gelatin maleimide hydrogel system to create monodisperse gelatin microgels via a flow-focusing microfluidic process. We report characteristic hydrogel stiffness, stability, and swelling characteristics as well as encapsulation of murine hematopoietic stem and progenitor cells, and mesenchymal stem cells within microgels. Microgels support cell viability, confirming compatibility of the microfluidic encapsulation process with these sensitive bone marrow cell populations. Overall, this work presents a microgel-based gelatin maleimide hydrogel as a foundation for future development of a multicellular artificial bone marrow culture system.

Unlocking the Next Frontier in Precision Oncology: Addressing Drug-Tolerant Residual Disease.

SUMMARY: Drug-tolerant residual disease (DTRD) after the initial maximal response to a systemic therapy can serve as a tumor reservoir for the development of acquired drug resistance and represents a major clinical challenge across various cancers and types of therapies. To unlock the next frontier in precision oncology, we propose a fundamental paradigm shift in the treatment of metastatic cancers with a sharpened focus towards defining, monitoring, and therapeutically targeting the DTRD state.

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.

Oral cavity cancer and its pre-treatment radiological evaluation: A pictorial overview.

PURPOSE: Oral cavity cancer, primarily squamous cell carcinoma (SCC), is a prevalent malignancy globally, necessitating accurate clinical assessment and staging to enable effective treatment planning. Diagnosis requires biopsy and is followed by surgical resection and reconstruction as the primary therapeutic modality. Imaging plays a pivotal role during this process, aiding in the evaluation of tumour extent, nodal involvement and distant metastases. However, despite its value, both radiologists and clinicians must recognise its inherent limitations. METHODS: This pictorial review article aims to illustrate the application of various imaging modalities in the pre-treatment evaluation of oral cavity SCC and highlights potential pitfalls. It underscores the importance of understanding the anatomical subsites of the oral cavity, the diverse patterns of spread tumours exhibit at each site, alongside the role of imaging in facilitating informed management strategies, while also acknowledging its limitations. RESULTS: The review delves into fundamentals of current staging including nodal involvement, while, emphasising imaging strategies and potential limitations. Finally, it touches on the potential of novel radiomic techniques in characterising tumours and predicting treatment response. CONCLUSIONS: Pre-treatment oral cavity cancer staging reflects an ongoing quest for enhanced diagnostic accuracy and prognostic prediction. Recognising the value of imaging alongside its limitations fosters a multidisciplinary approach to treatment planning, ultimately improving patient outcomes.

Impact of an artificial intelligence based model to predict non-transplantable recurrence among patients with hepatocellular carcinoma.

OBJECTIVE: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR). METHODS: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors. RESULTS: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001). CONCLUSION: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/).

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.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Perioperative Changes in Serum Transaminase Levels: Impact on Postoperative Morbidity Following Liver Resection of Hepatocellular Carcinoma.

OBJECTIVES: To define how dynamic changes in pre- versus post-operative serum aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels may impact postoperative morbidity after curative-intent resection of hepatocellular carcinoma (HCC). BACKGROUND: Hepatic ischemia/reperfusion can occur at the time of liver resection and may be associated with adverse outcomes following liver resection. METHODS: Patients who underwent curative resection for HCC between 2010-2020 were identified from an international multi-institutional database. Changes in AST and ALT (CAA) on postoperative day (POD) 3 versus preoperative values () were calculated using the formula: based on a fusion index via Euclidean norm, which was examined relative to the comprehensive complication index (CCI). The impact of CAA on CCI was assessed by the restricted cubic spline regression and Random Forest analyses. RESULTS: A total of 759 patients were included in the analytic cohort. Median CAA was 1.7 (range, 0.9 to 3.25); 431 (56.8%) patients had a CAA<2, 215 (28.3%) patients with CAA 2-5, and 113 (14.9%) patients had CAA ≥5. The incidence of post-operative complications was 65.0% (n=493) with a median CCI of 20.9 (IQR, 20.9-33.5). Spline regression analysis demonstrated a non-linear incremental association between CAA and CCI. The optimal cutoff value of CAA=5 was identified by the recursive partitioning technique. After adjusting for other competing risk factors, CAA≥5 remained strongly associated with risk of post-operative complications (Ref. CAA<5, OR 1.63, 95%CI 1.05-2.55, P=0.03). In fact, the use of CAA to predict post-operative complications was very good in both the derivative (AUC 0.88) and external (ACU 0.86) cohorts (n=1137). CONCLUSIONS: CAA was an independent predictor of CCI after liver resection for HCC. Use of routine labs such as AST and ALT can help identify patients at highest risk of post-operative complications following HCC resection.

Systematic Review of Preoperative Prognostic Biomarkers in Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

The Evolving Landscape of Neoadjuvant Immunotherapy in Gastroesophageal Cancer.

Despite advances in treatment strategies and surgical approaches in recent years, improving survival outcomes in esophagogastric cancer (EGC) patients treated with curative intent remains a significant area of unmet need. The recent emergence of adjuvant immunotherapy as the standard of care for resected EGC demonstrates the impact of immunotherapy in improving recurrence-free survival. Neoadjuvant and perioperative immunotherapies represent another promising approach with potential advantages over adjuvant therapy. Despite the promising results of early neoadjuvant immunotherapy studies, there are several challenges and future research needs. The optimal timing, duration and number of doses in relation to surgery and the optimal combination of immunotherapies are still unclear. In addition, rigorous correlative studies need to be performed to identify biomarkers for patient selection and treatment response prediction to maximize the benefits of neoadjuvant immunotherapy. In this review, we provide a concise summary of the current standard of care for resectable EGC and discuss the rationale for the use of immune checkpoint inhibitors in this setting and the pre-clinical and early clinical data of these novel therapies. Finally, we will examine the potential role and future direction of immunotherapy in the treatment paradigm and the perceived challenges and opportunities that lay ahead.