Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study.

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .

In Vivo Cellular Expansion of Lisocabtagene Maraleucel and Association With Efficacy and Safety in Relapsed/Refractory Large B-Cell Lymphoma.

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor T-cell product for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. In vivo cellular expansion after single-dose administration of liso-cel has been characterized. In this article, in vivo liso-cel expansion in the pivotal study TRANSCEND NHL 001 (ClinicalTrials.gov identifier, NCT02631044) was further characterized to assess the relationship between in vivo cellular expansion after single-dose administration of liso-cel and efficacy or safety after adjusting for key baseline characteristics. Two bioanalytical methods, quantitative polymerase chain reaction and flow cytometry, were used for the assessment of cellular kinetics of liso-cel, which showed high concordance for in vivo cellular expansion. Multivariable logistic regression analyses demonstrated that higher in vivo cellular expansion of liso-cel was associated with a higher overall response and complete response rate, and a higher incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory LBCL. Age and tumor burden (by sum of the product of perpendicular diameters) were likely to confound the relationship between in vivo cellular expansion and efficacy, where the association became stronger after controlling for these factors. Repeat dosing of liso-cel was tested in the study; however, in vivo cellular expansion of liso-cel was lower after repeat dosing than after the initial dose. These findings should enable a comprehensive understanding of the in vivo cellular kinetics of liso-cel and the association with outcomes in relapsed/refractory LBCL.

Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma.

BACKGROUND AND OBJECTIVES: Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients. METHODS: We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors. RESULTS: Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71-3.97), 0.755 (0.667-0.821), 9.29 (8.81-9.70), 5.00 (4.15-5.90), and 352 (241-647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population. CONCLUSIONS: The covariates tested were not considered to have a meaningful impact on liso-cel kinetics. CLINICAL TRIAL REGISTRATION: NCT02631044.

Postinfusion monitoring costs by site of care for patients with relapsed/refractory large B-cell lymphoma receiving third- or later-line treatment with lisocabtagene maraleucel in the TRANSCEND NHL 001 and OUTREACH trials.

This retrospective study estimated postinfusion health care resource utilization (HCRU) by site of care among 303 patients with relapsed/refractory large B-cell lymphoma who received third- or later-line treatment with lisocabtagene maraleucel (liso-cel) in the TRANSCEND NHL 001 and OUTREACH trials. Inpatients (n = 256) had higher rates of hospitalization versus outpatients (n = 47; >99% vs 62%), by definition, and higher rates of tocilizumab use for cytokine release syndrome and/or neurological events (22% vs 9%). Rates of intensive care unit admission, corticosteroid use, vasopressor use, hemodialysis, and intubation were generally low and similar between groups. Median (range) total hospital length of stay was 15 (0-88) days (inpatients) and 4 (0-77) days (outpatients). Over 6 months, estimated mean postinfusion cost of care was $89,535 (inpatients) and $36,702 (outpatients). Most costs were incurred in the first month post infusion (inpatients, $50,369 [56%]; outpatients, $19,837 [54%]). Lower overall HCRU was observed with outpatient postinfusion monitoring.

Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.

Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis.

BACKGROUND: High-dose ibuprofen (HDI) is a clinically beneficial anti-inflammatory regimen that may be a useful reagent to study induced sputum inflammatory marker changes over short study periods appropriate for early-phase CF clinical trials. METHODS: We conducted a 28-day, open-label, randomized, controlled trial among 72 clinically stable CF subjects (FEV1≥40% predicted) randomized to HDI or routine care that assessed IL-6, IL-8, TNF-α, IL-1-ß, free neutrophil elastase, and white cell counts with differentials change from baseline in induced sputum. RESULTS: IL-6 was the only biomarker with significant within-group change: 0.13 log10 pg/mL mean reduction among ibuprofen-treated subjects (p=0.04); and no change in the control group. IL-6 change between groups was statistically significant (p=0.024). No other inflammatory biomarker differences were observed between groups after 28 days. CONCLUSION: Although we studied only one agent, HDI, these results suggest that one month may be inadequate to assess anti-inflammatory candidates using markers from induced sputum.

Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial.

Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247.

Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function.

Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.

Pseudomonas aeruginosa serology and risk for re-isolation in the EPIC trial.

BACKGROUND: The prognostic value of Pseudomonas aeruginosa serology for antibiotic therapy in cystic fibrosis patients is not well understood. METHODS: Using five antigens from two ELISAs, we assessed whether positive serology in CF patients participating in the multi-center Early Pseudomonas Infection in Children (EPIC) trial would predict treatment failure, time to pulmonary exacerbation and risk for recurrent P. aeruginosa isolation post eradication. RESULTS: Baseline positive P. aeruginosa serology was not significantly associated with failure of initial P. aeruginosa eradication measured at week 10 (adjusted for baseline culture) but seropositivity to the antigens alkaline protease and exotoxin A was significantly associated with increased risk for recurrent P. aeruginosa isolation during the 60 week post eradication follow-up period (p=0.003 and p=0.001 respectively). There was no association between baseline seropositivity and time to pulmonary exacerbation. CONCLUSION: P. aeruginosa serology may complement culture results in clinicians' efforts to successfully monitor recurrence of early P. aeruginosa in CF patients.

Comparison of 7-day and repeated 24-hour recall of symptoms of cystic fibrosis.

BACKGROUND: Patient reporting of symptoms in a questionnaire with a 7-day recall period is expected to differ from reporting in daily symptom diaries. METHODS: 38 patients with cystic fibrosis (CF) completed 77 week-long symptom diaries. Each diary day comprised 13 symptom items with 5-point response scales. Days 1-6 of the diary had a 24-hour recall period. Day 7 had a 7-day recall period. Concordance of 7-day recall with summary descriptors of daily reports (e.g. mean, maximum) was examined and ability of 7-day recall and mean of daily reports to discriminate between well and ill periods of health compared. RESULTS: The average difference in scores was less than 0.25 response scale points. 7-day recall was most concordant with the mean of daily reports. Discriminant ability was comparable. CONCLUSIONS: In this study sample, a questionnaire with 7-day recall provided information similar to a daily diary about the week-long experience of CF symptoms.

Criterion validity of the Short Mood and Feelings Questionnaire and one- and two-item depression screens in young adolescents.

BACKGROUND: The use of short screening questionnaires may be a promising option for identifying children at risk for depression in a community setting. The objective of this study was to assess the validity of the Short Mood and Feelings Questionnaire (SMFQ) and one- and two-item screening instruments for depressive disorders in a school-based sample of young adolescents. METHODS: Participants were 521 sixth-grade students attending public middle schools. Child and parent versions of the SMFQ were administered to evaluate the child's depressive symptoms. The presence of any depressive disorder during the previous month was assessed using the Diagnostic Interview Schedule for Children (DISC) as the criterion standard. First, we assessed the diagnostic accuracy of child, parent, and combined scores of the full 13-item SMFQ by calculating the area under the receiver operating characteristic curve (AUC), sensitivity and specificity. The same approach was then used to evaluate the accuracy of a two-item scale consisting of only depressed mood and anhedonia items, and a single depressed mood item. RESULTS: The combined child + parent SMFQ score showed the highest accuracy (AUC = 0.86). Diagnostic accuracy was lower for child (AUC = 0.73) and parent (AUC = 0.74) SMFQ versions. Corresponding versions of one- and two-item screens had lower AUC estimates, but the combined versions of the brief screens each still showed moderate accuracy. Furthermore, child and combined versions of the two-item screen demonstrated higher sensitivity (although lower specificity) than either the one-item screen or the full SMFQ. CONCLUSIONS: Under conditions where parents accompany children to screening settings (e.g. primary care), use of a child + parent version of the SMFQ is recommended. However, when parents are not available, and the cost of a false positive result is minimal, then a one- or two-item screen may be useful for initial identification of at-risk youth.

Passive versus active parental permission: implications for the ability of school-based depression screening to reach youth at risk.

BACKGROUND: Depression is prevalent among children and adolescents and often goes untreated with adverse effects on academic success and healthy development. Depression screening can facilitate early identification and timely referral to prevention and treatment programs. Conducting school-based emotional health screening, however, raises the controversial issue of how to obtain informed parental permission. METHODS: During implementation of a depression screening program in an urban school district in the Pacific Northwest, the district's parental permission protocol changed from passive (information provided to parents via a school mailer with parents having the option to actively decline their child's participation) to active (information provided to parents via a school mailer requiring the written permission of the parents for their child's participation). This change provided an opportunity to examine differences in participation under these 2 conditions. RESULTS: A total of 1533 students were enrolled in this program across both years. Compared to conditions of passive permission, participation was dramatically reduced when children were required to have written parental permission, dropping from 85% to 66% of eligible children. Furthermore, under conditions of active parental permission, participation decreased differentially among student subgroups with increased risk for depression. CONCLUSIONS: Successful implementation of school-based emotional health screening programs requires careful consideration of how to inform and obtain permission from parents.

Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis.

BACKGROUND & AIMS: Although hepatocellular carcinoma (HCC) occurs with increased frequency in patients with primary biliary cirrhosis (PBC), the exact frequency is relatively low. Optimal selection of PBC patients for HCC screening needs to be determined for effective screening. In this study, we aimed to explore clinical predictors of HCC in PBC patients. METHODS: We performed a case-control study using 17 PBC patients with HCC identified from 1976 to 2002 at the Mayo Clinic. Control PBC patients who had no evidence of HCC were selected for each case by matching the first year of their visit to the Mayo Clinic. All medical information was collected within 2 years from when the cases were diagnosed with HCC. Logistic regression models were used for the analyses. RESULTS: Age, sex, history of blood transfusion, current smoking, histologic stage at PBC diagnosis, any signs of portal hypertension, Mayo score, hemoglobin level, platelet count, aspartate aminotransferase level, and albumin level were associated with the presence of HCC (P < .05 for each). In multivariable analysis, older age (OR, 1.7; 95% confidence interval [CI], 1.1-2.5 for 5 years), male sex (OR, 9.7; 95% CI, 1.4-68.3), history of blood transfusion (OR, 5.0; 95% CI, 1.0-24.3), and any signs of portal hypertension (OR, 22.9; 95% CI, 3.4-155.3) were associated significantly with increased odds of HCC and yielded an excellent diagnostic performance (area under the receiver operating characteristics curve rate, 0.91). CONCLUSIONS: Older age, male sex, history of blood transfusion, and any signs of portal hypertension or cirrhosis indicate higher likelihood of HCC and should be considered for HCC screening. Further studies in larger patient cohorts are required to verify the diagnostic model.

Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Choosing endpoints in nonalcoholic steatohepatitis (NASH) trials is challenging because of the lack of validated surrogates and the trade-off between accuracy and invasiveness. In this study, we assessed diagnostic accuracy of serum aminotransferase changes in predicting histological changes in NASH trials. METHODS: We conducted a longitudinal cohort study by using 102 participants in ursodeoxycholic acid-NASH trial who had both baseline and 2-year liver biopsy and multiple measurements of serum aminotransferases. We calculated rates of alanine aminotransferase (ALT) [or aspartate aminotransferase (AST)] change as slopes of linear regression over 2 years (IU/l/month) and changes in each histological feature as differences in Brunt's scores of two biopsies in each individual. RESULTS: Rate of aminotransferase change correlated with changes in inflammation and fibrosis, but not steatosis and only with change in inflammation in multivariable analysis. In each histological feature, changes were inversely correlated with baseline histological grade. In predicting improvement of inflammation, areas under the receiver-operating characteristic curve of aminotransferase information alone were 0.72 for ALT and 0.73 for AST and were improved to 0.88 and 0.89, respectively, when baseline histology were taking account of. CONCLUSIONS: Serum aminotransferase changes could be useful as surrogates in screening therapies for NASH in clinical trials with appropriate consideration of baseline aminotransferase and histology.

Colorectal cancer prognosis among patients with inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is associated with an increased risk for colorectal cancer (CRC). However, the genetic, endoscopic, and histologic features of IBD-associated CRC differ from cancers that arise sporadically. The objectives of this study were to describe the clinicopathologic features of IBD-associated CRC and to compare survival rates between patients with IBD-associated CRC and patients with sporadic CRC. METHODS: There were 290 patients with IBD-associated CRC (241 with chronic ulcerative colitis [CUC] and 49 with Crohn's disease) and an equal number of age- and sex-matched sporadic CRC patients who were evaluated at the Mayo Clinic between 1976 and 1996. Medical records were reviewed retrospectively for demographic features, endoscopic and histologic characteristics, and vital status at the time of the last follow-up evaluation. The actuarial survival of each group was calculated by the Kaplan-Meier method. The influence of clinical features on survival was assessed using Cox proportional hazards regression modeling. RESULTS: The median age at diagnosis of IBD-related CRC was 48 years. Fifty-five percent of IBD-related tumors were distal to the splenic flexure compared with 78% of sporadic tumors. During a median follow-up period of 5 years, 163 IBD-associated CRC patients died (56%), compared with 164 sporadic CRC patients (57%). The 5-year survival rates were 54% in the IBD-CRC subgroup vs 53% in the sporadic CRC subgroup (P = .94, log-rank). CONCLUSIONS: CUC-related CRC is diagnosed at a relatively young age, and IBD-related tumors tend to be distributed more evenly across the colorectum than sporadic tumors. The survival rates for IBD-associated and sporadic CRC were similar.

Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study.

The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. We conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia. The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4+CD28null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4+CD28null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in our study population. Expansion of CD4+CD28null T cells in these patients may contribute to the progression of atherosclerosis.

The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis.

CA 19-9 has been used with questionable accuracy to aid diagnosis of cholangiocarcinoma complicating primary sclerosing cholangitis. We aimed to characterize the test properties of CA 19-9 and of a change in CA 19-9 over time in predicting cholangiocarcinoma. Charts of 208 patients were reviewed. Fourteen patients had cholangiocarcinoma. Median CA 19-9 was higher with cholangiocarcinoma (15 vs. 290 U/ml, p < 0.0001). A cutoff of 129 U/ml provided: sensitivity 78.6%, specificity 98.5%, adjusted positive predictive value 56.6% and negative predictive value 99.4%. The median change over time was 664 U/ml in cholangiocarcinoma compared to 6.7 U/ml in primary sclerosing cholangitis alone (p < 0.0001). A cutoff of 63.2 U/ml for change in CA 19-9 provided: sensitivity 90%, specificity 98% and positive predictive value 42%. Only 2 patients with cholangiocarcinoma were the candidates for curative therapy. In conclusion, the positive predictive value of an elevated CA 19-9 was 56.6%; only advanced cases were detected by this method.

Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease.

BACKGROUND/AIMS: The effects of lifestyle modifications in nonalcoholic fatty liver disease (NAFLD) are incompletely defined. We aimed at determining the association of changes in body weight and lifestyle with changes in serum ALT levels. METHODS: We analyzed annual health checkup data from 1546 employees. Of 469 subjects with elevated ALT, we selected 348 male subjects by excluding those who had other causes of liver disease. They were followed for one year to assess the association of change in lifestyle with change in serum ALT. The 136 subjects who had ALT normalization were followed for two years to assess the association between lifestyle management and persistently normal ALT. RESULTS: In adjusted analysis, weight loss and regular exercise were significantly associated with improvement in serum ALT and increased the odds of ALT normalization, while starting smoking was significantly associated with deterioration in serum ALT. Subjects achieving > or = 5% weight reduction showed improvement in serum ALT. Reduction in alcohol consumption was not associated with changes in serum ALT. Maintaining reduced weight (<5% gain) was significantly associated with persistently normal ALT. CONCLUSIONS: Reducing weight by at least 5% with subsequent weight control and exercising regularly may be beneficial in treating NAFLD.