Feasibility of institution-agnostic, EHR-integrated regional clinical trial matching.

BACKGROUND: A lack of onsite clinical trials is the largest barrier to participation of cancer patients in trials. Development of an automated process for regional trial eligibility screening first requires identification of patient electronic health record data that allows effective trial screening, and evidence that searching for trials regionally has a positive impact compared with site-specific searching. METHODS: To assess a screening framework that would support an automated regional search tool, a set of patient clinical variables was analyzed for prescreening clinical trials. The variables were used to assess regional compared with site-specific screening throughout the United States. RESULTS: Eight core variables from patient electronic health records were identified that yielded likely matches in a prescreen process. Assessment of the screening framework was performed using these variables to search for trials locally and regionally for an 84-patient cohort. The likelihood that a trial returned in this prescreen was a provisional trial match was 45.7%. Expanding the search radius to 20 miles led to a net 91% increase in matches across cancers within the tested cohort. In a U.S. regional analysis, for sparsely populated areas, searching a 100-mile radius using the prescreening framework was needed, whereas for urban areas a 20-mile radius was sufficient. CONCLUSION: A clinical trial screening framework was assessed that uses limited patient data to efficiently and effectively identify prescreen matches for clinical trials. This framework improves trial matching rates when searching regionally compared with locally, although the applicability of this framework may vary geographically depending on oncology practice density. PLAIN LANGUAGE SUMMARY: Clinical trials provide cancer patients the opportunity to participate in research and development of new drugs and treatment approaches. It can be difficult to find available clinical trials for which a patient is eligible. This article describes an approach to clinical trial matching using limited patient data to search for trials regionally, beyond just the patient's local care site. Feasibility testing shows that this process can lead to a net 91% increase in the number of potential clinical trial matches available within 20 miles of a patient. Based on these findings, a software tool based on this model is being developed that will automatically send limited, deidentified information from patient medical records to services that can identify possible clinical trials within a given region.

A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01.

BACKGROUND: Gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors. METHODS: In this phase 2 trial, patients 18 years or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status 0-1 were randomized across six academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks. RESULTS: Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5% women with a median age of 62.5 years. The observed primary outcome of 6-month progression-free survival (PFS) rates in the evaluable population was 59.4% in Arm A and 21.2% in Arm B. The median PFS and overall survival (OS) in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade 3 or higher hematologic adverse event was neutropenia in 34.3% (Arm A) and nonhematologic adverse events were fatigue (8.6% Arm A) and elevated transaminases (9.1% Arm B). CONCLUSIONS: The addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggests benefit in a small cohort of patients.

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971.

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

Liquid Biopsy for Cancer: Review and Implications for the Radiologist.

Imaging and image-guided procedures play an imperative role in the screening, diagnosis, and surveillance of cancer. Although emerging imaging techniques now enable more precise molecular characterization of tumors, multigenetic tumor profiling for targeted therapeutic selection remains limited to direct tissue acquisition. Even in the context of targeted therapy, tumors adapt to acquire resistance. This necessitates serial monitoring, traditionally through tissue acquisition, to identify the molecular mechanism of resistance and to guide second-line therapy. An alternative to tissue acquisition is the collection of circulating tumor markers such as cell-free nucleic acids and circulating tumor cells in the peripheral blood. This noninvasive diagnostic approach is referred to as the liquid biopsy. The liquid biopsy is currently used clinically for therapeutic guidance when tissue acquisition is impossible or when the specimen is inadequate. It is also being studied in the context of screening, diagnosis, and surveillance. As cancer treatment continues to move toward a focus on precision medicine, this developing technology may alter and/or augment the role of imaging in the management of cancer. This review aims to outline the use of liquid biopsy in cancer and its potential impact on diagnostic imaging and image-guided procedures.

Unique Patterns of Distant Metastases in HPV-Positive Head and Neck Cancer.

BACKGROUND: HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC) demonstrates favorable outcomes compared to HPV-negative SCC, but distant metastases (DM) still occur. The pattern of DM in HPV+ HNSCC is unclear. METHODS: 1,494 HNSCC patients were treated from 2006 to 2012. Recurrence time and metastatic sites in HPV+ HNSCC (Group 1) were compared to patients with HPV-negative/unknown cancers arising in the hypopharynx, larynx, or glottis (Group 2) as well as to patients with HPV-negative/unknown cancers in theoral cavity, oropharynx, hard palate, or tonsil (Group 3). RESULTS: 7/109 (6.4%) patients with HPV+ HNSCC developed DM. The median time to metastases was 11 months. At a median follow-up of 18-25 months, there was no difference in the overall rate of DM for the HPV+ HNSCC group compared to Group 2 (HPV-/unknown) (p = 0.21) and Group 3 (HPV-/unknown) (p = 0.13). There was a significant difference in the rate of DM to the lung in the HPV+ HNSCC group compared to Group 2 (HPV-/unknown) (p = 0.012) and Group 3 (HPV-/unknown) (p = 0.002). CONCLUSIONS: There was no observed difference in the time to development of DM between the HPV-/unknown and HPV+ HNSCC groups. However, the HPV+ HNSCC group showed a higher rate of DM to the lung compared to the HPV-/unknown -HNSCC group (p = 0.002).

Sociodemographic Disparities in the Receipt of Adjuvant Chemotherapy Among Patients With Resected Stage I-III Pancreatic Adenocarcinoma.

BACKGROUND: Adjuvant therapy for resected pancreatic adenocarcinoma was given a category 1 NCCN recommendation in 2000, yet many patients do not receive chemotherapy after definitive surgery. Whether sociodemographic disparities exist for receipt of adjuvant chemotherapy is poorly understood. METHODS: The National Cancer Database was used to identify patients diagnosed with nonmetastatic pancreatic adenocarcinoma who underwent definitive surgery from 2004 through 2015. Multivariable logistic regression defined the adjusted odds ratio (aOR) and associated 95% CI of receipt of adjuvant chemotherapy. Among patients receiving chemotherapy, multivariable logistic regression assessed the odds of treatment with multiagent chemotherapy. RESULTS: Among 18,463 patients, 11,288 (61.1%) received any adjuvant chemotherapy. Sociodemographic factors inversely associated with receipt of any adjuvant chemotherapy included uninsured status (aOR, 0.61; 95% CI, 0.50-0.74), Medicaid insurance (aOR, 0.66; 95% CI, 0.57-0.77), and lower income (P<.001 for all income levels compared with ≥$46,000). Black race (aOR, 0.72; 95% CI, 0.57-0.90) and female sex (aOR, 0.75; 95% CI, 0.65-0.86) were associated with lower odds of receiving multiagent chemotherapy. There was a statistically significant interaction term between black race and age/comorbidity status (P=.03), such that 26.4% of black versus 35.8% of nonblack young (aged ≤65 years) and healthy (Charlson-Deyo comorbidity score 0) patients received multiagent adjuvant chemotherapy (P=.006), whereas multiagent adjuvant chemotherapy rates were similar among patients who were not young and healthy (P=.15). CONCLUSIONS: In this nationally representative study, receipt of adjuvant chemotherapy appeared to be associated with sociodemographic characteristics, independent of clinical factors. Sociodemographic differences in receipt of adjuvant chemotherapy may represent a missed opportunity for improving outcomes and a driver of oncologic disparities.

The NQO1 bioactivatable drug, ß-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism.

Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. ß-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. ß-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD+/ATP depletion. However, the effects of this drug on energy metabolism due to NAD+ depletion were never described. The futile redox cycle rapidly consumes O2, rendering standard assays of Krebs cycle turnover unusable. In this study, a multimodal analysis, including metabolic imaging using hyperpolarized pyruvate, points to reduced oxidative flux due to NAD+ depletion after ß-lapachone treatment of NQO1+ human pancreatic cancer cells. NAD+-sensitive pathways, such as glycolysis, flux through lactate dehydrogenase, and the citric acid cycle (as inferred by flux through pyruvate dehydrogenase), were down-regulated by ß-lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose responses of ß-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may have the potential to synergize with ß-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with ß-lapachone.

Trends in Outcomes of Patients With Metastatic Cancer Undergoing Intubation and Mechanical Ventilation: Results of the National Hospital Discharge Survey.

Background: There has been an overall decline in intensive care unit mortality over the past 2 decades, including in patients undergoing intubation and mechanical ventilation (MV). Whether this decline extends to patients with metastatic cancer remains unknown. We analyzed the outcomes of patients with metastatic cancer undergoing intubation/MV using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis and procedure codes were used to identify patients with metastatic cancer who underwent intubation/MV. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study trends in outcomes. Results: During the 10-year study period, 200,350 patients with metastatic cancer and who underwent intubation/MV were identified; the mean age was 65.3 years and 46.2% were men. There was an increase in the total number of patients with metastatic cancer who underwent intubation/MV during the study period, from 36,881 in 2001-2002 to 51,003 in 2009-2010 (P<.001). The overall inpatient mortality rate was 57.3%, discharge to a care facility (DTCF) rate was 40.9% among patients alive at discharge, and mean LOS was 11.1 days. No significant trends were seen in rates of mortality, DTCF, or LOS from 2001 to 2010. Conclusions: In this national database, there was an increase in the number of patients with metastatic cancer who underwent intubation/MV. These patients had high rates of inpatient mortality and DTCF, which did not improve during the study period. Therefore, novel solutions are required to improve outcomes for these patients.

Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.

Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1-12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.

Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus.

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.

Trends in the Incidence and Outcomes of Hospitalized Cancer Patients With Clostridium difficile Infection: A Nationwide Analysis.

Background: Patients with cancer have several risk factors for Clostridium difficile infection (CDI), but the impact of CDI on outcomes in this population needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in patients with cancer using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis codes were used to identify patients with cancer and CDI events. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study CDI incidence and CDI-associated outcomes. Analyses were performed using SAS version 9.4. Results: During the 10-year study period, 20.1 million discharges had a cancer diagnosis. CDI developed in 1.09% of patients with cancer versus 0.77% of patients without cancer (adjusted odds ratio [aOR], 1.28; 95% CI, 1.28-1.29; P<.001). The incidence of CDI in patients with cancer increased during the 10-year study period (64.7 per 10,000 discharges in 2001-2002 to 109.1 in 2009-2010; P<.001). In multivariable analysis, compared with patients with cancer without CDI, patients with cancer and CDI had a longer mean LOS (5.67 days; 95% CI, 5.39-5.94) and higher rates of in-hospital mortality (aOR, 1.18; 95% CI, 1.16-1.20) and discharge to a care facility (aOR, 1.74; 95% CI, 1.72-1.75; all P<.001). Conclusions: In this national database, CDI incidence increased significantly in patients with cancer over the study period and was associated with prolonged hospitalization, increased mortality, and discharge to a care facility. Despite increased attention, CDI remained a serious infection and merits appropriate prevention and management.

A Variant in PNPLA3 Associated With Fibrosis Progression but not Hepatocellular Carcinoma in Patients With Hepatitis C Virus Infection.

BACKGROUND & AIMS: A single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 gene (PNPLA3, rs738409) has been associated with fibrosis and development of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis, although its association with outcomes in patients with hepatitis C virus (HCV) infection is less clear. We evaluated the association between this SNP in PNPLA3 and fibrosis progression and development of HCC among HCV-infected patients. METHODS: We performed a secondary analysis of data from participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. Patients were randomly assigned to groups given weekly pegylated interferon or no further therapy for 3.5 y and then followed without further treatment until October 2009. Multivariate logistic regression was used to identify factors associated with fibrosis at baseline, fibrosis progression (defined as 2-point increase in Ishak score), and HCC development. RESULTS: Among 937 HCV patients with known PNPLA3 genotype, 384 (41.0%) had cirrhosis at baseline. The PNPLA3 CG/GG SNP at rs738409 was significantly associated with the presence of cirrhosis (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.34-2.30), after adjusting for age, sex, diabetes, and race. Among 493 patients without cirrhosis at baseline who had at least 1 follow-up biopsy, 142 had fibrosis progression. In multivariate analyses, fibrosis progression was associated with obesity (OR, 1.67; 95% CI, 1.11-2.51) and the PNPLA3 CG/GG genotype (OR, 1.70; 95% CI, 1.13-2.56). PNPLA3 genotype was not associated with HCC development (P = .85). Using these data to update prior meta-analysis results, the rs738409 SNP in PNPLA3 was not significantly associated with development of HCC in HCV-infected patients (OR 1.29; 95% CI, 0.97-1.99). CONCLUSIONS: Based on data from the HALT-C trial, the PNPLA3 CG/GG SNP at rs738409 is associated with fibrosis progression but not development of HCC in patients with HCV infection.

Quantification of renal steatosis in type II diabetes mellitus using dixon-based MRI.

PURPOSE: To evaluate renal lipid content in subjects with and without type II diabetes mellitus (DM2) using Dixon-based magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective study was approved by the Institutional Review Board and compliant with the Health Insurance Portability and Accountability Act. Sixty-nine adults with or without DM2 (n = 29, n = 40) underwent 3T MRI of the abdomen using 3D multiecho Dixon gradient-echo acquisition and proton-density fat fraction (FF) reconstruction. FF values were recorded within segmented regions of interest in the kidneys and liver. The FF measurement error was estimated from the within-subject difference between the right and left kidneys using Bland-Altman analysis. Correlation between renal FF, hepatic FF, and body mass index (BMI) was evaluated. The association between renal FF and DM2 was evaluated by Wilcoxon rank sum test as well as by multivariate regression to correct for potential confounding effects of age, sex, BMI, creatinine, and hepatic FF. P < 0.05 was considered statistically significant. RESULTS: Per-subject 95% limits of agreement of the renal FF measurement were [-3.26%, +3.22%]. BMI was significantly correlated with renal FF (r = 0.266, P = 0.027) and with liver FF (r = 0.344, P = 0.006). Correlation between renal and hepatic FF did not reach statistical significance (r = 0.215, P = 0.090). Median renal FF (±interquartile range) was 2.18% (±2.52%) in the DM2 cohort, significantly higher than 0.80% (±2.63%) in the non-DM2 cohort (P < 0.001). After correcting for potential confounders, the relationship between DM2 and renal FF remained statistically significant (P = 0.005). CONCLUSION: Renal lipid content can be measured noninvasively using Dixon-based MRI and may be increased in subjects with DM2 compared to those without DM2. J. Magn. Reson. Imaging 2016;44:1312-1319.

The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis.

OBJECTIVES: The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease. METHODS: We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model. RESULTS: Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20-1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12-1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27-2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96-1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed. CONCLUSIONS: PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome.

PURPOSE: To evaluate differences in overall survival in patients with hepatocellular carcinoma (HCC) after the establishment of a multidisciplinary clinic (MDC) for HCC. METHODS: Patient demographic and tumor characteristics of 355 patients diagnosed with HCC were collected between October 2006 and September 2011. Patients diagnosed after the initiation of the HCC MDC on October 1, 2010, were compared to patients diagnosed in the 4 years before. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. RESULTS: A total of 105 patients were diagnosed in the time period after HCC MDC initiation compared to 250 patients in the previous 4 years. Patients diagnosed with HCC after the HCC MDC had fewer symptoms at presentation (64 vs. 78 %, p = 0.01) and earlier stage of tumor presentation [Barcelona Clinic for Liver Cancer (BCLC) A stage, 44 vs. 26 %, p = 0.0003; tumor, node, metastasis classification system stage 1, 44 vs. 30 %, p = 0.003) compared with patients diagnosed before MDC formation. The median time to treatment after diagnosis in the later period was significantly shorter than in the earlier time period (2.3 vs. 5.3 months, p = 0.002). On multivariate analysis, being seen in the HCC MDC remained independently associated with better overall survival (hazard ratio 2.5, 95 % confidence interval 2-3), after adjusting for BCLC stage and recipient of curative treatment. Patients diagnosed after HCC MDC initiation had a median survival of 13.2 months compared to the 4.8 months observed in patients diagnosed before MDC formation (p = 0.005). CONCLUSIONS: The implementation of a MDC for the evaluation and treatment of patients with HCC is associated with improved overall survival.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Trends in utilization of first-line palliative treatments for anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma patients often present with significant symptoms, including pain, bleeding, and obstructive symptoms. This requires palliation-directed therapy as a first-line treatment to alleviate symptoms. The proportion of patients receiving first-line palliative treatments is unknown. We aimed to study the factors associated with the use of first-line palliative treatments in stage II-IV anal squamous cell carcinoma patients. METHODS: We used the National Cancer Database to identify adult patients diagnosed with stage II-IV anal squamous cell carcinoma between 2004 and 2016. We performed univariable and multivariable logistic regression analysis to determine the clinical and sociodemographic variables associated with the utilization of palliative treatment in the first-line setting, including palliative radiotherapy, chemotherapy, surgery, and pain management. RESULTS: Among 16,944 patients diagnosed with stage II-IV anal squamous cell carcinoma, only a small proportion of 492 (2.9%) required first-line palliative treatments to control symptoms. The majority of these patients received palliative radiotherapy (32%), followed by palliative surgery (25%), palliative chemotherapy (19%), combination therapies (14%), and pain management (10%). On multivariable analysis, higher stage disease, lower income, Medicare and Medicaid insurance, and life expectancy <6 months were associated with higher odds of use of first-line palliative therapy. CONCLUSIONS: First-line use of palliative treatments to control symptoms is needed in a small proportion of anal squamous cell cancer patients. It was utilized in all stages, but it was most frequently observed in patients with stage IV disease and patients with <6 months life expectancy. First-line palliative therapy was also more frequent in lower-income patients and patients with Medicare and Medicaid insurance which highlights the disparities in anal cancer management.