The association of histopathologic features after neoadjuvant chemo-immunotherapy with clinical outcome: Sub-analyses from the randomized double-blinded, placebo-controlled, Phase III IMagyn050/GOG3015/ENGOT-ov39 study.

OBJECTIVE: Histopathologic characteristics after neoadjuvant chemotherapy (NACT) may correlate with outcome. This study evaluates histopathologic features after immunotherapy and NACT/bevacizumab, and associated clinical outcomes. METHODS: Evaluable tissue from IMagyn050/GOG3015/ENGOT-ov39 patients from prespecified anatomic sites from interval cytoreductive surgery (ICS) after NACT/bevacizumab plus atezolizumab/placebo underwent central histopathologic scoring and analyzed with clinical outcomes. RESULTS: The predefined population had 243 evaluable NACT patients, with 48.1% tumors being PD-L1-positive. No statistically significant differences in PFS (16.9 months vs. 19.2 months, p = 0.21) or OS (41.5 months vs. 45.1 months, p = 0.67) between treatment arms were seen. Substantial residual tumor (RT) (3+) was identified in 26% atezolizumab vs. 24% placebo arms (p = 0.94). Most showed no (1+) necrosis (82% vs. 96%, respectively, p = 0.69), moderate (2+) to severe (3+) fibrosis (71% vs. 75%, respectively, p = 0.82), and extensive (2+) inflammation (53% vs. 47% respectively, p = 0.48). No significant histopathologic differences were identified by tissue site or by arm. Multivariate analyses showed increased risk for progression with moderate and substantial RT (13.6 mon vs. 21.1 mon, hazard ratio 2.0, p < 0.01; 13.6 mon vs. 21.1 mon, HR 1.9, p < 0.01, respectively); but decreased risk for death with extensive inflammation (46.9 mon vs. 36.3 mon, HR 0.65, p = 0.02). Inflammation also correlated with greater likelihood of response to NACT/bevacizumab plus immunotherapy (odds ratio 2.9, p < 0.01). Modeling showed inflammation as a consistent but modest predictor for OS. CONCLUSIONS: Detailed histologic assessment of ICS specimens appear to identify characteristics, such as inflammation and residual tumor, that may provide insight to certain clinical outcomes. Future work potentially leveraging emerging tools may provide further insight into outcomes.

Patient perceptions regarding alcohol use after bariatric surgery.

INTRODUCTION: Patients who have undergone bariatric surgery are at increased risk of an alcohol use disorder. Though patients understand this risk, the majority engage in post-surgical alcohol use. This suggests that education alone is not sufficient to reduce post-surgical drinking. To prevent development of post-surgical alcohol use disorders, we need better understanding of the reasons patients use alcohol following surgery. The purpose of this study was to identify factors associated with post-surgical alcohol use. METHOD: Patients (N = 20) who were 1-3 years post-bariatric surgery and were consuming alcohol at least twice monthly participated in a 60-min interview. Participants responded about their knowledge regarding risk of post-surgical alcohol use and reasons why patients may start drinking. Deductive and inductive coding were completed by two independent raters. RESULTS: Although nearly all participants were aware of the risks associated with post-surgical alcohol use, most believed that lifelong abstinence from alcohol was unrealistic. Common reasons identified for using alcohol after bariatric surgery included social gatherings, resuming pre-surgical use, and addiction transfer. Inductive coding identified three themes: participants consumed alcohol in different ways compared to prior to surgery; the effect of alcohol was substantially stronger than pre-surgery; and beliefs about why patients develop problematic alcohol use following surgery. CONCLUSION: Patients consume alcohol after bariatric surgery for a variety of reasons and they do not believe recommending abstinence is useful. Understanding patient perceptions can inform interventions to minimize alcohol use after bariatric surgery. Modifications to traditional alcohol relapse prevention strategies may provide a more robust solution to decreasing negative outcomes experienced by individuals undergoing bariatric surgery.

Differential brain responses to alcohol-related and natural rewards are associated with alcohol use and problems: Evidence for reward dysregulation.

Multiple theoretical perspectives posit that drug use leads to biased valuation of drug-related reward, at the expense of naturally occurring rewarding activities (i.e., reward dysregulation). Recent research suggests that the comparative balance of drug-related and nondrug-related reward valuation is a powerful determinant of substance misuse and addiction. We examined differential neurophysiological responses-indexed with the P3 component of the event-related potential (ERP)-elicited by visual alcohol cues and cues depicting natural reward as a neurobiological indicator of problematic drinking. Nondependent, young adult drinkers (N = 143, aged 18-30 years) completed questionnaire measures assessing alcohol use and problems, and viewed alcohol cues (pictures of alcoholic beverages), high-arousing natural reward cues (erotica, adventure scenes), nonalcoholic beverage cues, and neutral scenes (e.g., household items) while ERPs were recorded. When examined separately, associations of P3-ERP reactivity to alcohol cues and natural reward cues with alcohol use and problems were weak. However, differential P3 response to the two types of cues (i.e., reward dysregulation P3) showed consistent and robust associations with all indices of alcohol use and problems and differentiated high-risk from lower-risk drinkers. The current results support the idea that the differential incentive-motivational value of alcohol, relative to naturally rewarding activities, is associated with increased risk for substance misuse and dependence, and highlight a novel neurophysiological indicator-the reward dysregulation P3-of this differential reward valuation.

Young Adults Make Rational Sexual Decisions.

We examined risky sexual choice under the lens of rational decision-making. Participants (N = 257) completed a novel sexual-choice task in which they selected from among hypothetical sexual partners varying in physical attractiveness and in the probability that one would contract a sexually transmitted infection (STI) from a one-time sexual encounter with them. We found that nearly all participants evaluated the sexual-choice alternatives in a coherent fashion consistent with utility-based theories of rational choice. In subsequent analyses, we classified participants' responses according to whether their sexual preferences were based on maximizing attractiveness or minimizing the risk of STIs. Finally, we established an association between sexual choice in our task and reported real-world sexual risk-taking.

To Infuse or Ingest in Human Laboratory Alcohol Research.

Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper was to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, "To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs." We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants' brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes.

A Holistic Approach to Diagnosing and Treating Dysphagia.

We report a 39-year-old Native American female with an almost 20-year history of dysphagia that had increased in the 6 months prior to the initial evaluation. Investigation revealed a number of distinct esophageal disorders including Plummer-Vinson syndrome, gastroesophageal reflux disease with esophagitis, distal esophageal stricture, esophageal intramural pseudo-diverticulosis, and recurrent esophageal Candida infections. Although prolonged therapy with proton pump inhibitors, fluconazole, nystatin, and repeated esophageal balloon dilations relieved her symptoms, her prognosis remains uncertain.

Giant Gastric Ulcers: An Unusual Culprit.

Mycophenolate Mofetil (MMF) is routinely used immunosuppressant in solid organ transplantation is commonly associated with several gastrointestinal (GI) side effects. Here we present a case of giant gastric ulcer of 5 cm from MMF use post cardiac transplant. CASE DESCRIPTION: A 56-year-old male with history of severe ischemic cardiomyopathy post heart transplant was on immunosuppression with MMF, tacrolimus and prednisone for 5 months. He presented with severe epigastric pain and intermittent episodes of melena for 1 month. His pain radiated to back that is worsened with eating. Associated with loss of appetite, vomiting and 16-pound weight loss in 3 months. He never smoked, drank alcohol or used over the counter pain medications. He was profoundly anemic requiring blood transfusions. EGD performed demonstrated very large clean-based ulcer of 5 cm diameter in the body, smaller ulcer of 8 mm diameter in pre-pyloric region and 5-10 small aphthous ulcers in the gastric body and fundus. Gastric biopsies taken from the ulcer were negative for Helicobacter pylori, cytomegalovirus and malignancy. Flexible sigmoidoscopy revealed non-bleeding inflamed internal hemorrhoids. Consequently, MMF was discontinued and switched to azathioprine. He was treated with twice daily proton pump inhibitor therapy with resolution of abdominal pain, improved appetite and weight gain. DISCUSSION: MMF is well known for common GI side-effects such as nausea, diarrhea, vomiting, ulcers, abdominal pain and rarely gastrointestinal bleeding. Few studies reported 3 to 8% incidence of ulcer perforation and GI bleeding within 6 months. Risk of gastroduodenal erosions is nearly 1.83 times for MMF, with the highest lesions associated with MMF-tacrolimus-corticosteroid combination treatment as seen in our patient. Hypothesis is that GI tract is vulnerable because of dependence of enterocytes on de novo synthesis of purines, which is disrupted by MMF. Typically, upper GI mucosal injuries of mucosal irritation leading to esophagitis, gastritis and/or ulcers are seen. Endoscopy is both diagnostic and therapeutic if bleeding gastric ulcers are noted. Minor complications improve with reduction of drug dose or use of enteric coated preparation if feasible. Discontinuation of the drug is main stay in the management of MMF related ulcer disease. Simple medical treatment with either H2-receptor antagonists, proton-pump inhibitors, coating agents, prostaglandins or combination has proven effective in most cases. Considering excellent results with medical management of ulcer, role of surgery is limited.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Explicit Attitudes, Working Memory Capacity, and Driving After Drinking.

BACKGROUND: Attitudes toward driving after drinking are strongly predictive of drinking and driving behavior. This study tested working memory capacity (WMC) as a moderator of the association between attitudes and drinking and driving behavior. Consistent with dual process models of cognition, we hypothesized that the association between perceived danger and drinking and driving would be stronger for individuals with higher WMC. METHODS: Participants (N = 161) enrolled in larger alcohol administration study were randomly assigned to an alcohol (n = 57), placebol (n = 52), or control (n = 52, not included) beverage condition. Past-year frequency of driving after drinking and WMC were assessed at baseline. Attitudes were assessed by asking participants to rate the perceived danger of driving at their current level of intoxication twice on the ascending limb (AL1, AL2), at peak breath alcohol concentration (BrAC), and twice on the descending limb (DL1, DL2). RESULTS: Analyses across the BrAC curve indicated that the hypothesized interaction was observed for the alcohol but not placebo condition. Analyses for each assessment point indicated that the interaction was significant for the ascending limb and peak BrAC. In the alcohol condition, for those higher in WMC, lower perceived dangerousness was strongly associated with increased driving after drinking (AL1: incident rate ratios [IRR] = 5.87, Wald's χ2  = 12.39, p = 0.006, 95% CI [2.19, 15.75]; AL2: IRR = 8.17, Wald's χ2  = 11.39, p = 0.001, 95% CI [2.41, 27.66]; Peak: IRR = 5.11, Wald's χ2  = 9.84, p = 0.002, 95% CI [1.84, 14.16]). Associations were not significant at low WMC. CONCLUSIONS: Results suggest that individuals higher in WMC are more likely to act consistently with their explicit attitudes toward drinking and driving. Findings may have implications for existing drinking and driving interventions and suggest the potential for novel interventions targeting implicit associations or WMC.

A Longitudinal Examination of Decisions to Ride and Decline Rides with Drinking Drivers.

BACKGROUND: Riding with a drinking driver (RWDD) is a serious concern that leads to numerous preventable deaths every year. There is a significant gap in research on empirically tested predictors of RWDD that could be implemented in prevention efforts. College students are in need of such prevention efforts, as they have some of the highest rates of alcohol-related crash fatalities and may engage in RWDD more than their noncollege peers. This study utilized behavioral decision-making approach to examine predictors of RWDD and declining a ride from a drinking driver (Decline) in older college students. METHODS: Students (n = 791) in their third year of college were enrolled from 3 large and diverse universities. Psychosocial (e.g., expectancies, norms) and decision-making variables (willingness to RWDD and intentions to use alternatives) were assessed in the fall of their third year. One year later, RWDD and Decline behaviors were assessed. Zero-inflated Poisson analyses were used to assess how decision-making variables predicted RWDD and Decline behavior. Associations between psychosocial and decision-making variables were also assessed. RESULTS: Thirteen percent of students reported RWDD and ~28% reported Decline behavior. Willingness to RWDD and typical weekly drinking were both associated with increases in RWDD (odds ratio [OR] = 1.58 and 1.40, respectively), whereas intentions to use alternatives, sex, and ethnicity were not associated with RWDD. Only weekly drinking was associated with Decline, with an increase in drinking associated with increased Decline (OR = 1.48). All psychosocial variables were significantly associated with the decision-making variables except positive expectancies. CONCLUSIONS: Results provide evidence that willingness to RWDD is a predictor of future RWDD, even if students intend to use safe alternatives. Future research is needed to better understand decision-making factors that influence Decline. Results also suggest prevention and interventions efforts, such as brief motivational intervention, Parent-Based Interventions, and normative feedback interventions could be adapted to reduce RWDD.

Association between overall rate of change in rising breath alcohol concentration and the magnitude of acute tolerance of subjective intoxication via the Mellanby method.

OBJECTIVE: The magnitude of acute tolerance is a strong predictor of the development of longer-term chronic tolerance and plays a decisive role in risky decisions (e.g., driving after drinking). Therefore, it is important to identify factors that increase the magnitude of this adaptive process. This study explored whether acute tolerance magnitude varied as a function of the overall rate of increase in breath alcohol concentration (BrAC). METHODS: Twenty-nine young adult social drinkers (M age = 22.55, SD = 3.10; 62.1% women) consumed a moderate dose of alcohol (men: 0.86 g/kg, women: 0.75 g/kg) in a controlled laboratory setting. Subjective intoxication was assessed at matched BrACs (~0.060 g/dl) on each limb of the BrAC curve. RESULTS: Hierarchical regression results indicated that faster overall increases in BrAC on the ascending limb were associated with greater acute tolerance for subjective intoxication ratings (p < .01, R2  = .29). CONCLUSIONS: These results present some of the first evidence that faster increases in BrAC may be associated with greater acute tolerance, as indicated by greater reduction in subjective intoxication across the limbs of the BrAC curve. This greater reduction may, in turn, promote heavier drinking and/or engagement in behaviors for which one is unfit (e.g., driving after drinking).

The Alcohol Sensitivity Questionnaire: Evidence for Construct Validity.

BACKGROUND: Variability in sensitivity to the acute effects of alcohol is an important risk factor for the development of alcohol use disorder (AUD). The most commonly used retrospective self-report measure of sensitivity, the Self-Rating of the Effects of Alcohol (SRE) form, queries a limited number of alcohol effects and relies on respondents' ability to recall experiences that might have occurred in the distant past. Here, we investigated the construct validity of an alternative measure that queries a larger number of alcohol effects, the Alcohol Sensitivity Questionnaire (ASQ), and compared it to the SRE in predicting momentary subjective responses to an acute dose of alcohol. METHODS: Healthy young adults (N = 423) completed the SRE and the ASQ and then were randomly assigned to consume either alcohol or a placebo beverage (between-subjects manipulation). Stimulation and sedation (Biphasic Alcohol Effects Scale) and subjective intoxication were measured multiple times after drinking. RESULTS: Hierarchical linear models showed that the ASQ reliably predicted each of these outcomes following alcohol but not placebo consumption, provided unique prediction beyond that associated with differences in recent alcohol involvement, and was preferred over the SRE (in terms of model fit) in direct model comparisons of stimulation and sedation. CONCLUSIONS: The ASQ compared favorably with the better-known SRE in predicting increased stimulation and reduced sedation following an acute alcohol challenge. The ASQ appears to be a valid self-report measure of alcohol sensitivity and therefore holds promise for identifying individuals at-risk for AUD and related problems.