Search

Hepatic artery infusion (HAI) is a liver-directed therapy that delivers high-dose chemotherapy to the liver through the hepatic arterial system for colorectal liver metastases and intrahepatic cholangiocarcinoma. Utilization of HAI is rapidly expanding worldwide.This review describes the conduct of HAI pump implantation, with focus on common technical pitfalls and their associated solutions. Perioperative identification and management of common postoperative complications is also described.HAI therapy is most commonly performed with the surgical implantation of a subcutaneous pump, and placement of its catheter into the hepatic arterial system for inline flow of pump chemotherapy directly to the liver. Intraoperative challenges and abnormal hepatic perfusion can arise due to aberrant anatomy, vascular disease, technical or patient factors. However, solutions to prevent or overcome technical pitfalls are present for the majority of cases. Postoperative HAI-specific complications arise in 22% to 28% of patients in the form of pump pocket (8%-18%), catheter (10%-26%), vascular (5%-10%), or biliary (2%-8%) complications. The majority of patients can be rescued from these complications with early identification and aggressive intervention to continue to deliver safe and effective HAI therapy.This HAI toolkit provides the HAI team a reference to manage commonly encountered HAI-specific perioperative obstacles and complications. Overcoming these challenges is critical to ensure safe and effective pump implantation and delivery of HAI therapy, and key to successful implementation of new programs and expansion of HAI to patients who may benefit from such a highly specialized treatment strategy.

Background Colorectal cancer (CRC) is the second-leading cause of cancer-related death worldwide and resection of CRC metastases confined to the liver is the treatment of choice when feasible. Ferumoxytol is an off-label contrast agent that opacifies vasculature and may be helpful in distinguishing metastases from small hemangiomas and blood vessels on gadoxetic acid-enhanced magnetic resonance imaging (MRI). Purpose To compare the diagnostic accuracy of MRI using a standard gadoxetic acid protocol and a combined gadoxetic acid/ferumoxytol protocol in patients with suspected colorectal hepatic metastases. Material and Methods In this institutional review board-approved, single-institution, retrospective study, eight patients underwent gadoxetic acid-enhanced liver MRI, supplemented with additional T1-weighted ferumoxytol enhanced sequences. Two radiologists in consensus identified all metastases using all available sequences, which served as the reference standard. Two different radiologists reviewed each exam twice, once using the standard protocol and once with additional ferumoxytol sequences. The detection rate was estimated as the predicted probability of a metastasis along with the 95% confidence interval (CI) using hierarchical logistic regression models. Results A total of 49 metastases were identified. The mean diameter was 10 mm, measured in greatest axial dimension (median=7 mm; range=2–70 mm). Readers 1 and 2 had detection rates of 69.6% (95% CI = 48.2–85.0) and 53.1% (95% CI = 35.2–70.3) for gadoxetic acid alone and 98.0% (95% CI = 86.3–99.7) and 83.5% (95% CI = 59.3–94.7) for combined protocol. Conclusion In this preliminary investigation, adding ferumoxytol-enhanced sequences to gadoxetic acid liver MRI protocol increased the detection rate of CRC hepatic metastases and may aid in preoperative decision making.

SWOG 0809 is the only prospective study of adjuvant chemotherapy followed by chemoradiation focusing on margin status in patients with extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer (GBCA); however, the effects of adjuvant therapy by nodal status have never been reported in this population.Patients with resected EHCC and GBCA, stage pT2-4, node-positive (N+) or margin-positive (R1) who completed four cycles of chemotherapy followed by radiotherapy were included. Cox regression was used to compare overall survival (OS), disease-free survival (DFS), local recurrence, and distant metastasis by nodal status. DFS rates were compared with historical data via a one-sample t-test.Sixty-nine patients [EHCC, n = 46 (66%); GBCA, n = 23 (33%)] were evaluated, with a median age of 61.7 years and an R0 rate of 66.7% and R1 rate of 33.3%. EHCC versus GBCA was more likely to be N+ (73.9% vs. 47.8%, p = 0.03). Nodal status did not significantly impact OS (hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.86-4.54, p = 0.11) or DFS (HR 1.63, 95% CI 0.77-3.44, p = 0.20). Two-year OS was 70.6% for node-negative (N0) disease and 60.9% for N+ disease, while 2-year DFS was 62.5% for N0 tumors and 49.8% for N+ tumors. N+ versus N0 tumors showed higher rates of distant failure (42.2% vs. 25.0%, p = 0.04). The 2-year DFS rate in N+ tumors was significantly higher than in historical controls (49.8% vs. 29.7%, p = 0.004).Adjuvant therapy is associated with favorable outcome independent of nodal status and may impact local control in N+ patients. These data could serve as a benchmark for future adjuvant trials, including molecular-targeted agents.

The application of advanced genomic testing to develop tumor-specific molecular profiles is essential to facilitating precision medicine pharmacotherapy. These approaches are highly relevant in colorectal cancer, where tumors frequently contain druggable molecular mutations, as well as the potential to respond to immunotherapy. Here we review the literature characterizing biomarker-driven pharmacotherapy for colorectal cancer, and highlight the pivotal ongoing trials that will help inform future treatment of this disease. Both prospective and retrospective studies have confirmed that the benefit from adding anti-epidermal growth factor receptor therapy is limited to patients with stage IV disease, RAS wild-type tumors, and left-sided primary tumors. Furthermore, patients with BRAF-mutated tumors derive significantly less benefit from the addition anti-epidermal growth factor receptor therapy. The use of BRAF inhibitors in the second-line setting is associated with a relatively high response rate, and regimens incorporating first-line treatment with BRAF inhibitors may soon become standard of care for patients with BRAF-mutated tumors. In the relapsed setting, the use of targeted agents and immunotherapy should be prioritized for patients with respective tumor profiles. There has been significant advancement in the understanding of how to utilize molecular profiling and tumor biomarkers to tailor pharmacotherapy in colorectal cancer. Future studies should continue to incorporate these tests at enrollment to further define patient cohorts deriving the greatest benefit from precision medicine, characterize ideal sequence of therapy, and advance understanding of drug resistance mechanisms.

ImportanceDespite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood.ObjectiveTo define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics.Design, Setting, and ParticipantsPragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment.InterventionThe intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care).Main Outcomes and MeasuresThe primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program.ResultsThe trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, −13.0% [95% CI, −19.1% to −6.9%]; P P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, −6.3% [95% CI, −11.4% to −1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, −1.2% [95% CI, −3.1% to 0.7%]; P = .32).Conclusions and RelevanceIn participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy.Trial RegistrationClinicalTrials.gov Identifier: NCT03269994

To provide an overview of the key findings from studies in upper gastrointestinal, hepatobiliary, pancreas, and colorectal malignancies presented at ASCO GI 2022.We reviewed the abstracts presented at ASCO GI 2022. The studies highlighted were selected by the authors based on their significant discoveries and potential impact on clinical practice.This year's hybrid ASCO-GI symposium (2022) introduced many promising new treatment strategies in GI oncology, with several changes in clinical practice for patients with advanced hepatocellular carcinoma (HCC), cholangiocarcinoma, and metastatic colorectal cancer (CRC).

Background: Widespread implementation of HAI pump chemotherapy has been limited by logistic and feasibility concerns. Recent studies demonstrating excellent outcomes have fueled renewed enthusiasm and multiple new programs have emerged. This survey aims to identify barriers critical to establish a successful HAI program. Methods: Using SurveyMonkey™, a 17-question survey assessing factors required for establishing a successful program was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses. Frequency of categories and average rank scores for each choice were calculated. Results: Twenty-eight HCRN members responded to the survey. Implementation time varied, with 15 institutions requiring less than a year. Most programs (n = 17) became active in the past 5 years. Medical and surgical oncology were ranked most important for building a program (average ranking scores: 7.96 and 6.59/8). Administrative or regulatory approval was required at half of the institutions. The top 3 challenges faced when building a program were related to regulatory approval (6.65/9), device/equipment access (6.33/9), and drug (FUDR) access (6.25/9). Conclusion: Development of successful programs outside of historically established centers is feasible and requires a multidisciplinary team. Future collaborative efforts are critical for sustainability of safe/effective new programs.

BACKGROUND: Two-stage hepatectomy (TSH) is an important tool in the management of bilateral colorectal liver metastases (CRLM). This study sought to examine the presentation, management and outcomes of patients completing TSH in major hepato-biliary centers in the United States. METHODS: A retrospective review from 5 liver centers in the United States identified patients who completed a TSH procedure for bilateral CRLM. RESULTS: From December 2000 to March 2016, a total of 196 patients were identified. The majority of procedures were performed with an open technique (n = 194, 99.5%). The median number of tumors was 7 (range, 2–33). One-hundred twenty-eight (65.3%) patients underwent portal vein embolization. More patients received chemotherapy prior to the first stage than chemotherapy administration preceding the second stage (92% vs. 60%, p = 0.308). Median overall survival was 50 months with a median follow-up of 28 months (range, 2–143). Hepatic artery infusion chemotherapy was administered to 64 (32.7%) patients with similar overall survival (OS) to those managed without an infusion pump (p = 0.848). Postoperative morbidity following the second stage resection was 47.4%. Chemotherapy prior to the second stage did not demonstrate an increased complications rate (p = 0.202). Readmission following the second stage was 10.3% and was associated with a decrease in disease-free survival (p = 0.003). Overall survival was significantly decreased by positive resection margins and increased estimated blood loss (EBL) (p = 0.036 and p = 0.05, respectively). CONCLUSION: This is the largest TSH series in the U.S. and demonstrates evidence of safety and feasibility in the management of bilateral CRLM. Outcomes are influenced by margin status and operative EBL.

BackgroundHepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population.MethodsConsecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regressionwas used to determine whether laterality was an independent prognostic factor.ResultsFrom 1993 to 2012, 487 patients [182 with right colon cancer (RCC),305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5years. Fifty-seven percent(n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%,P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%;P

BACKGROUND Controversy exists regarding the safety and feasibility of minimally invasive resection for lesions in segments 7 or 8. We compare outcomes of minimally invasive surgery (MIS) and Open parenchymal sparing liver resections at two high-volume centers. METHODS From 2003 to 2016 we identified patients who underwent MIS or Open resections for lesions in segments 7 or 8 at two institutions (MSKCC and SGH). Outcomes were compared using univariate and multivariate analyses. RESULTS Two-hundred and forty-five patients underwent resection of lesions in segments 7 or 8 (MIS 30% and Open 70%). Compared to the Open group, the MIS group had longer operative time (223 ± 88 vs 188 ± 72 minutes, P = .003), lower blood loss (297 ± 287 vs 448 ± 670 mL, P = .03), and shorter mean length of stay (5.2 ± 7.4 vs 8.3 ± 11.7 days, P

TPS265 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repair genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N = 75), patients with previously treated MSS, BRAFV600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients will receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and patients in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α = .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional patient specimens will be collected for exploratory correlative research. The study activated across the United States in June 2022 and as of September 2022 has enrolled 2 of 75 planned participants. Funding: NIH/National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by The Hope Foundation for Cancer Research STrS award. Clinical trial information: NCT05308446 .

249 Background: An estimated 85% of CRC are microsatellite stable (MSS) and this population has limited response to immune checkpoint inhibitors (ICIs). Biomarkers are needed to identify responders. Although pembrolizumab received FDA universal approval for chemorefractory cancers with tissue TMB-H > 10 mut/Mb, it is not effective across all TMB-H cancers. We aim to identify TMB-H/MSS CRC patients that derive benefit from ICIs through analysis of circulating tumor DNA (ctDNA). Methods: We retrospectively queried Guardant Health database (2020-2022) for patients with advanced CRC who had ctDNA NGS (Guardant360, Redwood City, CA) as part of routine clinical care. The assay covers a 1Mb panel for TMB that counts synonymous and non-synonymous somatic SNVs and indels to calculate a TMB score. Co-mutations were evaluated for MSS cancers with plasma TMB-H; ≥20mut/Mb vs those with low TMB (TMB-L; < 20mut/Mb). RAS- mutated signature was defined as those harboring an activating somatic alteration in KRAS, NRAS, or BRAF. Statistical significance was calculated using Fisher’s exact test. Results: We identified 6412 CRC patients: 11% (711) TMB-H/MSS (median age 64), 69% (4426) TMB-L/MSS (median age 62), 3% MSI-H, and 17% unevaluable. When compared to TMB-L/MSS, patients with TMB-H/MSS had a significantly higher frequency of select genetic mutations, including TP53, APC, KRAS, EGFR, and PIK3CA (p < 0.001). Treatment-naïve TMB-H/MSS cancers had a higher frequency of ARID1A (p = 0.05) and TERT (p = 0.02) alterations, while those post therapy progression had higher frequency of KRAS (p = 0.02), EGFR (p < 0.001), and MAP2K1 (p = 0.002) alterations. A total of 556 (78%) CRC patients in the TMB-H/MSS cohort harbored a RAS-mutated genetic signature. Of those, 432 (78%) belonged to the post therapy progression group, likely representing adaptive clones post anti-EGFR therapy. While RAS-mutated tumors had a higher prevalence of PIK3CA (p = 0.001) and SMAD4 (p = 0.007) co-alterations, RAS-wildtype ones carried a higher frequency of ERBB2 (p = 0.068) alterations. Conclusions: We describe the genomic landscape of patients with plasma TMB-H/MSS CRC. A clinical cohort of TMB-H/MSS CRC patients identified by ctDNA and treated with ICIs will be presented.

166 Background: Recently, there has been a breakthrough in the treatment and disease control of HER-2 positive mCRC using Trastuzumab (TRA) +Tyrosine Kinase inhibitor (TKI) regimens and regimens with trastuzumab based antibody drug conjugates (ADCs). Methods: A total of 14 randomized controlled trials and single arm clinical trials were collected from PubMed, Cochrane library, and Embase. 7 trials were excluded for being duplicate, irrelevant or because of lack of response from the trial researchers. Data from the remaining 7 articles was extracted either from the full publication or from researchers for undergoing studies. Trials using similar drug combinations were added up and results were reported cumulatively. Results: The data demonstrate an ORR of 30% or greater with the ADC, TRA deruxtecan or TRA+Tucatinib regimen with the Tucatinib combination being the most efficacious (38.10%), followed closely by the Deruxtecan ADC (36.99%). Promising disease control rate (DCR) was observed with all the combinations with TRA-Ematasin + Pertuzumab leading the charts (77.40%). TRA-Lapatinib provided the longest PFS (16.75 months) followed by TRA-Tucatinib (8.2 months) (Table). Most common treatment related adverse events (AEs) were fatigue, nausea, vomiting, diarrhea and dermatitis. More nausea/vomiting reported with TRA-deruxtecan (64.4%), while more diarrhea reported with TRA-lapatinib (81%) and TRA-tucatinib (52.3%). Dermatitis was reported mostly with TRA-lapatinib (44%) and TRA-tucatinib (17.4%). Conclusions: Our analysis shows that combination treatment with TRA-Deruxtecan and TRA-tucatinib are associated with the highest ORR and DCR in HER2+ mCRC. Long term data are needed to define clinical efficacious based on survival endpoints.[Table: see text]

TPS784 Background: Small bowel adenocarcinoma is a rare malignancy with limited evidence to support the choice of systemic chemotherapy beyond the frontline setting. Though second-line therapy has historically been extrapolated from colorectal cancers, recent molecular data has demonstrated small bowel adenocarcinoma to be genomically unique when compared to either colon or gastric cancer. Retrospective analyses of irinotecan- and taxane-based therapies and one prospective phase II clinical trial of nab-paclitaxel have demonstrated clinical activity in this cancer. Ramucirumab/paclitaxel represents an active combination in the management of gastric cancer. SWOG 1922 evaluates the use of FOLFIRI or ramucirumab/paclitaxel in the second- and later-line setting for small bowel adenocarcinoma. Methods: This is randomized, phase II, selection design clinical trial of FOLFIRI (5-fluorouracil, leucovorin and irinotecan) every two weeks or ramucirumab D1,15 and paclitaxel D1,8,15 every 4 weeks with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response rate, overall survival, and safety. Archived paraffin tumor tissue collection and serial blood collections are included for correlative analyses. Key eligibility criteria include having mismatch repair proficient/microsatellite stable small bowel adenocarcinoma (ampullary location excluded); metastatic or locally advanced unresectable disease; prior fluoropyrimidine and/or oxaliplatin therapy; no prior treatment with irinotecan, ramucirumab, or taxanes; no recent bleeding, blood clots, or bowel perforation/fistula; and Zubrod performance status of 0/1. Measurable disease is not required. The null hypothesis is median PFS of 2.5 months. If a median PFS of at least 3.5 months is observed in one or both arms, the goal is to choose the better regimen with respect to this endpoint. The design provides a 90% probability of selecting the more active arm, assuming a hazard ratio of 1.4, if both arms meet this threshold. This trial is open and, as of September 1, 2021, 21 of 94 planned patients have been enrolled. NCT04205968 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by Eli Lilly and Company. Clinical trial information: NCT04205968 .

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]

Simple Summary Cholangiocarcinoma (CCA) is a group of rare cancers that are associated with poor prognosis. Biomarker testing may provide CCA patients access to effective, personalized treatment options. However, several barriers exist to the seamless adoption of precision medicine in patients with CCA. Experts from the University of California (UC) Davis and UC Irvine identified gaps in standard practices for biomarker testing and recommended best practices, which are summarized in this review. Abstract Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Author(s): Bateni, Sarah B; Gingrich, Alicia A; Kirane, Amanda R; Sauder, Candice AM; Gholami, Sepideh; Bold, Richard J; Meyers, Frederick J; Canter, Robert J

Background Early infantile epileptic encephalopathy is a severe form of epilepsy that is genetically extremely heterogeneous and characterized by seizures or spasms at the beginning of infancy. Homozygous or compound heterozygous mutation in the CAD gene cause early infantile epileptic encephalopathy-50 (EIEE50). This case report describes the clinical and molecular features of three patients affected with early infantile epileptic encephalopathy. Case presentation In this report, we describe the clinical features of two deceased daughters and one recently deceased son affected with seizure, muscular hypotonia, and developmental delay. After genetic counseling, blood samples were obtained from the parents, and whole-exome sequencing was performed. Genomic DNA was extracted from whole blood, and mutation analysis was performed using PCR and sequencing methods for the CAD gene. Genetic analysis using the whole-exome sequencing method has detected a novel likely pathogenic mutation on CAD gene, c.2995G > A (p.Val999Met), in heterozygous states in asymptomatic parents and homozygous state in affected newborn son. This mutation has not been reported in the literature for its pathogenicity. Conclusions The asymptomatic parents are carriers for the likely pathogenic variant in the CAD gene, and the recently deceased newborn son had the same mutation in a homozygous state. Given that, multiple lines of in silico computational analysis support the detrimental impact of the variant on the gene, and this variant is absent in population databases. Pathogenic mutations in the CAD gene are related to autosomal recessive EIEE50 with similar signs and symptoms to our patients. Ultimately, it is confirmed that this mutation is causative in our patients.

Background Although malignant bowel obstruction (MBO) often is a terminal event, systemic therapies are advocated for select patients to extend survival. This study aimed to evaluate factors associated with receipt of chemotherapy after MBO and to determine whether chemotherapy after MBO is associated with survival. Methods This retrospective cohort study investigated patients 65 years of age or older with metastatic gastrointestinal, gynecologic, or genitourinary cancers who were hospitalized with MBO from 2008 to 2012 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Fine and Gray models were used to identify factors associated with receipt of chemotherapy accounting for the competing risk of death. Cox models identified factors associated with overall survival. Results Of the 2983 MBO patients, 39% (n = 1169) were treated with chemotherapy after MBO. No differences in receipt of chemotherapy between the surgical and medical patients were found in the univariable analysis (subdistribution hazard ratio [SHR], 0.96; 95% confidence interval [CI], 0.86–1.07; p = 0.47) or multivariable analysis (SHR, 1.12; 95% CI, 1.00–1.26; p = 0.06). Older age, African American race, medical comorbidities, non-colorectal and non-ovarian cancer diagnoses, sepsis, ascites, and intensive care unit stays were inversely associated with receipt of chemotherapy after MBO (p < 0.05). Chemotherapy with surgery was associated with longer survival than surgery (adjusted hazard ratio [aHR], 2.97; 95% CI, 2.65–3.34; p < 0.01) or medical management without chemotherapy (aHR, 4.56; 95% CI, 4.04–5.14; p < 0.01). Subgroup analyses of biologically diverse cancers (colorectal, pancreatic, and ovarian) showed similar results, with greater survival related to chemotherapy (p < 0.05). Conclusions Chemotherapy plays an integral role in maximizing oncologic outcome for select patients with MBO. The data from this study are critical to optimizing multimodality care for these complex patients.

Low back pain (LBP) as a recurrent and costly health problem and one of the leading causes of disability, is common in nurses. It can have adverse effects on the quality of life of nurses and quality of care of patients. The aim of the study was to evaluate the effectiveness of Back School program on the LBP and functional disability of Iranian nurses. A quasi-experimental methodological design was utilized for this study. Participants were nurses with back pain who participated in the Back School program workshop and completed a self-report visual analogue scales and Roland-Morris Disability questionnaire that measuring LBP and functional disability. Data were analyzed descriptively and comparisons in LBP and functional disability made between groups with t-test for pre-intervention and analysis of covariance for after intervention. Sixty-four participants (16 males, 48 females) completed this survey. The study participants' mean age was 38.9 ± 8.1 years in intervention group and 38.1 ± 8.2 in control group. There were no significant differences in terms of pain (P = 0.575) and disability scores (P = 0.844) before intervention. Although, the intervention led to a decrease in the functional ability and LBP scores of the nurses (P

The main aim of this study is simple and fast authentication of extra virgin olive oil by different spectroscopic techniques individually and also in combination with minimal chemical waste. UV spectra of the EVOO and mixed olive oil samples were recorded before the heating test and then along the thermal degradation experiments at the 45- and 90-mins intervals set for the analysis. The EVOO and mixed oils samples showed high absorption values around 240-300 nm band. The results showed that the characteristics of FTIR spectra including peak number, peak position and peak shape in mixed samples were significantly different from EVOO samples. According to the studies, the frequencies of around 2920 cm−1 and 2856 cm−1 could be related with C–H stretching (e.g. cis-double bonds) and with –C–H asymmetrical and symmetrical stretching in methylene groups. The frequency at 2925 cm−1 is associated with aliphatic CH2 groups. Around 1366 cm−1 and 1451 cm−1, these frequencies could be associated with the bending vibrations of C–H groups. The results reveal that the UV–VIS and FT-IR analytical tools are the most suitable and reliable tools to detect and quantify high levels (over 10%) of adulteration in mixes of EVO with other vegetable oils.

4142 Background: The composition of the tumor microenvironment (TME) in PDACs is more heavily driven by mutant (mt) KRAS than any other cancer. How genomic alterations of PDAC including KRAS status affect the immune cell (IC) landscape remains unclear. Thus, we characterized IC types and the prevalence of immuno-oncologic (IO) biomarkers in PDAC by genomic and transcriptomic analysis, and investigated associations of mt KRAS with IC estimates in the TME. Our findings were compared to our previous study in CRC. Methods: A total of 4,142 PDAC and 3,727 CRC with KRAS- mts were analyzed using next-generation DNA sequencing (NextSeq, 592 gene panel or NovaSeq, WES), IHC, and whole transcriptome RNA sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by FA, IHC and NGS. TMB-H was classified based on a cut-off of >10 mutations per MB. ICs were estimated by QuantiSeq (Finotello 2019, Genome Medicine) or MCP counter (Betcht 2016, Genome Biology). Significance was determined by X2 and Fisher-Exact and p-adjusted for multiple comparisons (q+ & CD8+ T cells, T-reg, NK, myeloid dendritic and endothelial cells compared to KRAS wt. In CRC, a similar pattern was observed but more pronounced in PDAC. Immune-regulatory markers, were among multiple genes downregulated in KRAS-mt PDAC, including CTLA-4 and LAG3. Overall changes were most pronounced in cases harboring KRAS G12D, G12V, Q61, and rare KRAS variants. Conclusions: The TME of KRAS mt PDAC shows IC patterns similar to KRAS mt CRC. Actionable IO-targets, such as PDL1, are enriched in tumors harboring specific variants of KRAS mt PDAC including the targetable G12C variant. If G12D becomes druggable, it could be targetable in 35% patients with PDAC or 15% in CRC. These results demonstrate that the TME of PDAC and CRC shows immune-cold features. Tailored immunotherapeutic strategies would have to overcome these barriers in KRAS mt PDAC and CRC, possibly in combination with molecularly targeted treatment strategies.