Receipt of Serial Endoscopy Procedures Prior to Esophageal Adenocarcinoma Diagnosis Is Associated with Better Survival.

BACKGROUND: The poor prognosis of esophageal adenocarcinoma (EAC) has focused efforts on early detection by serial endoscopic surveillance of Barrett's esophagus (BE). Previously, we reported that receipt of endoscopy before EAC diagnosis was associated with improved survival. AIM: We aimed to refine our previous analysis, assessing surveillance as measured by performance of serial endoscopy before EAC diagnosis and evaluating its association with stage and survival. METHODS: A retrospective cohort study was performed using the Surveillance, Epidemiology and End Results-Medicare database. Patients aged ≥ 70 years with EAC diagnosed during 1998-2009 were identified. Diagnosis with BE and receipt of ≥ 2 upper endoscopic procedures within 5 years before cancer diagnosis were identified. We compared a reference group not receiving serial endoscopy to 3 patterns based on ≥ 2 endoscopy dates relative to a timepoint 2 years before cancer diagnosis: "remote," "recent," and "sustained." RESULTS: Among 5532 patients, 28% (n = 1,575) had localized stage. Thirteen percent (n = 703) received ≥ 2 endoscopic procedures before cancer diagnosis: 224, 298, and 181 in the "recent," "remote," and "sustained" groups. Serial endoscopy and prior BE were associated with localized stage ("sustained" group OR 2.95, 95% confidence interval [CI] 2.07, 4.19; prior BE OR 2.68, 95% CI 2.03, 3.56). Serial endoscopy was associated with improved survival even with adjustment for lead time bias ("sustained" group HR 0.45, 95% CI 0.37, 0.55) and length time bias. CONCLUSIONS: Sustained endoscopy was associated with earlier stage and improved survival. These results support the role of sustained surveillance in early detection of EAC.

Validating the New Primary Care Measure in the Medical Expenditure Panel Survey.

BACKGROUND: The advancement of primary care research requires reliable and validated measures that capture primary care processes embedded within nationally representative datasets. OBJECTIVE: The objective of this study was to assess the validity of a newly developed measure of primary care processes [Medical Expenditure Panel Survey (MEPS)-PC] with preliminary evidence of moderate to excellent reliability. STUDY DESIGN: A retrospective cohort study of community-dwelling adults with history of office-based provider visit/s using the MEPS (2013-2014). METHODS: The 3 MEPS-PC subscales (Relationship, Comprehensiveness, and Health Promotion) were tested for construct validity against known measures of primary care: Usual Source of Care, Known Provider, and Family-Usual Source of Care. Concurrent and predictive logistic regression analyses were calculated and compared with a priori hypotheses for direction and strength of association. RESULTS: For concurrent validity, all odds ratio estimates conformed with hypotheses, with 91% displaying statistical significance. For predictive validity, all estimates were in the direction of hypotheses, with 92% displaying statistically significant results. Although Relationship and Health Promotion subscales conformed uniformly with hypotheses, the Comprehensiveness subscale yielded significant results in 60% of bivariate odds ratio estimates (P<0.05). CONCLUSION: The MEPS-PC composite measures display modest to strong preliminary evidence of concurrent and predictive validity relative to known indicators of primary care. IMPLICATIONS FOR POLICY AND PRACTICE: The MEPS-PC composite measures display preliminary evidence of concurrent and predictive construct validity, and it may be useful to researchers investigating primary care processes and complexities in the health care environment.

Assessing the Longitudinal Impact of Physician-Patient Relationship on Functional Health.

PURPOSE: Access to a usual source of care is associated with improved health outcomes, but research on how the physician-patient relationship affects a patient's health, particularly long-term, is limited. The aim of this study was to investigate the longitudinal effect of changes in the physician-patient relationship on functional health. METHODS: We conducted a prospective cohort study using the Medical Expenditure Panel Survey (MEPS, 2015-2016). The outcome was 1-year change in functional health (12-Item Short-Form Survey). The predictors were quality of physician-patient relationship, and changes in this relationship, operationalized with the MEPS Primary Care (MEPS-PC) Relationship subscale, a composite measure with preliminary evidence of reliability and validity. Confounders included age, sex, race/ethnicity, educational attainment, insurance status, US region, and multimorbidity. We conducted analyses with survey-weighted, covariate-adjusted, predicted marginal means, used to calculate Cohen effect estimates. We tested differences in trajectories with multiple pairwise comparisons with Tukey contrasts. RESULTS: Improved physician-patient relationships were associated with improved functional health, whereas worsened physician-patient relationships were associated with worsened functional health, with 1-year effect estimates ranging from 0.05 (95% CI, 0-0.10) to 0.08 (95% CI, 0.02-0.13) compared with -0.16 (95% CI, -0.35 to -0.03) to -0.33 (95% CI, -0.47 to -0.02), respectively. CONCLUSION: The quality of the physician-patient relationship is positively associated with functional health. These findings could inform health care strategies and health policy aimed at improving patient-centered health outcomes.

Apparatus and Method for Rapid Detection of Acoustic Anisotropy in Cartilage.

PURPOSE: Articular cartilage is known to be mechanically anisotropic. In this paper, the acoustic anisotropy of bovine articular cartilage and the effects of freeze-thaw cycling on acoustic anisotropy were investigated. METHODS: We developed apparatus and methods that use a magnetic L-shaped sample holder, which allowed minimal handling of a tissue, reduced the number of measurements compared to previous studies, and produced highly reproducible results. RESULTS: SOS was greater in the direction perpendicular to the articular surface compared to the direction parallel to the articular surface (N=17, P = 0.00001). Average SOS was 1,758 ± 107 m/s perpendicular to the surface, and 1,617 ± 55 m/s parallel to it. The average percentage difference in SOS between the perpendicular and parallel directions was 8.2% (95% CI: 5.4% to 11%). Freeze-thaw cycling did not have a significant effect on SOS (P>0.4). CONCLUSION: Acoustic measurement of tissue properties is particularly attractive for work in our laboratory since it has the potential for nondestructive characterization of the properties of developing engineered cartilage. Our approach allowed us to observe acoustic anisotropy of articular cartilage rapidly and reproducibly. This property was not significantly affected by freeze-thawing of the tissue samples, making cryopreservation practical for these assays.

Developing a New Measure of Primary Care Using the Medical Expenditure Panel Survey.

OBJECTIVE: To develop and assess the reliability of a measure of primary care using items from the Medical Expenditure Panel Survey (MEPS), a US representative survey of community-dwelling persons. METHODS: On the basis of the domains from the literature on primary care characteristics, we identified relevant items within the 2013-2014 MEPS family of surveys. In a sample of primary survey respondents with at least 1 office-based physician visit in the last 12 months, we conducted exploratory factor analysis, retaining items with a factor loading of 0.30 and factors ≥3 items. Using a hold-out sample, internal consistency, reproducibility, and confirmatory factor analyses were performed. RESULTS: On the basis of 16 care domains, we found 32 candidate items in the MEPS. Factor analyses of data from 4549 persons meeting inclusion criteria (27.6% of the total sample), yielded 3 unique factors involving 24 items. We named these subscales Relationship, Comprehensiveness, and Health Promotion, displaying internal consistency reliability of 0.86, 0.78, and 0.69, respectively. Confirmatory factor analysis corroborated the stability of the exploratory findings in the hold out sample. Sensitivity analyses showed robustness to differences in underlying correlation structure, alternative approach to missing data, and extension to indirect survey respondents. CONCLUSIONS: The MEPS Primary Care measure with 3 subscales is reliable and may be useful in conducting primary care health services and outcomes research in the rich MEPS dataset. Further validation is needed, and is described in a companion paper.

Cancer preventive services, socioeconomic status, and the Affordable Care Act.

BACKGROUND: Out-of-pocket expenditures are thought to be an important barrier to the receipt of cancer preventive services, especially for those of a lower socioeconomic status (SES). The Affordable Care Act (ACA) eliminated out-of-pocket expenditures for recommended services, including mammography and colonoscopy. The objective of this study was to determine changes in the uptake of mammography and colonoscopy among fee-for-service Medicare beneficiaries before and after ACA implementation. METHODS: Using Medicare claims data, this study identified women who were 70 years old or older and had not undergone mammography in the previous 2 years and men and women who were 70 years old or older, were at increased risk for colorectal cancer, and had not undergone colonoscopy in the past 5 years. The receipt of procedures in the 2-year period before the ACA's implementation (2009-2010) and after its implementation (2011 to September 2012) was also identified. Multivariate generalized estimating equation models were used to determine the independent association and county-level quartile of median income and education with the receipt of testing. RESULTS: For mammography, a lower SES quartile was associated with less uptake, but the post-ACA disparities were smaller than those in the pre-ACA period. In addition, mammography rates increased from the pre-ACA period to the post-ACA period in all SES quartiles. For colonoscopy, in both the pre- and post-ACA periods, there was an association between uptake and educational level and, to some extent, income. However, there were no appreciable changes in colonoscopy and SES after implementation of the ACA. CONCLUSIONS: The removal of out-of-pocket expenditures may overcome a barrier to the receipt of recommended preventive services, but for colonoscopy, other procedural factors may remain as deterrents. Cancer 2017;123:1585-1589. © 2017 American Cancer Society.

Rapid visualization of nonmelanoma skin cancer.

BACKGROUND: Mohs micrographic surgery examines all margins of the resected sample and has a 99% cure rate. However, many nonmelanoma skin cancers (NMSCs) are not readily amenable to Mohs micrographic surgery. This defines an unmet clinical need to assess the completeness of non-Mohs micrographic surgery resections during surgery to prevent re-excision/recurrence. OBJECTIVE: We sought to examine the utility of quenched activity-based probe imaging to discriminate cancerous versus normal-appearing skin tissue. METHODS: The quenched activity-based probe GB119 was applied to NMSC excised from 68 patients. We validated activation of the probe for hematoxylin-eosin-confirmed cancerous tissue versus normal-appearing skin tissue. RESULTS: Topical application of the probe differentiated basal cell carcinoma and squamous cell carcinoma from normal-appearing skin with overall estimated sensitivity and specificity of 0.989 (95% confidence interval 0.940-1.00) and 0.894 (95% confidence interval 0.769-0.965), respectively. Probe activation accurately defined peripheral margins of NMSC as compared with conventional hematoxylin-eosin-based pathology. LIMITATIONS: This study only examined NMSC debulking excision specimens. The sensitivity and specificity for this approach using final NMSC excision margins will be clinically important. CONCLUSIONS: These findings merit further studies to determine whether quenched activity-based probe technology may enable cost-effective increased cure rates for patients with NMSC by reducing re-excision and recurrence rates with a rapid and easily interpretable technological advance.

Music-based magnetic resonance fingerprinting to improve patient comfort during MRI examinations.

PURPOSE: Unpleasant acoustic noise is a drawback of almost every MRI scan. Instead of reducing acoustic noise to improve patient comfort, we propose a technique for mitigating the noise problem by producing musical sounds directly from the switching magnetic fields while simultaneously quantifying multiple important tissue properties. THEORY AND METHODS: MP3 music files were converted to arbitrary encoding gradients, which were then used with varying flip angles and repetition times in a two- and three-dimensional magnetic resonance fingerprinting (MRF) examination. This new acquisition method, named MRF-Music, was used to quantify T1 , T2 , and proton density maps simultaneously while providing pleasing sounds to the patients. RESULTS: MRF-Music scans improved patient comfort significantly during MRI examinations. The T1 and T2 values measured from phantom are in good agreement with those from the standard spin echo measurements. T1 and T2 values from the brain scan are also close to previously reported values. CONCLUSIONS: MRF-Music sequence provides significant improvement in patient comfort compared with the MRF scan and other fast imaging techniques such as echo planar imaging and turbo spin echo scans. It is also a fast and accurate quantitative method that quantifies multiple relaxation parameters simultaneously. Magn Reson Med 75:2303-2314, 2016. © 2015 Wiley Periodicals, Inc.

Outcomes after endoscopic versus surgical therapy for early esophageal cancers in an older population.

BACKGROUND AND AIMS: Endoscopic treatment of early esophageal cancer provides an alternative to esophagectomy, which older patients may not tolerate. Population-based data regarding short-term outcomes and recurrence after endoscopic treatment for esophageal cancer are limited. We compared short-term outcomes, treated recurrence, and survival after endoscopic versus surgical therapy for early esophageal cancers in an older population. METHODS: We conducted a retrospective cohort study identifying patients aged ≥66 years with Tis or T1a tumors without nodal involvement diagnosed from 1994 to 2011 from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. RESULTS: Of 2193 patients, 41% (n = 893) underwent esophagectomy, and 12% (n = 255) underwent endoscopic treatment within 6 months of diagnosis. Those treated endoscopically were older and more likely to have a Charlson comorbidity score ≥2. A composite endpoint, hospitalization and/or adverse events at 60 days, was higher in surgical patients than in the endoscopic treatment group (30% vs 12%; P < .001). In a Cox model stratified by histology, adjusting for other factors, endoscopic treatment was associated with improved 2-year survival (hazard ratio 0.51; 95% CI, 0.36-0.73). CONCLUSIONS: In this older population, a composite short-term endpoint was worse in the surgical group. Endoscopic treatment was associated with improved survival through 2 years. These results suggest that endoscopic treatment is a reasonable approach for early esophageal cancers in the elderly.

Diverticulosis and the risk of interval colorectal cancer.

BACKGROUND: Diverticulosis, a prevalent condition at screening colonoscopy, has been associated with colorectal cancers that develop after a clearing colonoscopy, or interval cancers. AIMS: To quantify the overall risk of diverticulosis in the development of interval cancers and examine this association in relevant subgroups. METHODS: Using a linked database containing SEER tumor registry data and Medicare claims, we identified patients aged ≥69 years with colorectal cancer who underwent colonoscopy within 6 months of diagnosis. Patients with an additional colonoscopy from 36 to 6 months prior to cancer diagnosis were characterized as having interval cancers. We compared characteristics of patients with interval cancers and detected cancers according to a diagnosis of diverticulosis not associated with a colonoscopy procedure from 1991 through the date of the most recent colonoscopy in both univariate and multivariate models. RESULTS: A previous diagnosis of diverticulosis was documented in 14,452 (26.9 %) patients with detected cancers compared to 2,905 (69.3 %) patients with interval cancers (p < 0.001); these results were consistent in multivariable analysis. Moreover, the association was found as well in the proximal colon (OR 2.88, 95 % CI 2.66, 3.12), distal colon (OR 3.56, 95 % CI 3.09, 4.11), and rectum (OR 4.07, 95 % CI 3.34, 4.95). The vast majority of diverticulosis diagnoses were without complications such as hemorrhage or diverticulitis. CONCLUSIONS: Diverticulosis was strongly associated with interval colorectal cancers in all segments of the colon. Given its known predominance in the left colon, the findings argue against impaired visualization of lesions at colonoscopy as the only pathogenic factor.

Use of colonoscopy for polyp surveillance in Medicare beneficiaries.

BACKGROUND: Professional society guidelines recommend follow-up colonoscopy for patients with resected colonic adenomas. However, adherence to guideline recommendations in routine clinical practice has not been well characterized. METHODS: The authors used a population-based sample of Medicare beneficiaries to identify all patients aged ≥70 years who had a claim for colonoscopy with polypectomy or hot biopsy during the period from 2001 to 2004. Medicare claims through 2009 identified colonoscopy within the following 5 years as well as fecal occult blood testing, sigmoidoscopy, and barium enema. RESULTS: In total, 12,771 patients were included. At 5 years, 45.7% of patients underwent another colonoscopy, and 32.3% of procedures included a polypectomy. The rates of fecal occult blood testing, flexible sigmoidoscopy, and barium enema at 5 years were 54%, 3.8%, and 2.9%, respectively. There was a marked decrease in repeat colonoscopy at 1 year, 3 years, and 5 years with more recent years of index procedures. Other predictors of undergoing repeat colonoscopy were younger age, African American race, and a colonoscopy before the index examination. There was no association with physician specialty. The decreasing use of colonoscopy with time was maintained in a multivariable analysis. CONCLUSIONS: In a sample of elderly Medicare beneficiaries, there was under use of follow-up colonoscopy at 5 years after polypectomy, and <50% of patients received a repeat examination. In particular, the use of this procedure decreased over the 4-year study period. Coupled with other data indicating the overuse of follow-up colonoscopy in patients without polyps, there appeared to be significant discordance between guidelines and actual practice.

Management of malignant colonic polyps: a population-based analysis of colonoscopic polypectomy versus surgery.

BACKGROUND: The management of colon polyps containing invasive carcinoma includes surgical resection or colonoscopic polypectomy. To date, there are very limited population-based data comparing outcomes with the 2 management approaches. METHODS: Using the linked Surveillance Epidemiology and End Results-Medicare database, we identified 2077 patients aged ≥66 years with an initial diagnosis of stage T1N0M0 malignant polyp from 1992-2005. Patients were categorized as surgical or polypectomy depending on the most invasive treatment. To adjust for potential selection bias in treatment assignment, using multivariate analysis, patients were divided into quintiles of likelihood of polypectomy (propensity scores), and outcomes were compared in each quintile. RESULTS: Surgical resection was performed in 1340 (64.5%) patients and polypectomy was performed in 737 (35.5%) patients. Predictors for undergoing polypectomy (P<.001) included older age, greater comorbidity, no history of polyps, diagnosis in 2002 or later, left colon site of cancer, well-differentiated tumors, and colonoscopy performed in an outpatient setting. Both 1-year and 5-year survival were higher in the surgical group (92% and 75%, respectively) than in the polypectomy group (88% and 62%, respectively). The unadjusted hazard ratio was 1.51 (95% confidence interval [CI], 1.31-1.74). After adjusting for propensity quintile, the hazard ratio was 1.15 (95% CI, 0.98-1.33). Within each propensity quintile, the risk of death was similar between the 2 groups (interaction test P = .96). CONCLUSIONS: In this large, population-based sample, more than one-third of patients with malignant polyps were treated with colonoscopic polypectomy. Outcomes were similar to surgical patients with comparable clinical characteristics and could be offered to patients who meet appropriate clinical criteria.

Prevalence and predictors of interval colorectal cancers in medicare beneficiaries.

BACKGROUND: After a colonoscopy that is negative for cancer, a subset of patients may be diagnosed with colorectal cancer, also termed interval cancer. The frequency and predictors have not been well studied in a population-based US cohort. METHODS: The authors used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify 57,839 patients aged ≥ 69 years who were diagnosed with colorectal cancer between 1994 and 2005 and who underwent colonoscopy within 6 months of cancer diagnosis. Colonoscopy performed between 6 and 36 months before cancer diagnosis was a proxy for interval cancer. RESULTS: By using the case definition, 7.2% of patients developed interval cancers. Factors that were associated with interval cancers included proximal tumor location (distal colon: multivariable odds ratio [OR], 0.42; 95% confidence interval [CI], 0.390-0.46; rectum: OR, 0.47; 95% CI, 0.42-0.53), increased comorbidity (OR, 1.89; 95% CI, 1.68 2.14 for ≥ 3 comorbidities), a previous diagnosis of diverticulosis (OR, 6.00; 95% CI, 5.57-6.46), and prior polypectomy (OR, 1.74; 95% CI, 1.62-1.87). Risk factors at the endoscopist level included a lower polypectomy rate (OR, 0.70; 95% CI, 0.63-0.78 for the highest quartile), higher colonoscopy volume (OR, 1.27; 95% CI, 1.13-1.43), and specialty other than gastroenterology (colorectal surgery: OR, 1.45; 95% CI, 1.16-1.83; general surgery: OR, 1.42; 95% CI, 1.24-1.62; internal medicine: OR, 1.38; 95% CI, 1.17-1.63; family practice: OR, 1.16; 95% CI, 1.00-1.35). CONCLUSIONS: A significant proportion of patients developed interval colorectal cancer, particularly in the proximal colon. Contributing factors likely included both procedural and biologic factors, emphasizing the importance of meticulous examination of the mucosa.

Jointly modeling the relationship between longitudinal and survival data subject to left truncation with applications to cystic fibrosis.

Numerous methods for joint analysis of longitudinal measures of a continuous outcome y and a time to event outcome T have recently been developed either to focus on the longitudinal data y while correcting for nonignorable dropout, to predict the survival outcome T using the longitudinal data y, or to examine the relationship between y and T. The motivating problem for our work is in joint modeling of the serial measurements of pulmonary function (FEV1% predicted) and survival in cystic fibrosis (CF) patients using registry data. Within the CF registry data, an additional complexity is that not all patients have been followed from birth; therefore, some patients have delayed entry into the study while others may have been missed completely, giving rise to a left truncated distribution. This paper shows in joint modeling situations where y and T are not independent, that it is necessary to account for this left truncation to obtain valid parameter estimates related to both survival and the longitudinal marker. We assume a linear random effects model for FEV1% predicted, where the random intercept and slope of FEV1% predicted, along with a specified transformation of the age at death follow a trivariate normal distribution. We develop an expectation-maximization algorithm for maximum likelihood estimation of parameters, which takes left truncation and right censoring of survival times into account. The methods are illustrated using simulation studies and using data from CF patients in a registry followed at Rainbow Babies and Children's Hospital, Cleveland, OH.

Statin effect on coronary calcium distribution, mass and volume scores and associations with immune activation among HIV+ persons on antiretroviral therapy.

BACKGROUND: Inflammation has been associated with whole heart coronary artery calcification (CAC) among people with HIV (PWH) on antiretroviral therapy (ART); however, prior studies have not evaluated the distribution of calcium or separated mass versus volume scores, which are differentially associated with clinical events in the general population. Statins may also have a greater effect on CAC mass compared with volume. METHODS: 147 PWH were randomized 1:1 to rosuvastatin 10 mg or placebo and followed for 96 weeks. We re-analysed coronary calcium scans from 0, 48 and 96 weeks to determine mass and volume scores and measures of CAC diffusivity. Mixed effects models and generalized estimating equations were used to examine longitudinal associations of CAC with treatment and biomarkers. RESULTS: Median age at study entry was 46 years; 78% were male and 68% African American. Median CD4+ was 613 and half were on protease inhibitors. Randomization to statin therapy was not associated with a change in mass score, volume score, number of involved vessels or diffusivity index (all P>0.1). Soluble CD14 was associated with the presence of CAC (P=0.05) and borderline associated with number of involved vessels (P=0.07) across all three time points. CONCLUSIONS: In PWH on ART, moderate intensity rosuvastatin does not appear to have a significant effect on volume, mass or regional distribution of CAC over 96 weeks. We extend previous cross-sectional observations to show that soluble CD14 is associated with whole heart CAC over time and independently of age and systolic blood pressure.

Photodynamic Therapy Is an Effective Adjuvant Therapy for Image-Guided Surgery in Prostate Cancer.

Local and metastatic relapses of prostate cancer often occur following attempted curative resection of the primary tumor, and up to 66% of local recurrences are associated with positive margins. Therefore, technologies that can improve the visualization of tumor margins and adjuvant therapies to ablate remaining tumor tissues are needed during surgical resection of prostate adenocarcinoma. Photodynamic agents have the potential to combine both fluorescence for image-guided surgery (IGS) and photodynamic therapy (PDT) to resect and ablate cancer cells. The objective of this study was to determine the utility of a targeted PDT agent for IGS and adjuvant PDT. Using a previously developed prostate-specific membrane antigen (PSMA)-targeted PDT agent, PSMA-1-Pc413, we showed that PSMA-1-Pc413 selectively highlighted PSMA-expressing tumors, allowing IGS and more complete tumor resection compared with white light surgery. Subsequent PDT further reduced tumor recurrence and extended animal survival significantly. This approach also enabled identification of tumor cells in lymph nodes. In summary, this study presents a potential new treatment option for patients with prostate cancer undergoing surgery, which improves tumor visualization and discrimination during surgery, including identification of cancer in lymph nodes. SIGNIFICANCE: These findings present a photodynamic agent that can be used for both photodynamic therapy and image-guided surgery, allowing better visualization of tumor margins and elimination of residual tumor tissues.

Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant.

Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.

Shared parameter models for joint analysis of longitudinal and survival data with left truncation due to delayed entry - Applications to cystic fibrosis.

Many longitudinal studies observe time to occurrence of a clinical event such as death, while also collecting serial measurements of one or more biomarkers that are predictive of the event, or are surrogate outcomes of interest. Joint modeling can be used to examine the relationship between the biomarker and the event, and also as a way of adjusting analyses of the biomarker for non-ignorable dropout. In settings such as registry studies, an additional complexity is caused when follow-up of subjects is delayed, referred to as left-truncation of follow-up in the survival analysis setting. If not adjusted for, this can cause bias in estimation of parameters of the survival distribution for the clinical event and in parameters of the longitudinal outcome such as the profile or rate of change over time because subjects may die or have the clinical event before follow-up starts. This paper illustrates how a broad class of shared parameter models can be used to jointly model a time to event outcome along with a longitudinal marker using available nonlinear mixed modeling software, when follow-up times are left truncated. Methods are applied to jointly model survival and decline in lung function in cystic fibrosis patients.

Surgical approach and the impact of epidural analgesia on survival after esophagectomy for cancer: A population-based retrospective cohort study.

BACKGROUND: Esophagectomy for esophageal cancer carries high morbidity and mortality, particularly in older patients. Transthoracic esophagectomy allows formal lymphadenectomy, but leads to greater perioperative morbidity and pain than transhiatal esophagectomy. Epidural analgesia may attenuate the stress response and be less immunosuppressive than opioids, potentially affecting long-term outcomes. These potential benefits may be more pronounced for transthoracic esophagectomy due to its greater physiologic impact. We evaluated the impact of epidural analgesia on survival and recurrence after transthoracic versus transhiatal esophagectomy. METHODS: A retrospective cohort study was performed using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database. Patients aged ≥66 years with locoregional esophageal cancer diagnosed 1994-2009 who underwent esophagectomy were identified, with follow-up through December 31, 2013. Epidural receipt and surgical approach were identified from Medicare claims. Survival analyses adjusting for hospital esophagectomy volume, surgical approach, and epidural use were performed. A subgroup analysis restricted to esophageal adenocarcinoma patients was performed. RESULTS: Among 1,921 patients, 38% underwent transhiatal esophagectomy (n = 730) and 62% underwent transthoracic esophagectomy (n = 1,191). 61% (n = 1,169) received epidurals and 39% (n = 752) did not. Epidural analgesia was associated with transthoracic approach and higher volume hospitals. Patients with epidural analgesia had better 90-day survival. Five-year survival was higher with transhiatal esophagectomy (37.2%) than transthoracic esophagectomy (31.0%, p = 0.006). Among transthoracic esophagectomy patients, epidural analgesia was associated with improved 5-year survival (33.5% epidural versus 26.5% non-epidural, p = 0.012; hazard ratio 0.81, 95% confidence interval [0.70, 0.93]). Among the subgroup of esophageal adenocarcinoma patients undergoing transthoracic esophagectomy, epidural analgesia remained associated with improved 5-year survival (hazard ratio 0.81, 95% confidence interval [0.67, 0.96]); this survival benefit persisted in sensitivity analyses adjusting for propensity to receive an epidural. CONCLUSION: Among patients undergoing transthoracic esophagectomy, including a subgroup restricted to esophageal adenocarcinoma, epidural analgesia was associated with improved survival even after adjusting for other factors.

Genetic modifiers of lung disease in cystic fibrosis.

BACKGROUND: Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS: We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1. RESULTS: In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02). CONCLUSIONS: Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.