Explore the vast range of titles available.

Background Assessment of patient performance status is often subjective. Sarcopenia—measurement of muscle wasting—may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). Methods Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. Results Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm 2 /m 2 ) was greater than women (413 mm 2 /m 2 ). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P  < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P  = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. Conclusions Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

Background Limited data are available regarding second‐line (2 L) treatment for advanced or metastatic biliary tract cancers (BTC) in the US real‐world setting. This study explores the rapidly evolving and growing treatment landscape in the 2 L setting for advanced or metastatic BTC with a large cohort of patients treated in a community oncology setting. Methods Adult patients with BTC initiating 2 L treatment after a platinum‐containing first‐line between 1/1/10‐ and 6/30/19 were identified from the US Oncology Network electronic healthcare record database and followed through 12/31/19. Baseline patient and treatment characteristics were analyzed descriptively, including overall response rate (ORR) in the real‐world clinical setting. Kaplan–Meier methods were used to measure duration of response, progression‐free survival (PFS), and overall survival (OS). Results The overall population (N = 160) included 74 patients (46.3%) with intrahepatic cholangiocarcinoma, 41 (25.6%) with extrahepatic cholangiocarcinoma, and 45 (28.1%) with gallbladder cancer. Thirty unique 2 L regimens were recorded for the study population, with folinic acid, fluorouracil and oxaliplatin (FOLFOX, 34.4%) and capecitabine monotherapy (20.0%) being the most common. ORR was 7.5% (95% CI, 3.9%–12.7%). From 2 L initiation, median PFS was 2.8 months (95% CI, 2.4–3.3 months), and median OS was 5.2 months (95% CI, 4.2–6.7 months). Conclusion Results from this study provide real‐world evidence that although patients treated in the community oncology setting receive a wide variety of 2 L treatments, the regimens are consistent with those recommended by guidelines. Although responses are observed with 2 L treatment, duration is brief and associated with poor OS in patients with advanced or metastatic disease.

Introduction Tumor recurrence remains a main limitation to the long-term survival of patients following liver transplantation for hepatocellular carcinoma (HCC). While the majority of patients recur in the first two years after transplantation, late recurrence is not infrequent. Discussion Most common sites of recurrence in order of decreasing frequency are liver graft, lung, bone, abdominal lymph nodes, adrenal glands and peritoneum. Reported five-year survival after surgical resection ranges from 27-88%. Few patients, however, are candidates for surgical resection. Other therapeutic options for recurrent HCC include systemic therapy, intra-arterial therapy, or radiation therapy. Although systemic molecular targeted therapy is generally tolerated with very few interactions with immunosuppressive medications, there is only modest success regarding prolongation of survival. Utilization of radiation therapy for extrahepatic recurrences similarly has minimal impact on overall survival, but may effectively in palliate symptoms. While late recurrence is associated with a more favorable prognosis than early recurrences, prognosis is still poor. Conclusion Late recurrence of HCC following transplantation should be borne in mind even after many years from transplant. Surgical salvage, when feasible, remains a viable treatment option in select patients with a chance for long-term survival. A multi-disciplinary approach is critical as different therapeutic modalities have a role in treating recurrent HCC following transplant.

Background There are no conclusive cost-effectiveness studies measuring the efficacy of salvage LT after liver resection (LR) and radiofrequency ablation (RFA) in patients with early hepatocellular carcinoma (HCC) and compensated cirrhosis. The aim of the present study is to compare liver transplantation (LT) versus locoregional therapy plus salvage LT (to treat tumor recurrence) in patients with early HCC and compensated cirrhosis. Methods Reference case: 55-year old male with HCC within Milan criteria and Child-Pugh A cirrhosis. The analysis was performed in two geographical cost settings: USA and Italy. Survival benefit measured in quality-adjusted life years (QALYs), costs (C) in US$, incremental cost-effectiveness, willingness to pay, and net health benefit (NHB). Results In the base-case analysis, NHB of LT vs. LR and RFA was −1.7 and −1.3 years for single tumor ≤3 cm, −1.2 and −0.7 for single nodules measuring 3.1–5 cm and −0.7 and −0.7 for multi-nodular tumor ≤3 cm in Italy. In USA, NHB of LT versus LR and RFA were −1.2 and −0.8 years for single tumor ≤3 cm, −0.9 and −0.5 for single nodules measuring 3.1–5 cm, and −0.5 and −0.4 for multi-nodular tumor ≤ 3 cm. On the Monte Carlo simulation, only young patients with multi-nodular HCC and short waiting list time had a positive NHB. Salvage LT proved to be an ineffective cost strategy after RFA or LR. Conclusion In patients with HCC within Milan criteria and Child-Pugh A cirrhosis, LR and RFA were more cost-effective than LT. Salvage LT was not cost-effective.

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts—we designate this variant as ‘chromophobe hepatocellular carcinoma with abrupt anaplasia’. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P =0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Background Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. Methods Physicians completed a national Web-based survey that consisted of varied CLM conjoint tasks. Respondents chose among three treatment strategies: immediate liver resection (LR), preoperative chemotherapy followed by surgery (C → LR), or palliative chemotherapy (PC). Data were analyzed by multinomial logistic regression, yielding odds ratios (OR). Results Of 219 respondents, 79 % practiced at academic centers and 63 % were in practice ≥10 years. Median number of cases evaluated was four per month. Surgical training varied: 51 % surgical oncology, 44 % hepato-pancreato-biliary/transplantation, 5 % no fellowship. Although each factor affected the choice of CLM therapy, the relative effect differed. Hilar lymph node disease predicted a strong aversion to LR with surgeons more likely to choose C → LR (OR 8.92) or PC (OR 49.9). Solitary lung metastasis also deterred choice of LR, with respondents favoring C → LR (OR 4.43) or PC (OR 6.97). After controlling for clinical factors, surgeons with more years in practice were more likely to choose PC over C → LR (OR 1.94) ( P  = 0.005). Surgical oncology-trained surgeons were more likely than hepatobiliary/transplant-trained surgeons to choose C → LR (OR 2.53) or PC (OR 4.15) ( P  < 0.001). Conclusions This is the first nationwide study to define the relative impact of key clinical factors on choice of therapy for CLM. Although clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.

Background Little is known about the patterns of utilization of surveillance imaging after treatment of hepatocellular carcinoma (HCC). We sought to define population-based patterns of surveillance and investigate if intensity of surveillance impacted outcome following HCC treatment. Methods The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients with HCC diagnosed between 1998 and 2007 who underwent resection, ablation, or intra-arterial therapy (IAT). The association between imaging frequency and long-term survival was analyzed. Results Of the 1,467 patients, most underwent ablation only (41.5 %), while fewer underwent liver resection only (29.6 %) or IAT only (18.3 %). Most patients had at least one CT scan (92.7 %) during follow-up, while fewer had an MRI (34.1 %). A temporal trend was noted with more frequent surveillance imaging obtained in post-treatment year 1 (2.5 scans/year) vs. year 5 (0.9 scans/year; P  = 0.01); 34.5 % of alive patients had no imaging after 2 years. Frequency of surveillance imaging correlated with procedure type (total number of scans/5 years, resection, 4.7; ablation, 4.9; IAT, 3.7; P  < 0.001). Frequency of surveillance imaging was not associated with a survival benefit (three to four scans/year, 49.5 months vs. two scans/year, 71.7 months vs. one scan/year, 67.6 months; P  = 0.01) Conclusion Marked heterogeneity exists in how often surveillance imaging is obtained following treatment of HCC. Higher intensity imaging does not confer a survival benefit.

Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Merck & Co, Inc.

An oncogenic mutation (G49A:E17K) in the AKT1 gene has been described recently in human breast, colon, and ovarian cancers. The low frequency of this mutation and perhaps other selective pressures have prevented the isolation of human cancer cell lines that harbor this mutation thereby limiting functional analysis. Here, we create a physiologic in vitro model to study the effects of this mutation by using somatic cell gene targeting using the nontumorigenic human breast epithelial cell line, MCF10A. Surprisingly, knock in of E17K into the AKT1 gene had minimal phenotypic consequences and importantly, did not recapitulate the biochemical and growth characteristics seen with somatic cell knock in of PIK3CA hotspot mutations. These results suggest that mutations in critical genes within the PI3-kinase (PI3K) pathway are not functionally equivalent, and that other cooperative genetic events may be necessary to achieve oncogenic PI3K pathway activation in cancers that contain the AKT1 E17K mutation.

We previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP. Immunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC). MUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC. The distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway.