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BackgroundPancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC).MethodsWe conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses.ResultsA total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P

IntroductionNon-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though it is not known how this applies across all B-cell lymphoid malignancies.MethodsWe conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution.ResultsTwo-hundred twenty-three adults (aged = 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG< 500 mg/mL. For this analysis, we grouped DLBCL (n=90), Primary CNS (n=5), and Burkitt lymphoma (n=1) together as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and Waldenstrom macroglobulinemia (n=5) were low-grade. The incidence of hypogammaglobulinemia in our cohort of both high and low-grade lymphoma patients was 13.5% (n=30). Across all NHL subtypes, individuals with baseline IgG< 500 mg/dL showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI: 1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG=500 mg/dL. There was a higher hospitalization rate (3.237, CI: 1.77-6.051, p=0.0017) in those with high-grade lymphoma with hypogammaglobulinemia when compared with low-grade. There was no statistically significant difference in individuals who were alive after three years in those with baseline IgG

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

Background and aimsPortal hypertension (PH) is a serious adverse event of liver cirrhosis. The hepatic venous pressure gradient or portal pressure gradient (PPG) accurately reflects the degree of PH and is the single best prognostic indicator in liver disease. This is usually obtained by interventional radiology (IR), although it is not routinely performed. Recently, we developed a simple novel technique for EUS-guided PPG measurement (PPGM). Our animal studies showed excellent correlation between EUS-PPGM and IR-PPGM. We present the first human pilot study of EUS-PPGM in patients with liver disease.MethodsEUS-PPGM was performed by experienced endosonographers using a linear echoendoscope, a 25-gauge fine-needle aspiration needle, and a novel compact manometer. The portal vein and hepatic vein (or inferior vena cava) were targeted using a transgastric-transduodenal approach. Clinical parameters of PH were evaluated in each patient. Feasibility was defined as successful PPGM in each patient. Safety was based on adverse events captured in a postprocedural interview.ResultsTwenty-eight patients underwent EUS-PPGM with 100% technical success and no adverse events. PPG ranged from 1.5 to 19 mm Hg and had excellent correlation with clinical parameters of portal hypertension including the presence of varices (P = .0002), PH gastropathy (P = .007), and thrombocytopenia (P = .036). PPG was increased in patients with high clinical evidence of cirrhosis (P = .005).ConclusionThis novel technique of EUS-PPGM using a 25-gauge needle and compact manometer is feasible and appears safe. Given the availability of EUS and the simplicity of the manometry setup, EUS-guided PPG may represent a promising breakthrough for procuring indispensable information in the management of patients with liver disease.

BackgroundGNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes.MethodsWe defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin

Background and objectivesTo investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC).MethodsNinety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure.ResultsThe mean (±SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 ± 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P

The aim of this study was to evaluate the change of breast density in the normal breast of patients receiving neoadjuvant chemotherapy (NAC). Forty-four breast cancer patients were studied. MRI acquisition was performed before treatment (baseline), and 4 and 12 weeks after treatment. A computer-algorithm-based program was used to segment breast tissue and calculate breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) (the ratio of FV over BV × 100%). The reduction of FV and PD after treatment was compared with baseline using paired t-tests with a Bonferroni-Holm correction. The association of density reduction with age was analyzed. FV and PD after NAC showed significant decreases compared with the baseline. FV was 110.0 ml (67.2, 189.8) (geometric mean (interquartile range)) at baseline, 104.3 ml (66.6, 164.4) after 4 weeks (p < 0.0001), and 94.7 ml (60.2, 144.4) after 12 weeks (comparison with baseline, p < 0.0001; comparison with 4 weeks, p = 0.016). PD was 11.2% (6.4, 22.4) at baseline, 10.6% (6.6, 20.3) after 4 weeks (p < 0.0001), and 9.7% (6.2, 17.9) after 12 weeks (comparison with baseline, p = 0.0001; comparison with 4 weeks, p = 0.018). Younger patients tended to show a higher density reduction, but overall correlation with age was only moderate (r = 0.28 for FV, p = 0.07, and r = 0.52 for PD, p = 0.0003). Our study showed that breast density measured from MR images acquired at 3T MR can be accurately quantified using a robust computer-aided algorithm based on non-parametric non-uniformity normalization (N3) and an adaptive fuzzy C-means algorithm. Similar to doxorubicin and cyclophosphamide regimens, the taxane-based NAC regimen also caused density atrophy in the normal breast and showed reduction in FV and PD. The effect of breast density reduction was age related and duration related.

Gallbladder cancer is a rare malignancy, which often goes undiagnosed until advanced stages of disease and is associated with poor prognosis. The only potentially curative treatment is surgical resection. This retrospective study aims to investigate the validity of the revised 7th edition American Joint Committee on Cancer staging criteria and determine prognostic factors. Forty-two patients with confirmed gallbladder cancer who underwent attempted curative resection from 1999 to 2012 at the University of California, Irvine Medical Center were reviewed. Survival probability was determined using the Kaplan-Meier method. Ten patients underwent laparoscopy, were deemed unresectable, and no further surgical intervention was performed. R0 surgical resection, which included radical portal lymphadenectomy, liver segment IVb/V resection, with or without bile duct resection, was performed in the remaining 32 patients. N2 nodes were resected if positive on frozen section. Overall survival probability for Stage I to II patients was 100 per cent. Overall survival probability for Stage III patients was 80 per cent (95% confidence interval [CI], 61 to 99%) and 39.3 per cent (95% CI, 28 to 78%) for Stage IV patients. This study demonstrates that 7th edition clinical stage, T stage, and liver involvement are statistically significant predictors of prognosis. These data also demonstrate a benefit to extended resection in patients even with Stage III and IV disease.

The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, χ(2) or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; P(interaction) = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45).

Background & aimsCombination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.MethodsWe analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.ResultsIn the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).ConclusionsA combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.

ObjectiveThe validity of quality of care measurement has important implications for practicing clinicians, their patients, and all involved with health care delivery. We used empirical data from managed care patients enrolled in west coast physician organizations to test the hypothesis that observed changes in health-related quality of life across a 2.5-year window reflecting process of care.Data sources/study settingPatient self-report data as well as clinically detailed medical record review regarding 963 patients with chronic disease associated with managed care from three west coast states.Study designProspective cohort study of change in health-related quality of life scores across 30 months as measured by change in SF-12 physical component scores.Data collection/extraction methodsPatient self-report and medical record abstraction.Principal findingsWe found a positive relationship between better process scores and higher burden of illness (p

BackgroundThe validity of quality of care assessments relies upon data quality, yet little is known about the relative completeness and validity of data sources for evaluating the quality of care.ObjectivesWe evaluated concordance between ambulatory medical record and patient survey data. Levels of concordance, variations by type of item, sources of disagreement between data sources, and implications for quality of care assessment efforts are discussed.Design and subjectsThis was an observational study that included 1270 patients sampled from 39 West Coast medical organizations with at least 1 of the following: diabetes, ischemic heart disease, asthma or chronic obstructive pulmonary disease, or low back pain.MeasuresItems from both data sources were grouped into 4 conceptual domains: diagnosis, clinical services delivered, counseling and referral, and medication use. We present total agreement, kappa, sensitivity, and specificity at the item and domain-levels and for all items combined.ResultsWe found good concordance between survey and medical records overall, but there was substantial variation within and across domains. The worst concordance was in the counseling and referrals domain, the best in the medication use domain. Patients were able to report with good sensitivity on memorable items.ConclusionsQuality ratings are likely to vary in differing directions, depending on the data source used. The most appropriate data source for analyses of components of and overall quality of care must be considered in light of study objectives and resources. We recommend data collection from multiple sources to most accurately portray the patient and provider experience of medical care.

ObjectiveTo create an efficient imputation algorithm for imputing the SF-12 physical component summary (PCS) and mental component summary (MCS) scores when patients have one to eleven SF-12 items missing.Study settingPrimary data collection was performed between 1996 and 1998.Study designMulti-pattern regression was conducted to impute the scores using only available SF-12 items (simple model), and then supplemented by demographics, smoking status and comorbidity (enhanced model) to increase the accuracy. A cut point of missing SF-12 items was determined for using the simple or the enhanced model. The algorithm was validated through simulation.Data collectionThirty-thousand-three-hundred and eight patients from 63 physician groups were surveyed for a quality of care study in 1996, which collected the SF-12 and other information. The patients were classified as "chronic" patients if they reported that they had diabetes, heart disease, asthma/chronic obstructive pulmonary disease, or low back pain. A follow-up survey was conducted in 1998.Principal findingsThirty-one percent of the patients missed at least one SF-12 item. Means of variance of prediction and standard errors of the mean imputed scores increased with the number of missing SF-12 items. Correlations between the observed and the imputed scores derived from the enhanced models were consistently higher than those derived from the simple model and the increments were significant for patients with > or =6 missing SF-12 items (p or =6 items missing, leading to estimated scores that are as accurate as that of patients with

ObjectiveTo illustrate, using empirical data, methodological challenges associated with patient responses to longitudinal surveys regarding the quality of process of care and health status, including overall response rate, differential response rate, and stability of responses with time.Data sources/study settingPrimary patient self-report data were collected from 30,308 patients in 1996 and 13,438 patients in 1998 as part of a two-year longitudinal study of quality of care and health status of patients receiving care delivered by 63 physician organizations (physician groups) across three West Coast states.Study designWe analyzed longitudinal, observational data collected by Pacific Business Group on Health (PBGH) from patients aged 18-70 using a four-page survey in 1996 and a similar survey in 1998 to assess health status, satisfaction, use of services, and self-reported process of care. A subset of patients with self-reported chronic disease in the 1996 study received an enriched survey in 1998 to more fully detail processes of care for patients with chronic disease.Data collection/extraction methodsWe measured response rate overall and separately for patients with chronic disease. Logistic regression was used to assess the impact of 1996 predictors on response to the follow-up 1998 survey. We compared process of care scores without and with nonresponse weights. Additionally, we measured stability of patient responses over time using percent agreement and kappa statistics, and examined rates of gender inconsistencies reported across the 1996 and 1998 surveys.Principal findingsIn 1998, response rates were 54 percent overall and 63 percent for patients with chronic disease. Patient demographics, health status, use of services, and satisfaction with care in 1996 were all significant predictors of response in 1998, highlighting the importance of analytic strategies (i.e., application of nonresponse weights) to minimize bias in estimates of care and outcomes associated with longitudinal quality of care and health outcome analyses. Process of care scores weighted for nonresponse differed from unweighted scores (p