Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Social Vulnerability Index and Survivorship after Colorectal Cancer Resection.

BACKGROUND: Race and socioeconomic status incompletely identify patients with colorectal cancer (CRC) at the highest risk for screening, treatment, and mortality disparities. Social vulnerability index (SVI) was designed to delineate neighborhoods requiring greater support after external health stressors, summarizing socioeconomic, household, and transportation barriers by census tract. SVI is implicated in lower cancer center use and increased complications after colectomy, but its influence on long-term prognosis is unknown. Herein, we characterized relationships between SVI and CRC survival. STUDY DESIGN: Patients undergoing resection of stage I to IV CRC from January 2010 to May 2023 within an academic health system were identified. Clinicopathologic characteristics were abstracted using institutional National Cancer Database and NSQIP. Addresses from electronic health records were geocoded to SVI. Overall survival and cancer-specific survival were compared using Kaplan-Meier and Cox proportional hazards methods. RESULTS: A total of 872 patients were identified, comprising 573 (66%) patients with colon tumor and 299 (34%) with rectal tumor. Patients in the top SVI quartile (32%) were more likely to be Black (41% vs 13%, p < 0.001), carry less private insurance (39% vs 48%, p = 0.02), and experience greater comorbidity (American Society of Anesthesiologists physical status III: 86% vs 71%, p < 0.001), without significant differences by acuity, stage, or CRC therapy. In multivariable analysis, high SVI remained associated with higher all-cause (hazard ratio 1.48, 95% CI 1.12 to 1.96, p < 0.01) and cancer-specific survival mortality (hazard ratio 1.71, 95% CI 1.10 to 2.67, p = 0.02). CONCLUSIONS: High SVI was independently associated with poorer prognosis after CRC resection beyond the perioperative period. Acknowledging needs for multi-institutional evaluation and elaborating causal mechanisms, neighborhood-level vulnerability may inform targeted outreach in CRC care.

Tumor size and survival in intrahepatic cholangiocarcinoma treated with surgical resection or ablation.

OBJECTIVES: We performed a retrospective analysis within a national cancer registry on outcomes following resection or ablation for intrahepatic cholangiocarcinoma (iCCA). METHODS: The National Cancer Database was queried for patients with clinical stage I-III iCCA diagnosed during 2010-2018, who underwent resection or ablation. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Of 2140 patients, 1877 (87.7%) underwent resection and 263 (12.3%) underwent ablation, with median tumor sizes of 5.5 and 3 cm, respectively. Overall, resection was associated with greater median OS (41.2 months (95% confidence interval [95% CI]: 37.6-46.2) vs. 28 months (95% CI: 15.9-28.6) on univariable analysis (p < 0.0001). There was no significant difference on multivariable analysis (p = 0.42); however, there was a significant interaction between tumor size and management. On subgroup analysis of patients with tumors <3 cm, there was no difference in OS between resection versus ablation. However, ablation was associated with increased mortality for tumors ≥3 cm. CONCLUSION: Although resection is associated with improved OS for tumors ≥3 cm, we observed no difference in survival between management strategies for tumors < 3 cm. Ablation may be an alternative therapeutic strategy for small iCCA, particularly in patients at risk for high surgical morbidity.

Comparing Survival After Resection, Ablation, and Radiation in Small Intrahepatic Cholangiocarcinoma.

BACKGROUND: Hepatectomy is the cornerstone of curative-intent treatment for intrahepatic cholangiocarcinoma (ICC). However, in patients unable to be resected, data comparing efficacy of alternatives including thermal ablation and radiation therapy (RT) remain limited. Herein, we compared survival between resection and other liver-directed therapies for small ICC within a national cancer registry. PATIENTS AND METHODS: Patients with clinical stage I-III ICC < 3 cm diagnosed 2010-2018 who underwent resection, ablation, or RT were identified in the National Cancer Database. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Of 545 patients, 297 (54.5%) underwent resection, 114 (20.9%) ablation, and 134 (24.6%) RT. Median OS was similar between resection and ablation [50.5 months, 95% confidence interval (CI) 37.5-73.9; 39.5 months, 95% CI 28.7-58.4, p = 0.14], both exceeding that of RT (20.9 months, 95% CI 14.1-28.3). RT patients had high rates of stage III disease (10.4% RT vs. 1.8% ablation vs. 11.8% resection, p < 0.001), but the lowest rates of chemotherapy utilization (9.0% RT vs. 15.8% ablation vs. 38.7% resection, p < 0.001). In multivariable analysis, resection and ablation were associated with reduced mortality compared with RT [hazard ratio (HR) 0.44, 95% CI 0.33-0.58 and HR 0.53, 95% CI 0.38-0.75, p < 0.001, respectively]. CONCLUSION: Resection and ablation were associated with improved survival in patients with ICC < 3 cm compared with RT. Acknowledging confounders, anatomic constraints of ablation, limitations of available data, and need for prospective study, these results favor ablation in small ICC where resection is not feasible.

Impact of Tumor Size and Management on Survival in Small Gastric Gastrointestinal Stromal Tumors.

BACKGROUND: Society guidelines remain inconsistent on the role of endoscopic and radiographic surveillance as an alternative to surgical resection of small gastric gastrointestinal stromal tumors (GISTs). Herein, we aimed to assess survival among patients with gastric GISTs undergoing observation versus surgical resection, stratified by tumor size. METHODS: The National Cancer Database (NCDB) was queried for gastric GISTs < 2 cm diagnosed from 2010-2017. Patients were stratified by management strategy-observation vs surgical resection. The primary outcome, overall survival (OS), was examined with Kaplan-Meier and multivariable Cox proportional hazard methods. Subgroup analyses were conducted on tumors < 1 cm and 1-2 cm in size. RESULTS: Altogether, 1208 patients were identified: 439 (36.3%) undergoing observation and 769 (63.7%) receiving surgical resection. In the overall cohort, patients undergoing surgical resection demonstrated improved survival (93.6 vs. 88.8% 5-year OS, p=0.02). In multivariable analysis, upfront surgical resection was not associated with a reduction in mortality; however, there was a significant interaction with tumor size. For patients with tumors < 1 cm, there was no difference in survival based on management strategy. However, resection of tumors 1-2 cm was associated with improved survival relative to surveillance. CONCLUSIONS: While surgical resection and surveillance were associated with similar survival for patients with gastric GISTs < 1 cm, this NCDB analysis suggests that patients with tumor size ≥ 1 cm may benefit from upfront surgical resection. Prospective studies comparing these two approaches and their impact on recurrence-free and disease-specific survival are needed to better align consensus guidelines and recommendations.

Primary tumor resection improves survival of gastrointestinal neuroendocrine carcinoma patients with nonresected liver metastases.

BACKGROUND: The role of primary tumor resection (PTR) in the survival of gastrointestinal neuroendocrine carcinoma (GI-NEC) patients with liver metastases only remains poorly defined. Therefore, we investigated the impact of PTR on the survival of GI-NEC patients with nonresected liver metastases. METHODS: GI-NEC patients with a liver-confined metastatic disease diagnosed between 2016 and 2018 were identified in the National Cancer Database. Multiple imputations by chained equations were used to account for missing data, and the inverse probability of treatment weighting (IPTW) method was used to eliminate selection bias. Overall survival (OS) was compared by adjusted Kaplan-Meier curves and log-rank test with IPTW. RESULTS: A total of 767 GI-NEC patients with nonresected liver metastases were identified. Among all patients, 177 (23.1%) received PTR and had a significantly favorable OS before (median: 43.6 months [interquartile range, IQR, 10.3-64.4] vs. 8.8 months [IQR, 2.1-23.1], p < 0.001 in log-rank test) and after (median: 25.7 months [IQR, 10.0-64.4] vs. 9.3 months [IQR, 2.2-26.4], p < 0.001 in IPTW-adjusted log-rank test) the IPTW adjustment. Additionally, this survival advantage persisted in an adjusted Cox model (IPTW adjusted hazard ratio = 0.431, 95% confidence interval: 0.332-0.560; p < 0.001). The improved survival persisted in subgroups stratified by primary tumor site, tumor grade, and N stage, even in the complete cohort (excluding patients with missing data). CONCLUSIONS: PTR led to improved survival for GI-NEC patients with nonresected liver metastases regardless of primary tumor site, tumor grade, and N stage. However, the decision for PTR should be made on an individualized basis following multidisciplinary evaluation.

Greater Compliance With Early Sepsis Management is Associated With Safer Care and Shorter Hospital Stay.

ABSTRACT: This retrospective, cross-sectional study of U.S. hospitals in Medicare's Inpatient Quality Reporting Program aimed to determine whether variation in Sepsis/Septic Shock (Bundle SEP-1) compliance is linked to hospital size and measures of safety and operational efficiency. Two thousand six hundred and fifty-three acute care hospitals in Medicare's Hospital Compare online database were included in the study. Relationships between SEP-1 bundle compliance, hospital size, and indices of operational excellence (including Patient Safety Index [PSI-90], average length of stay [ALOS] and readmission rate) were analyzed. SEP-1 compliance score was inversely associated with staffed bed number (r = -.14, p < .001), PSI-90 (r = -.01, p < .001), and ALOS (r = -.13, p < .001) in a multivariate analysis. Hospitals in the lowest versus highest quartile by bed number had SEP-1 compliance score of 49.8 ± 20.2% versus 46.9 ± 16.8%, p < .001. Hospitals in the lowest versus highest quartile for SEP-1 score had an ALOS of 5.0 ± 1.2 days versus 4.7 ± 1.1 days and PSI-90 rate of 1.03 ± 0.22 versus 0.98 ± 0.16, p < .001 for both. Although this does not establish a causal relationship, it supports the hypothesis that the ability of hospitals to successfully implement SEP-1 is associated with superior performance in key measures of operational excellence.

Retreatment with talimogene laherparepvec for advanced melanoma.

Aim: Talimogene laherparepvec (T-VEC) is a genetically modified oncolytic herpesvirus approved for the treatment of unresectable, locoregionally advanced and recurrent melanoma. There is little relevant literature in the context of retreatment with T-VEC. Materials & methods: We reviewed four patients aged 71-87 years old with stage IIIB-IV melanoma at treatment who were rechallenged with T-VEC after experiencing recurrence of locoregional disease or prior treatment-limiting toxicity. Results: Cessation of initial treatment was due to one of the following reasons: severe adverse event (one case), mixed response (one case) or complete response (two cases). Three males and one female underwent T-VEC retreatment with a mean of 5.5 injection cycles. Three patients experienced a complete response to retreatment, while one experienced disease progression. Conclusion: Intralesional T-VEC may be effective and well-tolerated in patients who have completed prior T-VEC therapy.

Gratitude at Work: Prospective Cohort Study of a Web-Based, Single-Exposure Well-Being Intervention for Health Care Workers.

BACKGROUND: Emotional exhaustion (EE) in health care workers is common and consequentially linked to lower quality of care. Effective interventions to address EE are urgently needed. OBJECTIVE: This randomized single-exposure trial examined the efficacy of a gratitude letter-writing intervention for improving health care workers' well-being. METHODS: A total of 1575 health care workers were randomly assigned to one of two gratitude letter-writing prompts (self- vs other focused) to assess differential efficacy. Assessments of EE, subjective happiness, work-life balance, and tool engagement were collected at baseline and 1-week post intervention. Participants received their EE score at baseline and quartile benchmarking scores. Paired-samples t tests, independent t tests, and correlations explored the efficacy of the intervention. Linguistic Inquiry and Word Count software assessed the linguistic content of the gratitude letters and associations with well-being. RESULTS: Participants in both conditions showed significant improvements in EE, happiness, and work-life balance between the intervention and 1-week follow-up (P<.001). The self-focused (vs other) instruction conditions did not differentially predict improvement in any of the measures (P=.91). Tool engagement was high, and participants reporting higher motivation to improve their EE had higher EE at baseline (P<.001) and were more likely to improve EE a week later (P=.03). Linguistic analyses revealed that participants high on EE at baseline used more negative emotion words in their letters (P=.005). Reduction in EE at the 1-week follow-up was predicted at the level of a trend by using fewer first-person (P=.06) and positive emotion words (P=.09). No baseline differences were found between those who completed the follow-up assessment and those who did not (Ps>.05). CONCLUSIONS: This single-exposure gratitude letter-writing intervention appears to be a promising low-cost, brief, and meaningful tool to improve the well-being of health care workers.

Improved overall survival is still observed in patients receiving delayed adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic adenocarcinoma.

BACKGROUND: Adjuvant chemotherapy (AC) is associated with improved survival following resection of pancreatic adenocarcinoma but is frequently delayed or deferred due to perioperative complications or patient deconditioning. The aim of this study was to assess impact of delayed AC on overall survival after pancreaticoduodenectomy for pancreatic head adenocarcinoma. METHODS: Patients with stage I-III pancreatic head adenocarcinoma in the 2006-2015 National Cancer Database were grouped by timing of AC (<6-weeks, 6-12-weeks, and 12-24-weeks). Overall survival was compared using Cox proportional hazard models adjusting for patient, tumor, and hospital factors. Subgroup analyses were conducted to assess the impact of comorbidities, readmission or extended hospital stay, and receipt of single- versus multi-agent chemotherapy. RESULTS: Of 13438 patients, 4552 (33.9%) received no AC, 2112 (15.7%) received AC <6-weeks following resection, 5580 (41.5%) within 6-12 weeks, and 1194 (8.9%) within 12-24 weeks. AC was associated with improved overall survival (adjusted hazard ratio [HR] <6-weeks: 0.765, 6-12-weeks: 0.744, and 12-24-weeks: 0.736 (p < 0.001)). This survival advantage persisted for patients with comorbidities, those with postoperative complications, and in those receiving single- or multi-agent regimens. CONCLUSIONS: For patients with stage I-III pancreatic adenocarcinoma, receipt of AC is associated with improved overall survival, even if delayed up to 24-weeks.

Correction to: Sentinel Lymph Node Biopsy and Completion Lymph Node Dissection for Melanoma.

The original version of this article, which published in Current Treatment Options in Oncology, Volume 19, Issue 11, November 2018, contained an error within the Conflict of Interest statements. It was originally stated that "Norma E. Farrow received support from an NIH T32 grant (T32-CA009111."

Efficacy of Talimogene Laherparepvec (T-VEC) Therapy in Patients with In-Transit Melanoma Metastasis Decreases with Increasing Lesion Size.

BACKGROUND: Talimogene laherparepvec (T-VEC) is the first injectable oncolytic viral therapy approved for in-transit melanoma metastasis, with a reported overall response rate (ORR) of 25% and complete response rate (CRR) of 10%. To ascertain the role of patient selection on outcomes in routine practice, we evaluated the impact of patient, lesion, and treatment factors on clinical response. METHODS: Medical records were extracted for patients with recurrent stage IIIB-IV melanoma completing T-VEC at Duke University Medical Center between 1 January 2016 and 1 September 2018. Kaplan-Meier analysis assessed time to response and survival, while logistic regression measured associations of clinicopathologic status, lesion burden, T-VEC dosing, and use of prior and concurrent therapy with ORR and CRR. RESULTS: Of 27 patients, an objective response was observed in 11 (40.7%), including one patient with partial response (3.7%) and 10 with complete response (37.0%). Time to complete response and overall response was a median 22 weeks (95% confidence interval [CI] 2.0-41.9 weeks and 15.8-28.2 weeks, respectively), and median progression-free survival was 17 weeks (95% CI 0-36 weeks). Logistic regression demonstrated each millimeter increase in maximum lesion diameter predicted decreased ORR (odds ratio [OR] 0.866, 95% CI 0.753-0.995; p = 0.04). Stage IV disease (OR 0.04, 95% CI 0.00-0.74; p = 0.031) and programmed death-1 inhibitor treatment (OR 0.06, 95% CI 0.01-0.74; p = 0.028) also predicted reduced clinical response. CONCLUSIONS: This study corroborates recent data suggesting response rates to T-VEC may be higher than reported in clinical trials, arising in part from patient selection. T-VEC lesion diameter was persistently associated with clinical response and is a readily assessed predictor of successful T-VEC therapy.

Sentinel Lymph Node Biopsy and Completion Lymph Node Dissection for Melanoma.

OPINION STATEMENT: This review critically evaluates recent trials which have challenged the practice of completion lymph node dissection (CLND) for melanoma patients diagnosed with regional metastasis by positive sentinel lymph node biopsy (SLNB). Two trials in the last 2 years, DeCOG-SLT and MSLT-II, found no significant differences in melanoma-specific survival between patients, whether they received immediate CLND or observation after positive SLNB, despite decreases in nodal recurrence achieved by dissection. These trials together disfavor routine CLND in most patients after positive SLNB. However, their conclusions are limited by study populations which overall harbored a lower burden of SLN disease. Special attention needs to be given to patients who do have higher risk disease, with SLN tumor burdens exceeding 1 mm in diameter, for whom CLND may remain both prognostic and therapeutic. Current guidelines thus recommend either CLND or careful observation after positive SLNB after appropriate risk stratification of patients. While a decline in CLND is inevitable, treatment of stage III melanoma is witnessing the concurrent rise of effective adjuvant therapies. PD-1 inhibitors such as nivolumab, or combination BRAF/MEK inhibitors for V600E or K mutant melanoma, which were previously available to only trial patients with completely resected stage III disease, are now approved for use in patients with positive SLNB alone. Providers are better equipped than ever to treat clinically occult, regional metastatic disease with SLNB followed by adjuvant therapy for most patients, but should take steps to avoid undertreatment of high-risk patients who may proceed to disease relapse or progression.

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

BET bromodomain inhibition of MYC-amplified medulloblastoma.

PURPOSE: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. EXPERIMENTAL DESIGN: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. RESULTS: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. CONCLUSION: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.