Grade Assignment by Ki-67 Proliferative Index, Mitotic Count, and Phosphohistone H3 Count in Surgically Resected Gastrointestinal and Pancreatic Neuroendocrine Tumors.

OBJECTIVES: The aim of this study was to evaluate the concordance in grade assignment for gastroenteropancreatic neuroendocrine tumors using mitotic count (MC), Ki-67 proliferative index (KPI), and phosphohistone H3 count (PHH3C). METHODS: Resected gastroenteropancreatic neuroendocrine tumors were graded based on MC, KPI, and PHH3C. Concordance was determined using a weighted κ statistic. Median survival across each grade category was determined using Kaplan-Meier methods. RESULTS: Of the 110 patients, the majority had gastrointestinal primaries and grade 1 or 2 tumors. Rates of discordance in grade assignment were 29% of cases for KPI versus MC (κW = 0.26), 32% for PHH3C versus MC (κW = 0.34), and 32% for PHH3C versus KPI (κW = 0.37). There was fair agreement between grading by KPI and MC. Relative to grade by KPI and MC, PHH3C tended to upgrade tumors. The proportion alive at 3 and 5 years was not significantly different for patients with grade 1 versus grade 2 tumors. CONCLUSIONS: The concordance between KPI and MC was fair. Phosphohistone H3 count tended to upgrade tumors using the cutoffs established by MC. Grade 1 and grade 2 tumors were associated with similar survival regardless of grading method. The overall relevance of the current cutoff values used in grading neuroendocrine tumors may need to be revisited.

CD200 Expression in Neuroendocrine Neoplasms.

OBJECTIVES: CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites. METHODS: Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison. RESULTS: CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade. CONCLUSIONS: CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

Pancreatic cancer: Update on immunotherapies and algenpantucel-L.

Pancreatic adenocarcinoma is notoriously lethal, and despite improvements in systemic chemotherapy approaches bringing survival rates for metastatic disease to almost 1 year, by 2030 it is expected to become the second leading cause of cancer death. Pancreatic cancer (PC) prognosis has been associated with both the presence of intratumoral helper and cytotoxic T lymphocytes, as well as humoral immune responses to tumor associated antigens like mesothelin. It is well described that the PC microenvironment is characterized by a fibroinflammatory and immunosuppressive stroma. On these premises several immune-targeted strategies have been developed to harness the adaptable immune system with a goal of improving survival with little toxicity. Cancer vaccines involve the administration of tumor-associated antigens with the goal of inducing an endogenous anti-tumor response. Among several strategies discussed, we will focus on the algenpantucel-L (HyperAcute™ Pancreas) immunotherapy. Algenpantucel-L is a whole cell immunotherapy consisting of irradiated allogeneic PC cells genetically engineered to express the murine enzyme α(1,3)-galactosyltransferase (αGT), which ultimately leads to hyperacute rejection with complement- and antibody-dependent cytotoxicity. While phase III data in the adjuvant treatment of pancreatic cancer are pending, phase II results have been encouraging, particularly for patients who demonstrated humoral immunologic responses. Novel strategies using immune checkpoint inhibitors, costimulatory antibodies, and combinations with cancer vaccines may overcome immunotolerance and improve treatment success.

Strategies to implement alcohol screening and brief intervention in primary care settings: a structured literature review.

Although alcohol screening and brief intervention (SBI) reduces drinking in primary care patients with unhealthy alcohol use, incorporating SBI into clinical settings has been challenging. We systematically reviewed the literature on implementation studies of alcohol SBI using a broad conceptual model of implementation, the Consolidated Framework for Implementation Research (CFIR), to identify domains addressed by programs that achieved high rates of screening and/or brief intervention (BI). Seventeen articles from 8 implementation programs were included; studies were conducted in 9 countries and represented 533,903 patients (127,304 patients screened), 2,001 providers, and 1,805 clinics. Rates of SBI varied across articles (2-93% for screening and 0.9-73.1% for BI). Implementation programs described use of 7-25 of the 39 CFIR elements. Most programs used strategies that spanned all 5 domains of the CFIR with varying emphases on particular domains and sub-domains. Comparison of SBI rates was limited by most studies' being conducted by 2 implementation programs and by different outcome measures, scopes, and durations. However, one implementation program reported a high rate of screening relative to other programs (93%) and could be distinguished by its use of strategies that related to the Inner Setting, Outer Setting, and Process of Implementation domains of the CFIR. Future studies could assess whether focusing on Inner Setting, Outer Setting, and Process of Implementation elements of the CFIR during implementation is associated with successful implementation of alcohol screening, as well as which elements may be associated with successful, sustained implementation of BI.

How primary care providers talk to patients about alcohol: a qualitative study.

BACKGROUND: Alcohol misuse is a common and well-documented source of morbidity and mortality. Brief primary care alcohol counseling has been shown to benefit patients with alcohol misuse. OBJECTIVE: To describe alcohol-related discussions between primary care providers and patients who screened positive for alcohol misuse. DESIGN: An exploratory, qualitative analysis of audiotaped primary care visits containing discussions of alcohol use. PARTICIPANTS: Participants were 29 male outpatients at a Veterans Affairs (VA) General Internal Medicine Clinic who screened positive for alcohol misuse and their 14 primary care providers, all of whom were participating in a larger quality improvement trial. MEASUREMENTS: Audiotaped visits with any alcohol-related discussion were transcribed and coded using grounded theory and conversation analysis, both qualitative research techniques. RESULTS: Three themes were identified: (1) patients disclosed information regarding their alcohol use, but providers often did not explore these disclosures; (2) advice about alcohol use was typically vague and/or tentative in contrast to smoking-related advice, which was more common and usually more clear and firm; and (3) discomfort on the part of the provider was evident during alcohol-related discussions. LIMITATIONS: Generalizability of findings from this single-site VA study is unknown. CONCLUSION: Findings from this single site study suggest that provider discomfort and avoidance are important barriers to evidence-based brief alcohol counseling. Further investigation into current alcohol counseling practices is needed to determine whether these patterns extend to other primary care settings, and to inform future educational efforts.

Readiness to change in primary care patients who screened positive for alcohol misuse.

PURPOSE: Readiness to change drinking may influence the content or effectiveness of brief alcohol counseling. This study was designed to assess readiness to change and its relationship to alcohol misuse severity among primary care patients whose screening questionnaire was positive for alcohol misuse. METHODS: This study was a cross-sectional analysis of data collected from 2 consecutive mailed questionnaires. Male outpatients at 7 Veterans Affairs (VA) general medicine clinics were eligible if they returned both questionnaires, screened positive for alcohol misuse (augmented CAGE Questionnaire > or =1 point), responded to 3 readiness-to-change questions, and completed the Alcohol Use Disorders Identification Test (AUDIT). A validated algorithm based on 3 standardized questions categorized participants into 3 readiness groups (precontemplation, contemplation, action). Measures of alcohol misuse severity included AUDIT, CAGE, and the 3 consumption questions from the AUDIT (AUDIT-C). Analyses were descriptive; linear-by-linear associations between alcohol misuse severity and readiness were tested with chi2 statistics. RESULTS: Response rates to the first and second surveys were 59% and 55%, respectively. Of the 6,419 eligible outpatients who screened positive for alcohol misuse, 4,797 (75%) reported any readiness to change (contemplation 24%, action 51%). Among patients with AUDIT scores >8, more than 90% indicated that they drank more than they should and/or had contemplated drinking less. Greater readiness was significantly associated with greater alcohol misuse severity (P <.001 for all measures). CONCLUSIONS: Most primary care patients who screen positive for alcohol misuse indicate some readiness to change. Contrary to stereotypes of denial, those with greater alcohol misuse severity are more likely to report readiness to change.

Using alcohol screening results and treatment history to assess the severity of at-risk drinking in Veterans Affairs primary care patients.

BACKGROUND: Primary care providers need practical methods for managing patients who screen positive for at-risk drinking. We evaluated whether scores on brief alcohol screening questionnaires and patient reports of prior alcohol treatment reflect the severity of recent problems due to drinking. METHODS: Veterans Affairs general medicine outpatients who screened positive for at-risk drinking were mailed questionnaires that included the Alcohol Use Disorders Identification Test (AUDIT) and a question about prior alcohol treatment or participation in Alcoholics Anonymous ("previously treated"). AUDIT questions 4 through 10 were used to measure past-year problems due to drinking (PYPD). Cross-sectional analyses compared the prevalence of PYPD and mean Past-Year AUDIT Symptom Scores (0-28 points) among at-risk drinkers with varying scores on the CAGE (0-4) and AUDIT-C (0-12) and varying treatment histories. RESULTS: Of 7861 male at-risk drinkers who completed questionnaires, 33.9% reported PYPD. AUDIT-C scores were more strongly associated with Past-Year AUDIT Symptom Scores than the CAGE (p < 0.0005). The prevalence of PYPD increased from 33% to 46% over the range of positive CAGE scores but from 29% to 77% over the range of positive AUDIT-C scores. Among subgroups of at-risk drinkers with the same screening scores, patients who reported prior treatment were more likely than never-treated at-risk drinkers to report PYPD and had higher mean Past-Year AUDIT Symptom Scores (p < 0.0005). We propose a simple method of risk-stratifying patients using AUDIT-C scores and alcohol treatment histories. CONCLUSIONS: AUDIT-C scores combined with one question about prior alcohol treatment can help estimate the severity of PYPD among male Veterans Affairs outpatients.