Evaluation of an automated feedback intervention to improve antibiotic prescribing among primary care physicians (OPEN Stewardship): a multinational controlled interrupted time-series study.

Tools to advance antimicrobial stewardship in the primary health care setting, where most antimicrobials are prescribed, are urgently needed. The aim of this study was to evaluate OPEN Stewarship (Online Platform for Expanding aNtibiotic Stewardship), an automated feedback intervention, among a cohort of primary care physicians. We performed a controlled, interrupted time-series study of 32 intervention and 725 control participants, consisting of primary care physicians from Ontario, Canada and Southern Israel, from October 2020 to December 2021. Intervention participants received three personalized feedback reports targeting several aspects of antibiotic prescribing. Study outcomes (overall prescribing rate, prescribing rate for viral respiratory conditions, prescribing rate for acute sinusitis, and mean duration of therapy) were evaluated using multilevel regression models. We observed a decrease in the mean duration of antibiotic therapy (IRR = 0.94; 95% CI: 0.90, 0.99) in intervention participants during the intervention period. We did not observe a significant decline in overall antibiotic prescribing (OR = 1.01; 95% CI: 0.94, 1.07), prescribing for viral respiratory conditions (OR = 0.87; 95% CI: 0.73, 1.03), or prescribing for acute sinusitis (OR = 0.85; 95% CI: 0.67, 1.07). In this antimicrobial stewardship intervention among primary care physicians, we observed shorter durations of therapy per antibiotic prescription during the intervention period. The COVID-19 pandemic may have hampered recruitment; a dramatic reduction in antibiotic prescribing rates in the months before our intervention may have made physicians less amenable to further reductions in prescribing, limiting the generalizability of the estimates obtained.IMPORTANCEAntibiotic overprescribing contributes to antibiotic resistance, a major threat to our ability to treat infections. We developed the OPEN Stewardship (Online Platform for Expanding aNtibiotic Stewardship) platform to provide automated feedback on antibiotic prescribing in primary care, where most antibiotics for human use are prescribed but where the resources to improve antibiotic prescribing are limited. We evaluated the platform among a cohort of primary care physicians from Ontario, Canada and Southern Israel from October 2020 to December 2021. The results showed that physicians who received personalized feedback reports prescribed shorter courses of antibiotics compared to controls, although they did not write fewer antibiotic prescriptions. While the COVID-19 pandemic presented logistical and analytical challenges, our study suggests that our intervention meaningfully improved an important aspect of antibiotic prescribing. The OPEN Stewardship platform stands as an automated, scalable intervention for improving antibiotic prescribing in primary care, where needs are diverse and technical capacity is limited.

Community antibiotic prescriptions during COVID-19 era: a population-based cohort study among adults.

OBJECTIVES: This study investigated the association between the COVID-19 pandemic and antibiotic prescription ratios and the determinants of antibiotic prescription in the community. METHODS: The study was based on a retrospective population cohort of adults in a community setting. Antibiotic prescription ratios from March 1, 2020 to February 28, 2021 (COVID-19 period) were compared to similar months in previous years. Differences in visit type, infectious disease-related visit, and antibiotic prescription ratios during these visits were compared. A logistic regression model was used to identify independent determinants of antibiotic prescription during the study period. RESULTS: The cohort included almost 3 million individuals with more than 33 million community medical encounters per year. In the COVID-19 period, the antibiotic prescription ratio decreased 45% (from 34.2 prescriptions/100 patients to 19.1/100) compared to the previous year. Visits due to an infectious disease etiology decreased by 10% and prescriptions per visit decreased by 39% (from 1 034 425 prescriptions/3 764 235 infectious disease visits to 587 379/3 426 451 respectively). This decrease was observed in both sexes and all age groups. Telemedicine visits were characterized by a 10% lower prescription ratio compared to in-person visits. Thus, a threefold increase in telemedicine visits resulted in a further decrease in prescription ratios. The COVID-19 period was independently associated with a decrease in antibiotic prescription, with an OR of 0.852 (95% CI 0.848-0.857). DISCUSSION: We describe a significant decrease in antibiotic prescription ratios during the COVID-19 periods that was likely related to a decrease in the incidence of certain infectious diseases, the transfer to telemedicine, and a change in prescription practices among community-based physicians.

Patients' Perceived Continuity of Care and Adherence to Oral Anticancer Therapy: a Prospective Cohort Mediation Study.

BACKGROUND: Oral anticancer therapy (OACT) poses adherence-related challenges to patients while generating a setting in which both primary care physicians (PCPs) and oncologists are involved in the active treatment of cancer. Continuity of care (COC) was shown to be associated with medication adherence. While maintaining COC is a central role of the PCP, how this affects continuity with oncologists, and jointly affects OACT adherence, is yet unknown. OBJECTIVES: To explore how aspects of COC act together to promote OACT adherence. Specifically, to examine whether better personal continuity with the PCP leads to better personal continuity with the oncologist, which together lead to better cross-boundary continuity between the oncologist and the PCP, jointly leading to good adherence to OACT. DESIGN AND SETTING: A prospective cohort study conducted in five oncology centers in Israel. A bootstrapping method was used to test the serial mediation model. PARTICIPANTS: Adult patients (age > 18 years) receiving a first OACT prescription (n = 119) were followed for 120 days. MAIN MEASURES: The Nijmegen Continuity Questionnaire was used to assess patients' perceived personal and cross-boundary continuity. The medication possession ratio was used to measure adherence. KEY RESULTS: Better personal continuity with the PCP was associated with better personal continuity with the oncologist (B = 0.35, p < 0.001), which was associated with better cross-boundary continuity (B = 0.33, p < 0.001), which, in turn, was associated with good adherence to OACT (B = 0.46, p = 0.03). Additionally, the indirect effect of personal continuity with the PCP on adherence to OACT through the mediation of personal continuity with the oncologist and cross-boundary continuity was found to be statistically significant (B = 0.053, 95% CI 0.0006-0.17). CONCLUSIONS: In a system where the PCP is the case manager, cancer patients' perceived personal continuity with the PCP has an essential role for initiating a sequence of care delivery events that positively affect OACT adherence.

Evaluation of an automated feedback intervention to improve antimicrobial prescribing among primary care physicians (OPEN Stewardship): protocol for an interrupted time-series and usability analysis in Ontario, Canada and Southern Israel.

INTRODUCTION: Antimicrobial resistance undermines our ability to treat bacterial infections, leading to longer hospital stays, increased morbidity and mortality, and a mounting burden to the healthcare system. Antimicrobial stewardship is increasingly important to safeguard the efficacy of existing drugs, as few new drugs are in the developmental pipeline. While significant progress has been made with respect to stewardship in hospitals, relatively little progress has been made in the primary care setting, where the majority of antimicrobials are prescribed. OPEN Stewardship is an international collaboration to develop an automated feedback platform to improve responsible antimicrobial prescribing among primary care physicians and capable of being deployed across heterogeneous healthcare settings. We describe the protocol for an evaluation of this automated feedback intervention with two main objectives: assessing changes in antimicrobial prescribing among participating physicians and determining the usability and usefulness of the reports. METHODS AND ANALYSIS: A non-randomised evaluation of the automated feedback intervention (OPEN Stewardship) will be conducted among approximately 150 primary care physicians recruited from Ontario, Canada and Southern Israel, based on a series of targeted stewardship messages sent using the platform. Using a controlled interrupted time-series analysis and multilevel negative binomial modelling, we will compare the antimicrobial prescribing rates of participants before and after the intervention, and also to the prescribing rates of non-participants (from the same healthcare network) during the same period. We will examine outcomes targeted by the stewardship messages, including prescribing for antimicrobials with duration longer than 7 days and prescribing for indications where antimicrobials are typically unnecessary. Participants will also complete a series of surveys to determine the usability and usefulness of the stewardship reports. ETHICS AND DISSEMINATION: All sites have obtained ethics committee approval to recruit providers and access anonymised prescribing data. Dissemination will occur through open-access publication, stakeholder networks and national/international meetings.

Quinolone Consumption by Mothers Increases Their Children's Risk of Acquiring Quinolone-Resistant Bacteriuria.

BACKGROUND: Quinolone resistance has been documented in the pediatric population, although their use is limited in children. This study investigated the effect of maternal quinolone use on gram-negative bacterial resistance to quinolones in their offspring. METHODS: We conducted a population-based, unmatched case-control study during 2010-2017. Cases were all children aged 0.5-17 years with community acquired, gram-negative quinolone-resistant bacteriuria. Controls were similar children with quinolone-sensitive bacteriuria. Only the first positive urine cultures for each child were included. Data on quinolones dispensed to the mother, any antibiotics dispensed to the children, age, sex, ethnicity, and prior hospitalizations were collected. Children with previous quinolone use were excluded. RESULTS: The study population consisted of 40 204 children. Quinolone resistance was detected in 2182 (5.3%) urine cultures. The median age was 5 years, with 93.7% females and 77.6% Jewish. A total of 26 937 (65%) of the children received any antibiotic and 1359 (3.2%) of the mothers received quinolones in the 6 months preceding bacteriuria. Independent risk factors were quinolone dispensed to the mothers (odds ratio [OR], 1.50 [95% confidence interval {CI}, 1.22-1.85]), Arab ethnicity (OR, 1.99 [95% CI, 1.81-2.19]), and antibiotic dispensed to the child (OR, 1.54 [95% CI, 1.38-1.71]). Compared with children aged 12-17 years, younger children had 1.33-1.43 increased odds for quinolone-resistant bacteriuria. CONCLUSIONS: Quinolone prescription to mothers was linked to increased risk of community-acquired, quinolone-resistant bacteria in their offspring, by about 50%. This is another example of the deleterious ecological effects of antibiotic use and should be considered when prescribing antibiotics.

Association between urinary community-acquired fluoroquinolone-resistant Escherichia coli and neighbourhood antibiotic consumption: a population-based case-control study.

BACKGROUND: It is unknown whether increased use of antibiotics in a community increases the risk of acquiring antibiotic resistance by individuals living in that community, regardless of prior individual antibiotic consumption and other risk factors for antibiotic resistance. METHODS: We used a hierarchical multivariate logistic regression approach to evaluate the association between neighbourhood fluoroquinolone consumption and individual risk of colonisation or infection of the urinary tract with fluoroquinolone-resistant Escherichia coli. We did a population-based case-control study of adults (aged ≥22 years) living in 1733 predefined geographical statistical areas (neighbourhoods) in Israel. A multilevel study design was used to analyse data derived from electronic medical records of patients enrolled in the Clalit state-mandated health service. FINDINGS: 300 105 events with E coli growth and 1 899 168 cultures with no growth were identified from medical records and included in the analysis. 45 427 (16·8%) of 270 190 women and 8835 (29·5%) of 29 915 men had fluoroquinolone-resistant E coli events. We found an independent association between residence in a neighbourhood with higher antibiotic consumption and an increased risk of bacteriuria caused by fluoroquinolone-resistant E coli. Odds ratios (ORs) for the quintiles with higher neighbourhood consumption (compared with the lowest quintile) were 1·15 (95% CI 1·06-1·24), 1·31 (1·20-1·43), 1·41 (1·29-1·54), and 1·51 (1·38-1·65) for women, and 1·17 (1·02-1·35), 1·24 (1·06-1·45), 1·35 (1·15-1·59), and 1·50 (1·26-1·77) for men. Results remained significant when the analysis was restricted to patients who had not consumed fluoroquinolones themselves. INTERPRETATION: These data suggest that increased use of antibiotics in specific geographical areas is associated with an increased personal risk of acquiring antibiotic-resistant bacteria, independent of personal history of antibiotic consumption and other known risk factors for antimicrobial resistance. FUNDING: None.

Impact of a nurse-based intervention on medication outcomes in vulnerable older adults.

BACKGROUND: Medication-related problems are common in older adults with multiple chronic conditions. We evaluated the impact of a nurse-based primary care intervention, based on the Guided Care model of care, on patient-centered aspects of medication use. METHODS: Controlled clinical trial of the Comprehensive Care for Multimorbid Adults Project (CC-MAP), conducted among 1218 participants in 7 intervention clinics and 6 control (usual care) clinics. Inclusion criteria included age 45-94, presence of ≥3 chronic conditions, and Adjusted Clinical Groups (ACG) score > 0.19. The co-primary outcomes were number of changes to the medication regimen between baseline and 9 month followup, and number of changes to symptom-focused medications, markers of attentiveness to medication-related issues. RESULTS: Mean age in the intervention group was 72 years, 59% were women, and participants used a mean of 6.6 medications at baseline. The control group was slightly older (73 years) and used more medications (mean 7.1). Between baseline and 9 months, intervention subjects had more changes to their medication regimen than control subjects (mean 4.04 vs. 3.62 medication changes; adjusted difference 0.55, p = 0.001). Similarly, intervention subjects had more changes to their symptomatic medications (mean 1.38 vs. 1.26 changes, adjusted difference 0.20, p = 0.003). The total number of medications in use remained stable between baseline and follow-up in both groups (p > 0.18). CONCLUSION: This nurse-based, primary care intervention resulted in substantially more changes to patients' medication regimens than usual care, without increasing the total number of medications used. This enhanced rate of change likely reflects greater attentiveness to the medication-related needs of patients. TRIAL REGISTRATION: This trial is registered at https://clinicaltrials.gov , trial number NCT01811173 .

Infectious disease burden and antibiotic prescribing in primary care in Israel.

BACKGROUND: Antibiotics are frequently prescribed at many of the visits to primary care clinics, often for conditions for which they provide no benefit, including viral respiratory tract infections. OBJECTIVES: The aim was to evaluate primary care visits due to infectious diseases, and to estimate antibiotic prescribing and antibiotic dispensing by pharmacies. METHODS: Diagnosis of infectious disease, antibiotic prescribing and dispensing data at the individual patient level were extracted for 2015 from Clalit Health Services' electronic medical records and linked to determine the condition for which the antimicrobial was prescribed. RESULTS: There were 6.6 million visits due to infections, representing 22% of all primary care visits. The most common events were upper respiratory tract infections (38%) and pharyngitis (10%). Highest prescription rates were for urinary tract infections (80%), otitis media (64%), pharyngitis (71%), sinusitis (63%), and lower respiratory tract infections (76%). The highest rates of undispensed prescriptions were for acute gastroenteritis, urinary tract infections, and pharyngitis (24, 23, and 16%, respectively). CONCLUSIONS: Infectious diseases constitute a heavy burden on primary care, with overprescribing of antibiotics. Intervention to reduce unwarranted antibiotic use is needed. In pediatric care, interventions should focus on better controlling antibiotic consumption and encouraging adherence to guidelines for upper respiratory tract infections, pharyngitis, and otitis media. In adults interventions should aim to monitor antibiotic prescribing for upper respiratory tract infections and improve adherence to guidelines for urinary tract infections.

Epidemic Use of Benzodiazepines among Older Adults in Israel: Epidemiology and Leverage Points for Improvement.

BACKGROUND: Benzodiazepines and benzodiazepine-receptor agonists (BDZRAs, often known as "Z-drugs") are commonly used in older adults despite well-documented harms. OBJECTIVE: To evaluate patterns of benzodiazepine and BDZRA use in Israel, focusing on potential leverage points where quality improvement initiatives might effectively curtail new use or the transition from intermittent to chronic use. DESIGN AND PARTICIPANTS: We used national electronic medical data to assess a 10% random sample of adults receiving care in Clalit Health Services, which serves half of Israel's population. The sample included 267,221 adults, of whom 56,808 (21%) were age 65 and older. MAIN MEASURES: Medication use from 2013 to 2015 was ascertained using pharmacy dispensing data. RESULTS: In 2014, 7% of adults age 21-64 and 32% of adults age 65 and older received at least one benzodiazepine/BDZRA, including 49% of adults age 85 and older (P < 0.001). The majority of older users (59%) were long-term users of the drugs, and 21% of older adults who were short-term users in 2014 transitioned to medium- or long-term use in 2015. Older Arab Israelis were much less likely to receive benzodiazepine/BDZRAs than older Jewish Israelis (adjusted OR 0.28, 95% 0.25-0.31), but within each community there was no major variation in prescribing rates across clinics. Depression diagnosis was associated with particularly high rates of benzodiazepine/BDZRA use: 17% of older adults with depression received a benzodiazepine/BDZRA but no antidepressant, and 42% received both. Recent hospitalization increased the risk of new benzodiazepine/BDZRA use (adjusted OR 1.41, 95% CI 1.01-1.96), but the absolute risk increase was only 3%. CONCLUSIONS: Benzodiazepines/BDZRAs are used at exceptionally high rates by older Israeli adults, especially the oldest old. Important leverage points for quality improvement efforts include curtailing the transition from short-term to long-term use, reducing use in older adults with depression, and identifying reasons that explain large differences in benzodiazepine/BDZRA prescribing between different ethnic groups.

High-risk case identification for use in comprehensive complex care management.

The current study aimed to develop a patient selection process for muiltimorbid care management that balances the needs to accurately identify patients who are at risk for future high costs and assures that those selected can clinically benefit from proactive care management. Six physicians were surveyed on characteristics of their current (2012) patients to elicit clinical considerations for high-risk patient identification. Data from 2010-2011 were extracted from Clalit Health Services' (Israel's largest managed care organization) comprehensive database to derive the Adjusted Clinical Groups (ACG) predictive model risk scores for risk of future high costs. Model discriminatory power was assessed using the c-statistic and positive predictive value (PPV), before and after application of the clinical exclusion criteria. Inclusion criteria were refined based on physician input from a survey on 375 patients. Recommended reasons for exclusion: active cancer, schizophrenia, dialysis, residence in nursing homes or long-term care facilities, and age 95 years or older. The high-risk group included 5341 patients (mean 50 patients per physician). The c-statistic of the ACG model before and after exclusions applied was 0.80 and 0.75, respectively. After exclusion, the PPV for the 6% highest risk patients was 40%. High-risk patients' age, number of chronic conditions, and utilization were substantially higher than those of all other patients. This study shows that a validated predictive modeling tool provides acceptable discriminatory power for selecting multimorbid patients for participation in proactive care management, even after some of the highest risk patients are excluded because of priori clinical considerations.

Antibiotic use in 26 departments of internal medicine in 6 general hospitals in Israel: variability and contributing factors.

OBJECTIVES: Increased antibiotic consumption is associated with increased bacterial resistance worldwide. We aimed to analyse antibiotic consumption and potential contributory factors in internal medicine departments in Israel. METHODS: Data (2003-04) from 26 departments in 6 hospitals were retrieved. Defined daily doses (DDD)/100 bed-days were calculated for total antibiotic use and by antibiotic class. Patterns identified were correlated with 15 patients' and departmental variables by univariate and multivariate analyses. RESULTS: Total antibiotic consumption differed by a factor of 2.3 (115 DDD/100 bed-days to 49.1 DDD/100 bed-days) between the highest and lowest consuming departments. Antibiotic classes differed by a factor of 22.8 for macrolides, a factor of 20 for piperacillin/tazobactam, a factor of 17 for carbapenems, a factor of 13.3 for quinolones, a factor of 9 for vancomycin, a factor of 6.8 for amoxicillin/clavulanate, a factor of 6.6 for aminoglycosides, a factor of 5.3 for penicillins and a factor of 2.8 for cephalosporins. Even among departments within hospitals, there was a difference of up to 1.5-fold for total use and antibiotic class differences ranged between 2.5- and 7.2-fold for third- and fourth-generation cephalosporins, despite similar Charlson scores and other patient variables. In the multivariate analysis, hospital affiliation and rate of 1 day hospitalization were the only significant variables predicting total antibiotic use, contributing 43% and 7.3%, respectively, to the variance. By antibiotic class, controlling for hospital affiliation, patients with neutropenia, lower respiratory tract infections and assisted ventilation were the most common significant contributors, ranging from 3.5% for quinolones to 7.7% for piperacillin/tazobactam. CONCLUSIONS: Patterns of antibiotic use vary widely among internal medicine departments in Israel, which cannot be explained by objective parameters related either to patients or wards. Ongoing monitoring and guideline formulation are needed to regulate antibiotic prescription.

Colorectal polyps in carriers of the APC I1307K polymorphism.

PURPOSE: The probability of colorectal cancer is moderately increased among carriers of the APC I1307K polymorphism. However, it is not known if endoscopic surveillance of this high-risk group is warranted. The prevalence of polyps and adenomas in specimens of colorectal cancer who are carriers and noncarriers of the APC I1307K polymorphism is compared. METHOD: Prevalence of adenomatous polyps in the pathology specimens of the study participants, stratified by their APC I1307K polymorphism status, was studied in 900 consecutive cases of colorectal cancer diagnosed in northern Israel between 1998 and 2002, within the framework of a population-based, case-controlled study (MECC Study). RESULTS: The APC I1307K mutation was detected in 78 colorectal cancer cases (8.7 percent) of the study population. Prevalence was higher among Ashkenazi Jews (11.2 percent) than among non-Ashkenazi Jews (2.7 percent) or Arabs (3.1 percent). After adjustment for age, APC I1307K carriers were significantly more likely than noncarriers to have polyps in their surgical specimen (51.3 percent vs. 32.6 percent, P = 0.002). Adenomas with a tubular component (either tubular adenomas or tubulovillous adenomas), but not villous adenomas, were significantly more frequent among carriers (37.2 percent vs. 23.6 percent, P = 0.005). CONCLUSION: Together with former evidence of I1307K being a risk factor for colorectal cancer, these data suggest that colonoscopic surveillance for colorectal adenomas and cancer may be warranted in I1307K carriers, even in the absence of other identifiable risk factors.

Statins and the risk of colorectal cancer.

BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. RESULTS: In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available. CONCLUSIONS: The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.

The association between hospital department, medical treatment and outcome in acute myocardial infarction.

BACKGROUND: Although the preferred management of a patient presenting with an acute myocardial infarction is in a coronary care unit, data based on discharge diagnoses in Israel indicate that many of these patients are treated outside of such units. OBJECTIVES: To compare the demographic and clinical characteristics, treatment and mortality of AMI patients treated inside and outside a CCU. METHODS: We compiled a registry of all patients admitted to three general hospitals in Haifa, Israel during January, March, May, July, September and November 1996. RESULTS: The non-CCU admission rate was 22%. CCU patients were younger (61.6 vs. 65.5 years), less likely to report a past AMI (18% vs. 34%), and arrived earlier at the emergency room. Non-CCU patients were more likely to present with severe heart failure (30 vs. 11%). Non-CCU patients received less aspirin (81 vs. 95%) and betablockers (62 vs. 80%). Upon discharge, these patients were less frequently prescribed beta-blockers and cardiac rehabilitation programs. CCU-treated patients had lower unadjusted mortality rates at both 30 days (odds ratio = 0.35) and in the long term (hazards ratio = 0.57). These ratios were attenuated after controlling for gender, age, type of AMI, and degree of heart failure (OR = 0.91 and HR = 0.78, respectively). CONCLUSIONS: A relatively high proportion of AMI patients were treated outside a CCU, with older and sicker patients being denied admission to a CCU. The process of evidence-based care by cardiologists was preferable to that of internists both during the hospital stay and at discharge. In Israel a significant proportion of all AMI admissions are initially treated outside a CCU. Emphasis on increasing awareness in internal medicine departments to evidence-based care of AMI is indicated.

Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.

The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location. As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.