Search

PURPOSE Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

Immune checkpoint inhibitor therapy represents a significant advance in cancer care. The interaction between PD-1 and PD-L1 induces immune tolerance and the inhibition of this interaction is an effective treatment strategy for numerous malignancies. Despite its demonstrated potential, immunotherapy is not clinically effective in immunogenically ‘cold’ tumors such as pancreatic cancer, prostate cancer and neuroendocrine tumors. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade in tumors that have traditionally shown a lack of clinical response to immunotherapy. This signal-seeking, single-arm, prospective clinical trial aims to determine the objective response of tivozanib and atezolizumab in advanced immunogenically cold solid tumors. Clinical Trial Registration: NCT05000294 ( ClinicalTrials.gov ).

PURPOSE: Recent literature suggests an increasing use of systemic treatment in patients with advanced cancer near the end of life (EOL), partially driven by the increasing adoption of immune checkpoint inhibitors (ICIs). While studies have identified this trend, additional variables associated with ICI use at EOL are limited. Our aim was to characterize a population of patients who received a dose of ICI in the last 30 days of life. METHODS: We performed a manual retrospective chart review of patients ≥ 18 years who died within 30 days of receiving a dose of ICI. Metrics such as Eastern Cooperative Oncology Group performance status (ECOG PS), number of ICI doses, need for hospitalization, and numerous other variables were evaluated. RESULTS: Over a 4-year time period, 97 patients received an ICI at EOL. For 40% of patients, the ICI given in the 30 days before death was their only dose. Over 50% of patients had an ECOG PS of ≥ 2, including 17% of patients with an ECOG PS of 3. Over 60% were hospitalized, 65% visited the emergency department, 20% required intensive care unit admission, and 25% died in the hospital. CONCLUSION: Our study contributes to the ongoing literature regarding the risks and benefits of ICI use in patients with advanced cancer near the EOL. While accurate predictions regarding the EOL are challenging, oncologists may routinely use clinical factors such as ECOG PS along with patient preferences to guide recommendations and shared decision making. Ultimately, further follow-up studies to better characterize and prognosticate this population of patients are needed.

Background Patient and clinician reminders were implemented as part of an adherence improvement project at University of Florida (UF) Internal Medicine Clinics. We sought to assess colorectal cancer (CRC) screening completion rates among patients not up-to-date with screening following distribution of reminders and to identify characteristics correlated with screening outcomes. Methods Retrospective chart review was performed for patients not up-to-date with CRC screening for whom at least one reminder (patient and/or clinician) was issued in June 2018. The primary endpoint, the completion of a CRC screening test, is characterized as the ratio of completed screening tests to the number of patients not up-to-date with screening. All analyses were performed using R 4.0 software. Results Of the 926 patients included, 403 (44%; 95% CI, 0.40–0.47) completed a CRC screening test within 24 months following a reminder. Family history of CRC (relative risk (RR) 1.33; P = 0.007), flu immunization within two years of the reminder (RR 1.23; P = 0.019), and receiving a patient reminder either alone (RR 1.62; P P = 0.006) were positively associated with CRC screening completion. Reporting being divorced, separated, or widowed was negatively associated with screening completion (RR 0.70; P = 0.004). Conclusion Reminders, in particular patient reminders, seem to be an effective method to enhance screening among patients not up-to-date with CRC screening. This study suggests that reminder efforts should be focused at the level of the patients and provides insight on target populations for practical interventions to further increase CRC screening adherence.

Background CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). Methods Patients received oleclumab 5–40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. Results 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. Conclusions Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab’s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. Clinical trial registration Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

Supplementary Figure legends for figures S1 and S2. Figure S1 Legend provides experimental information for the effect of YM155 on Panc-1 cells. Figure S2 Legend provides experimental information for the effect of YM155 on PC-3 cells.

Figure S1 shows the effect of YM155 on Panc-1 cells as evidenced by hoechst staining, DNA ladder assay and western blotting analysis of caspases 3, 8 as well as BID and PARP. Figure S2 shows the effect of YM155 on another pancreatic cell line PC-3 as evidenced by hoechst staining and western blotting analysis of survivin and DR5 expression.

Purpose:In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.Patients and Methods:Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.Results:Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples.Conclusions:The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

Supplemental Figure Legends

Figure SF3 Comparisons of the expression of the NRG family of ERBB ligands, at the RNA level, between post-anti-EGFR metastatic biopsies collected upon enrollment into FC-7, and post-neratinib residual tumor tissue samples.

Nicotine treatment does not lead to c-Met activation in PC cells.

Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the cross-talk between pancreatic cancer and its TAS in primary human cell culture models. Upon exposure of TAS to pancreatic cancer cell-conditioned media, we documented robust secretion of IL6 and IL8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T-cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared with healthy controls. The TAS response also directly suppressed CD8+ T-cell–mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Res; 77(3); 672–83. ©2016 AACR.

Supplemental Figure S2. Nicotine-mediated induction of c-Met is Src-dependent.

Purpose: The relationship between smoking and pancreatic cancer biology, particularly in the context of the heterogeneous microenvironment, remains incompletely defined. We hypothesized that nicotine exposure would lead to the augmentation of paracrine growth factor signaling between tumor-associated stroma (TAS) and pancreatic cancer cells, ultimately resulting in accelerated tumor growth and metastasis.Experimental Design: The effect of tobacco use on overall survival was analyzed using a prospectively maintained database of surgically resected patients with pancreatic cancer. Nicotine exposure was evaluated in vitro using primary patient–derived TAS and pancreatic cancer cells independently and in coculture. Nicotine administration was then assessed in vivo using a patient-derived pancreatic cancer xenograft model.Results: Continued smoking was associated with reduced overall survival after surgical resection. In culture, nicotine-stimulated hepatocyte growth factor (HGF) secretion in primary patient-derived TAS and nicotine stimulation was required for persistent pancreatic cancer cell c-Met activation in a coculture model. c-Met activation in this manner led to the induction of inhibitor of differentiation-1 (Id1) in pancreatic cancer cells, previously established as a mediator of growth, invasion and chemoresistance. HGF-induced Id1 expression was abrogated by both epigenetic and pharmacologic c-Met inhibition. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Similarly, elevated levels of phospho-Met in surgically resected pancreatic cancer specimens correlated with reduced overall survival.Conclusions: Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer. Clin Cancer Res; 22(7); 1787–99. ©2015 AACR.

Figure SF2: cfDNA mutational analysis cfDNA from plasma collected upon enrollment was analyzed for mutations with a 74-gene Guardant panel (1). Alterations were identified in 30 genes as shown in the figure. Patient IDs: Green=Stable Disease, Red=Progressive Disease, and Black=non-evaluable. Specific patients are discussed below and in the main text.

PURPOSE To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Traditional clinical trial eligibility criteria restrict study populations, perpetuating enrollment disparities. We aimed to assess implementation of modernized eligibility criteria guidelines among pancreatic cancer (PC) clinical trials. Interventional PC trials in the United States since January 1, 2014, were identified via clinicaltrials.gov with December 31, 2017, as the transition for pre- and postguidance eras. Trials were assessed for guideline compliance and compared using Fisher exact test. In total, 198 trials were identified: 86 (43.4%) were pre- and 112 (56.6%) postguidance era. Improvements were seen in allowing patients with history of HIV (8.6% vs 43.8%; P 95%) trials were compliant with laboratory reference ranges, QT interval corrected for heart rate (QTc) cutoffs, and rationalizing excluding prior therapies both pre- and postguidance eras. However, overall compliance with modernized criteria remains poor. We advocate for stakeholders to update protocols and scrutinize traditionally restrictive eligibility criteria.

We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients withThe pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.Sotorasib showed anticancer activity and had an acceptable safety profile in patients with

Preclinical cancer models harboringPatients aged ≥ 18 years with measurable disease and refractory solid tumors harboringThirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue.Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring

The ability to detect circulating tumor DNA (ctDNA), a novel surrogate for minimal residual disease (MRD) for patients with solid tumors, has significantly evolved over the past decade. Several studies have shown that ctDNA may provide clinical insight into the biological dynamics of MRD. The CIRCULATE-US (NRG-GI008; NCT05174169) trial will aim to address the role of ctDNA for risk stratification to intensify and deintensify adjuvant chemotherapy for patients with early-stage colon cancer.CIRCULATE-US, a prospective phase 2/3 randomized trial, is investigating the molecular dynamics and prognostic role of ctDNA (evaluated by Natera's Signatera assay) for patients with resected colon cancer. Patients with negative postoperative ctDNA will be enrolled in cohort A and randomized to receive either immediate treatment with 5-fluorouracil and folinic acid or capecitabine plus oxaliplatin (FOLFOX6 or CAPEOX; Arm 1) or serial ctDNA surveillance with delayed adjuvant therapy (Arm 2). Patients randomized to Arm 2 with subsequent positive ctDNA results will be enrolled in cohort B for a second randomization to receive either FOLFOX6/CAPEOX (Arm 3) or 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX; Arm 4) for 6 months. Patients with positive postoperative ctDNA results will be directly enrolled in cohort B and randomized to receive either FOLFOX6/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4). Patients with stage II or stage IIIC colon cancer with positive ctDNA results (tested as standard of care with commercial testing) will be eligible for enrollment in cohort B. The primary end point for cohort A is time to positive ctDNA status for phase 2 and disease-free survival for phase 3 with a noninferiority design. The primary end point for cohort B is disease-free survival for both phase 2 and phase 3 with a superiority design.CIRCULATE-US will aim to understand postoperative ctDNA dynamics in early-stage colon cancer and will investigate escalation and de-escalation approaches by using ctDNA status as a surrogate for MRD status.

BACKGROUND Social determinants of health (SDoH), such as geographic neighborhoods, access to healthcare, education, and social structure are important factors affecting people’s health and health outcomes. SDoH of patients are scarcely documented in a discrete format in electronic health records (EHRs) but are often available in free-text clinical narratives such as physician notes. Innovative methods like natural language processing (NLP) are being developed to identify and extract SDoH from EHRs, but it is imperative that the input of key stakeholders is included as NLP systems are designed. OBJECTIVE Understand the feasibility, challenges, and benefits of developing an NLP system to uncover SDoH from clinical narratives by conducting interviews with key stakeholders: 1) clinicians, 2) data analysts, 3) citizen scientists and 4) patient navigators. METHODS Individuals who frequently work with SDoH data were invited to participate in in-depth, semi-structured interviews. All interviews were recorded and subsequently transcribed. After coding transcripts and developing a codebook, the constant comparative method was used to generate themes. RESULTS A total of 16 participants were interviewed (five data analysts, four patient navigators, four physicians, and three citizen scientists). Two themes emerged related to collecting SDoH: 1) the importance of SDoH data and 2) SDoH arises during patient-clinician communication. The challenges of collecting SDoH data included: 1) informal communication and 2) the need for expertise and knowledge about SDoH. Ways of improving how SDoH data can be incorporated into health services research and patient care were to 1) empower patients and 2) make the data actionable. CONCLUSIONS Extracting SDoH from EHRs was considered valuable and necessary, but obstacles such as narrative data format can make the process difficult. NLP can be a potential solution, but as the technology is developed, it is important to consider how key stakeholders document SDoH, apply the NLP systems, and use the extracted SDoH in health outcome studies.natural language processing, qualitative, social determinants of health, electronic health records

Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Transjugular intrahepatic portosystemic shunt (TIPS) placement improves survival in patients with refractory/recurrent acute variceal bleeding (RAVB) and refractory ascites/hydrothorax. Recently, early TIPS was shown to reduce rebleeding and improve survival compared to the conventional TIPS. We aimed to study outcomes in patients with cirrhosis undergoing TIPS at first significant portal hypertensive (PHT) decompensation (termed anticipant TIPS) compared to those undergoing TIPS for recurrent or persistent PHT complications (conventional) and compared the former to matched controls on standard medical management (SMT). We retrospectively analyzed the clinical, biochemical, and liver disease severity parameters and survival at baseline and post-intervention in cirrhosis patients at two major hepatobiliary intervention centers undergoing anticipant (n = 27) or conventional TIPS (n = 30) and compared the former group to matched historical controls on SMT (n = 35). Baseline parameters were comparable between both the groups, including the Child-Pugh class and model for end-stage liver disease (MELD) scores. Length of stay in the intensive care unit, post-procedure admission rates, and sepsis events were higher among patients undergoing conventional TIPS (p < 0.05). Post-TIPS, at 1 year, overall and sub-grouped survivals were better in patients undergoing anticipant TIPS. On further sub-group analysis, based on the PHT events and stratified based on Child-Pugh and MELD scores, a higher proportion of patients survived after anticipant TIPS at 1 year. Compared to SMT, patients undergoing anticipant TIPS had significantly lesser hospitalizations, recurrence of varices, and ascites at 1 year, reducing hospital visits and financial burden. Anticipant TIPS at the first significant PHT event could improve liver-related events and survival compared to standard medical management and conventional TIPS, respectively.

Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60–89 mL/min), or moderate RI (CrCl 30–59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1–5 and 8–12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15–29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily. Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI. NCT02301117, registration date: November 21, 2014.

PURPOSE Using real-world data (RWD)–based trial simulation approach, we aim to simulate colorectal cancer (CRC) trials and examine both effectiveness and safety end points in different simulation scenarios. METHODS We identified five phase III trials comparing new treatment regimens with an US Food and Drug Administration–approved first-line treatment in patients with metastatic CRC (ie, fluorouracil, leucovorin, and irinotecan) as the standard-of-care (SOC) control arm. Using Electronic Health Record–derived data from the OneFlorida network, we defined the study populations and outcome measures using the protocols from the original trials. Our design scenarios were (1) simulation of the SOC fluorouracil, leucovorin, and irinotecan arm and (2) comparative effectiveness research (CER) simulation of the control and experimental arms. For each scenario, we adjusted for random assignment, sampling, and dropout. We used overall survival (OS) and severe adverse events (SAEs) to measure effectiveness and safety. RESULTS We conducted CER simulations for two trials, and SOC simulations for three trials. The effect sizes of our simulated trials were stable across all simulation runs. Compared with the original trials, we observed longer OS and higher mean number of SAEs in both CER and SOC simulation. In the two CER simulations, hazard ratios associated with death from simulations were similar to that reported in the original trials. Consistent with the original trials, we found higher risk ratios of SAEs in the experiment arm, suggesting potentially higher toxicities from the new treatment regimen. We also observed similar SAE rates across all simulations compared with the original trials. CONCLUSION In this study, we simulated five CRC trials, and tested two simulation scenarios with several different configurations demonstrated that our simulations can robustly generate effectiveness and safety outcomes comparable with the original trials using real-world data.

Breast cancer screening (BCS) with mammography is a crucial method for improving cancer survival. In this study, we examined the association of Alzheimer’s disease (AD) and AD-related dementias (ADRD) diagnosis and race–ethnicity with mammography use in BCS-eligible women. In the real-world data from the OneFlorida+ Clinical Research Network, we extracted a cohort of 21,715 BCS-eligible women with ADRD and a matching comparison cohort of 65,145 BCS-eligible women without ADRD. In multivariable regression analysis, BCS-eligible women with ADRD were more likely to undergo a mammography than the BCS-eligible women without ADRD (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.13–1.26). Stratified by race–ethnicity, BCS-eligible Hispanic women with ADRD were more likely to undergo a mammography (OR = 1.56, 95% CI = 1.39–1.75), whereas BCS-eligible non-Hispanic black (OR = 0.72, 95% CI = 0.62–0.83) and non-Hispanic other (OR = 0.65, 95% CI = 0.45–0.93) women with ADRD were less likely to undergo a mammography. This study was the first to report the impact of ADRD diagnosis and race–ethnicity on mammography use in BCS-eligible women using real-world data. Our results suggest ADRD patients might be undergoing BCS without detailed guidelines to maximize benefits and avoid harms.

We examine the survey responses of 278 individuals who transitioned from the workplace to working from home (WFH) as a result of the Covid 19 pandemic to understand how individuals' attainment of productivity in work and meaning in life are affected by WFH. We also assess their perceived stress and health challenges experienced since WFH. On average, workers perceive that productivity and meaning changed in opposite directions with the shift to WFH-productivity increased while the meaning derived from daily activities decreased. Stress was reduced while health problems increased. By investigating these changes, we identify important common sources of support and friction associated with remote work that affect multiple dimensions of work and life. For example, personal fortitude is an important source of support, and the intrusion of work into life is an important friction. Our findings lead to concrete recommendations for both organizational leaders and workers in setting key priorities for supporting remote work.

DNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) is found in about 15% of early-stage diseases and 5% of metastatic diseases. We reviewed a large, single-institutional database after implementation of universal reflex dMMR/MSI-H testing in CRC to compare profiles of younger (≤50) and older (50) patients.Between 2009 and 2017, all patients diagnosed with CRC at the University of Florida underwent reflex somatic tumor testing for dMMR by immunohistochemistry (MLH1, PMS2, MSH2, MSH6), MSI by PCR, and Next-Generation Sequencing. Statistical analysis was conducted with 2-sample comparison tests and logistic regression models.There were 375 patients included in the final analysis. Patients were grouped as younger (ages ≤50 years-old; n = 80) or older (50 years-old; n = 295). Compared to tumors from older patients, tumors from younger patients were less likely to be dMMR/MSI-H (12.5% vs. 21.4%, P = .013) and less likely to have a BRAF mutation (1.5% vs. 16.1%, P = .002). BRAF mutation status was highly associated with MMR status; BRAF-mutated tumors were 29.7 times more likely than BRAF-WT tumors to be dMMR/MSI-H (P = .001, 95% CI 11.3-78.3).Tumors of younger patients were less likely than tumors of older patients to have a dMMR/MSI-H or BRAF mutation. Universal MMR/MSI testing in our dataset identified a relatively large population of older patients with sporadic CRC who were eligible for immunotherapy.

Patients with autoimmune disorders, multiple comorbidities, poor performance status, advanced age, and infection with SARS-CoV-2 (COVID-19) each represent unique subgroups of patients with cancer to whom little is known of the effects, benefits, and complications of checkpoint inhibitor (CPI) therapy. Although prospective trials are lacking in these populations, retrospective data and cohort series suggest that these patients can safely receive and benefit from CPI therapy. Here, we review the relevant data available and offer clinical recommendations in managing these complex patients with CPI therapy, where otherwise indicated.

Background:Advance directives are legal documents that include living wills and durable health care power of attorney documents. They are critical components of care for seriously ill patients which are designed to be implemented when a patient is terminally ill and incapacitated. We sought to evaluate potential reasons for why advance directives were not appropriately implemented, by reviewing the electronic health record (EHR) in patients with terminal cancer.Methods:A retrospective analysis of the EHR of 500 cancer patients from 1/1/2013 to 12/31/2016 was performed. Data points were manually collected and entered in a central database.Results:Of the 500 patients, 160 (32%) had an advance directive (AD). The most common clinical terminology used by physicians indicating a terminal diagnosis was progressive (36.6%) and palliative (31%). The most common clinical terminology indicating incapacity was altered mental status (25.6%), and not oriented (14%). 34 (6.8%) patients met all criteria of having a terminal diagnosis, a documented AD, and were deemed incapacitated. Of these patients who met all of these data points, their ADs were implemented on average 1.7 days (SD: 4.4 days) after which they should have been. This resulted in a total of 58 days of additional care provided.Discussion:This study provided insight on to how ADs are managed in day to day practice in the hospital. From our analysis it appears that physicians are able to identify when a patient is terminal, however, it is typically later than it should have been recognized. Further studies should be performed focusing on harnessing the power of the EHR and providing physicians formative and evaluative feedback of practice patterns to ensure that ADs are honored when appropriate.

Background: Circulating tumor cells (CTCs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA) are minimally invasive biomarkers that carry vital tumor onset, progression, and metastasis information, which is crucial for cancer diagnosis, prognosis, and management. We report here our longitudinal study of these circulating biomarkers in resectable pancreatic ductal adenocarcinoma (PDAC) patients. Although the overall 5-year survival rate of PDAC is low (~6%), truly resectable patients are expected to have better outcomes than non-resectable PDAC patients, especially if liquid biopsy can help guide anticancer treatment selection. Method: We evaluated temporal changes in CTCs, cfDNA, and ctDNA in peripheral blood samples in a cohort of patients with resectable PDAC treated with pre-operative chemotherapy and surgical excision. Five PDAC survivors in complete remission for three years without evidence of disease served as negative controls. Samples of peripheral blood were collected prior to the start of treatment and every two weeks while patients underwent neoadjuvant chemotherapy, followed by surgical excision of the pancreatic tumor. CTCs were enumerated using a previously reported microfluidic device [1] that integrates immunoaffinity-based isolation with size-based filtration, while cfDNA and ctDNA were measured using quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR). Results: Among the initial seven patients who have completed the treatment sequences [2], CTCs were detectable in all patients (100%) at some points during treatment, but only 50% of patients had detectable CTCs before the start of chemotherapy. Median cfDNA concentrations were comparable to those negative controls throughout treatment. Using ddPCR to analyze peripheral blood samples, KRAS mutations were detected in in 71% of patients during anticancer therapy, but only in 29% patients prior to treatment. Overall, the majority of circulating biomarkers (81% for CTCs and 91% for ctDNA) were detected in blood samples collected after the start of neoadjuvant therapy and before surgery. Conclusion: This study suggests that a longitudinal study of circulating biomarkers provides additional data compared to single-point liquid biopsy, and that biologic “release” of biomarkers due to therapy can increase detectability. -Further study is needed to determine the clinical utility of liquid biopsy for resectable PDAC patients. [1] Chen, et al., Angew. Chem. Int. Ed., 58, 2019, 7606-7610. [2] Dopico, et al., Biosensors, 12, 2022, 206. Citation Format: Yang Zhang, Pablo J. Dopico, Minh-Chau N. Le, Zhijie Yang, Youxiang Wang, Sherise C. Rogers, Thomas J. George, Hugh Z. Fan. Temporal changes in circulating tumor cells and circulating tumor DNA in patients with resectable pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2315.

Background Despite improved survival rates, cancer survivors are experiencing worse health outcomes with complications of treatment, such as type 2 diabetes mellitus (T2D), that may deteriorate survivorship. The purpose of this review was to provide a comprehensive review of T2D incidence following cancer diagnosis. Methods: The study included: (1) cohort studies, (2) cancer diagnosis by a doctor, (3) incidence of T2D after diagnosis of cancer, and (4) adult patients over 18 years. Studies that focused on patients who had T2D as a preexisting condition at cancer diagnosis were excluded. Results: Of a total of 16 studies, overall incidence of T2D ranged from 5.4% to 55.3%. The highest T2D incidence rate was observed in colorectal patients with cancer (53%). While results in prostate patients with cancer were mixed, patients who underwent androgen deprivation therapy (ADT) had a significantly higher incidence of new‐onset T2D (12.8%, p = 0.01). Patients treated with chemotherapy within 1–5 years of initial diagnosis of colorectal cancer were at approximately 30% higher risk of T2D. One study found that 48% of T2D was preventable with optimal management during the process of patient care. Conclusion: Blood glucose management may allow physicians to intervene early and improve outcomes among patients with cancer., About half of patients with cancer reported new onset of type 2 diabetes after cancer diagnosis and treatment. Forty‐eight percent of type 2 diabetes incidence was preventable with optimal management during the process of patient care.

Objectives To compare the efficacy and safety of algenpantucel-L (HAPa; IND# 12311) immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Summary background data To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. Methods A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. Results Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (IQR) overall survival was 14.9 (12.2-17.8) months in the standard group (N=158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) (hazard ratio [HR] 1.02, 95% CI 0.66-1.58; P = 0.98). Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% CI 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). Conclusions Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. Trial registration ClinicalTrials.gov Identifier: NCT01836432.

PURPOSE Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. MATERIALS AND METHODS Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. RESULTS Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants ( KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR- P] = .0006), current or prior smokers (85% v 56%, FDR- P < .0001), and patients age > 60 years (73% v 63%, FDR- P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR- P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR- P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR- P < .01). CONCLUSION This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

PURPOSE Clinical trials determine safety and efficacy of cancer therapeutics and establish standards of care. Minority patient participation in cancer clinical trials is dismal. We aimed to determine the impact of eligibility criteria on disparities in pancreatic ductal adenocarcinoma (PDAC) clinical trial candidacy. METHODS Traditional PDAC trial eligibility criteria were obtained from ClinicalTrials.gov. Patients with PDAC who sought care at Virginia Commonwealth University Health from 2010 to 2019 were included. Clinical data were obtained from billing codes and discrete values in the electronic medical record. Eligibility criteria differences between racial groups were determined using chi-squared tests and unconditional maximum likelihood-based odds ratios. RESULTS Among 676 patients, most identified as Black or White race (42.5% and 51.6%, respectively). Using traditional criteria, Black patients were more likely to be ineligible for participation compared with White patients (42.4% v 33.2%, P = .023) secondary to hypoalbuminemia (14.1% v 7.9%, P = .023), HIV (3.1% v 0.3%, P = .010), hepatitis B (1.7% v 0%, P = .043), and hepatitis C (9.1% v 3.4%, P = .005). Black patients were also numerically more likely to be ineligible because of renal dysfunction, recent coronary stenting, and uncontrolled diabetes mellitus. Prior cancer treatment excluded fewer Black than White patients (9.1% v 14.0%, P = .072), most attributable to lower rates of neoadjuvant chemotherapy received. Strategic eligibility criteria revisions could equalize ineligibility rates between Black and White patients (26.8% v 24.8%, P = .581). CONCLUSION Traditional eligibility criteria differentially exclude Black patients from participating in PDAC clinical trials. These criteria perpetuate disparities, limit generalizability, and are often not medically justifiable. Revised criteria may improve participant diversity, without compromising safety or study results.

Promising single-agent activity from sotorasib and adagrasib inRetrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes andOf the 79,004 samples assessed, 13,758 (17.4%) harboredThis study presents the first large-scale, pan-cancer genomic characterization of

Recently, there has been a growing interest in using real-world data (RWD) to generate real-world evidence that complements clinical trials. To quantify treatment effects, it is important to develop meaningful RWD-based endpoints. In cancer trials, two real-world endpoints are of particular interest: real-world overall survival (rwOS) and real-world time to next treatment (rwTTNT). In this work, we identified ways to calculate these real-world endpoints with structured electronic health record (EHR) data and validate these endpoints against the gold-standard measurements of these endpoints derived from linked EHR and tumor registry (TR) data. In addition, we examined and reported data quality issues, especially inconsistencies between the EHR and TR data. Using a survival model, we show that the presence of next treatment was not significantly associated with rwOS, but patients who had longer rwTTNT had longer rwOS, validating the use of rwTTNT as a real-world surrogate marker for measuring cancer endpoints.

Social and behavioral determinants of health (SBDoH) have important roles in shaping people's health. In clinical research studies, especially comparative effectiveness studies, failure to adjust for SBDoH factors will potentially cause confounding issues and misclassification errors in either statistical analyses and machine learning-based models. However, there are limited studies to examine SBDoH factors in clinical outcomes due to the lack of structured SBDoH information in current electronic health record (EHR) systems, while much of the SBDoH information is documented in clinical narratives. Natural language processing (NLP) is thus the key technology to extract such information from unstructured clinical text. However, there is not a mature clinical NLP system focusing on SBDoH. In this study, we examined two state-of-the-art transformer-based NLP models, including BERT and RoBERTa, to extract SBDoH concepts from clinical narratives, applied the best performing model to extract SBDoH concepts on a lung cancer screening patient cohort, and examined the difference of SBDoH information between NLP extracted results and structured EHRs (SBDoH information captured in standard vocabularies such as the International Classification of Diseases codes). The experimental results show that the BERT-based NLP model achieved the best strict/lenient F1-score of 0.8791 and 0.8999, respectively. The comparison between NLP extracted SBDoH information and structured EHRs in the lung cancer patient cohort of 864 patients with 161,933 various types of clinical notes showed that much more detailed information about smoking, education, and employment were only captured in clinical narratives and that it is necessary to use both clinical narratives and structured EHRs to construct a more complete picture of patients' SBDoH factors.

Purpose: In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment. Patients and Methods: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies. Results: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples. Conclusions: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

Since the appearance of the novel coronavirus (severe acute respiratory syndrome-coronavirus-2) and related coronavirus disease 2019 (COVID-19) in China in December 2019, a very high number of small and large patient series have been published in literature from around the world. Even though the classical presentation of COVID-19 is one with respiratory symptoms with or without pneumonia that can be self-limiting or evolve into severe respiratory distress syndrome with multiple organ failure, and secondary bacterial sepsis, a large body of evidence suggests a plethora of other types of clinical presentation. In this exhaustive review, we reviewed all of the published literature on COVID-19 to identify different types of clinical presentations affecting various organ systems, to provide an in-depth analysis that may prove useful for clinicians and health-workers on the frontline, battling the severe pandemic.

Objective Despite efforts to reduce cancer disparities, Black women remain underrepresented in cancer research. Virtual health assistants (VHAs) are one promising digital technology for communicating health messages and promoting health behaviors to diverse populations. This study describes participant responses to a VHA‐delivered intervention promoting colorectal cancer (CRC) screening with a home‐stool test. Methods We recruited 53 non‐Hispanic Black women 50 to 73 years old to participate in focus groups and think‐aloud interviews and test a web‐based intervention delivered by a race‐ and gender‐concordant VHA. A user‐centered design approach prioritized modifications to three successive versions of the intervention based on participants' comments. Results Participants identified 26 cues relating to components of the VHA's credibility, including trustworthiness, expertise, and authority. Comments on early versions revealed preferences for communicating with a human doctor and negative critiques of the VHA's appearance and movements. Modifications to specific cues improved the user experience, and participants expressed increased willingness to engage with later versions of the VHA and the screening messages it delivered. Informed by the Modality, Agency, Interactivity, Navigability Model, we present a framework for developing credible VHA‐delivered cancer screening messages. Conclusions VHAs provide a systematic way to deliver health information. A culturally sensitive intervention designed for credibility promoted user interest in engaging with guideline‐concordant CRC screening messages. We present strategies for effectively using cues to engage audiences with health messages, which can be applied to future research in varying contexts.

Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis. In cirrhosis, hemodynamic perturbations, immune dysregulation, and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials. Patients with cirrhosis develop recurrent life-threatening infections that progress to multiple organ failure. The definition, pathophysiology, and treatment options for sepsis have been ever evolving. In this exhaustive review, we discuss novel advances in the understanding of sepsis, describe current and future biomarkers and scoring systems for sepsis, and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis. We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally, propose a treatment algorithm for management of sepsis in patients with cirrhosis.

Portosystemic shunts (PSS) are associated with recurrent or persistent hepatic encephalopathy (HE), severe portal hypertensive (PHT) complications, and poor survival in cirrhosis patients. Shunt embolization improves HE in patients with recurrent or persistent HE. The role of early shunt embolization (ESE) in comparison with no and late SE (LSE) in cirrhosis patients with PSS and associated clinical outcomes are not studied. ESE was defined as occlusion of PSS in patients with the first episode of spontaneous HE, while LSE was that when performed in patients with recurrent/persistent PSS-related HE. We retrospectively analyzed (November 2016 to March 2019) clinical outcomes, liver disease severity, and survival between patients undergoing ESE (n = 22) vs. LSE (n = 23) and compared ESE with matched historical controls (n = 22) not undergoing shunt embolization, followed-up for 18 months. Males predominated, and the lienorenal type of shunt was the most frequent. Significantly larger and multiple shunts were noted in the LSE group. Arterial ammonia, total bilirubin, and Child-Pugh scores were significantly higher at baseline in the LSE group. Post-procedure length of stay in the intensive unit (mean 0.6 vs. 2.1 days; p = 0.04), infections (31.8% vs. 66.7% beyond 100 days; p = 0.02), recurrence of HE in first 9 months (4.5% vs. 28.6%; p = 0.03), and liver- and PHT-related clinical events beyond 10 months were significantly higher in LSE compared with those in the ESE group respectively. HE beyond 10 months was comparable between both the groups. 18.2% died in ESE while 60.87% died in the LSE group (p = 0.002). Compared with patients on only standard medical care, the occurrence of ascites, variceal bleeding, recurrence of HE, and portal vein thrombosis were significantly lower in those undergoing ESE, even though differences in survival were not significant. Our study demonstrates the benefits of ESE of large PSS in patients with cirrhosis, probably by improving survival through a reduction in liver and PHT events that warrant validation through prospective randomized controlled multicenter trials.

The treatment of colon cancer has had numerous recent advances, in terms of surgical approach, adjuvant therapies, and more. In this review, the authors examine randomized clinical trials comparing open surgery to laparoscopic surgery (including total mesocolic excision), and also examine the role of robotic surgery. Novel surgical techniques including the no-touch technique, side-to-side anastomosis, suture technique, complete mesocolic excision (CME) with central vascular ligation (CVL), and natural orifice transluminal endoscopic surgery (NOTES) are outlined. The role of placing endoscopic self-expandable metal stents (SEMS) for colonic obstruction is compared and contrasted with the surgical approach, and the effect that the anti-VEGF inhibitor bevacizumab may have on this side effect profile is further explored. The role of the resection of the primary tumor in the setting of metastatic disease is examined with respect to survival benefit. Pathways of perioperative care which can accelerate post-surgical recovery, including enhanced recovery after surgery (ERAS) are examined. The role of adjuvant chemotherapy in patients with high-risk stage II and patients with stage III disease is examined, along with the role on circulating tumor DNA (ctDNA) as well as with the biologic targeted agents cetuximab and bevacizumab. Lastly, the authors detail the postoperative surveillance schedules after surgical resection with respect to survival outcomes.