Jordan J. Karlitz

Effectiveness of hepatitis C treatment with pegylated interferon and ribavirin in urban minority patients

Randomized controlled trials of hepatitis C virus (HCV) therapy with pegylated interferon and ribavirin have demonstrated sustained viral response rates (SVRs) of 54%‐63% (efficacy). Treatment results in clinical practice (effectiveness) may not be equivalent. The goal of this study was to assess the effectiveness of HCV treatment with pegylated interferon and ribavirin in a treatment‐naïve, human immunodeficiency virus (HIV)‐negative, United States urban population with many ethnic minority patients. We evaluated 2,370 outpatients for HCV therapy from 2001 to 2006 in the Faculty Practice of the Albert Einstein College of Medicine or the attending‐supervised Montefiore Medical Center Liver Clinic. Care was supervised by one experienced physician under conditions of everyday clinical practice, and appropriate ancillary resources were made available to all patients. Two hundred fifty‐five patients were treated with a mean age of 50 years (60% male, 40% female; 58% Hispanic, 20% African American, 9% Caucasian, 13% other; 68% genotype 1, the remainder genotypes 2 or 3). Patients had at least one liver biopsy. Intention‐to‐treat analysis (ITT) showed SVR in 14% of genotype 1 patients and 37% in genotype 2/3 patients (P < 0.001). SVR was significantly higher in faculty practice (27%) than in clinic patients (15%) by intention‐to‐treat (P = 0.01) but not per‐protocol analysis (46% faculty practice, 34% clinic). 3.3% of 1,656 treatment‐naïve, HIV antibody–negative individuals ultimately achieved SVR. Current hepatitis C therapies may sometimes be unavailable to, inappropriate for, and ineffective in United States urban patients. Treatment with pegylated interferon and ribavirin was less effective in this population than is implied by multinational phase III controlled trials. New strategies are needed to care for such patients. (HEPATOLOGY 2010.)

Population-Based Lynch Syndrome Screening by Microsatellite Instability in Patients ≤50: Prevalence, Testing Determinants, and Result Availability Prior to Colon Surgery.

Objectives:As there are no US population-based studies examining Lynch syndrome (LS) screening frequency by microsatellite instability (MSI) and immunohistochemistry (IHC), we seek to quantitate statewide rates in patients aged ≤50 years using data from a Centers for Disease Control and Prevention-funded Comparative Effectiveness Research (CER) project and identify factors associated with testing. Screening rates in this young, high-risk population may provide a best-case scenario as older patients, potentially deemed lower risk, may undergo testing less frequently. We also seek to determine how frequently MSI/IHC results are available preoperatively, as this may assist with decisions regarding colonic resection extent.Methods:Data from all Louisiana colorectal cancer (CRC) patients aged ≤50 years diagnosed in 2011 were obtained from the Louisiana Tumor Registry CER project. Registry researchers and physicians analyzed data, including pathology and MSI/IHC.Results:Of the 2,427 statewide all-age CRC patients, there were 274 patients aged ≤50 years, representing health care at 61 distinct facilities. MSI and/or IHC were performed in 23.0% of patients. Testing-associated factors included CRC family history (P<0.0045), urban location (P<0.0370), and care at comprehensive cancer centers (P<0.0020) but not synchronous/metachronous CRC or MSI-like histology. Public hospital screening was disproportionately low (P<0.0217). Of those tested, MSI and/or IHC was abnormal in 21.7%. Of those with abnormal IHC, staining patterns were consistent with LS in 87.5%. MSI/IHC results were available preoperatively in 16.9% of cases.Conclusions:Despite frequently abnormal MSI/IHC results, LS screening in young, high-risk patients is low. Provider education and disparities in access to specialized services, particularly in underserved populations, are possible contributors. MSI/IHC results are infrequently available preoperatively.

Analysis of stage and clinical/prognostic factors for colon and rectal cancer from SEER registries: AJCC and collaborative stage data collection system.

The Collaborative Stage (CS) Data Collection System enables multiple cancer registration programs to document anatomic and molecular pathology features that contribute to the Tumor (T), Node (N), Metastasis (M) — TNM — system of the American Joint Committee on Cancer (AJCC). This article highlights changes in CS for colon and rectal carcinomas as TNM moved from the AJCC 6th to the 7th editions.

Fatal CNS vasculopathy in a patient with refractory celiac disease and lymph node cavitation

Celiac disease is an enteropathy occurring in genetically predisposed individuals due to a dietary intolerance to gluten. Patients with celiac disease may develop a neurological disorder of unknown cause, although autoimmune mechanisms are suspected. We report on a 56-year-old man with celiac disease, who became refractory to a gluten-free diet and died of a rapidly progressive encephalopathy. Magnetic resonance imaging indicated focal lesions of the cerebellum and brainstem, and electrodiagnostic studies suggested an axonal neuropathy. Autopsy revealed a flattened small-bowel mucosa with intraepithelial lymphocytosis, a spectrum of degenerative changes of the intra-abdominal and mediastinal lymph nodes, including cavitary degeneration, and splenomegaly. Histologically, the lymph nodes showed pseudocyst formation and lymphocytic vasculitis with fibrinoid necrosis, and sections of the brain exhibited fibrinoid degeneration of small blood vessels, sparse perivascular lymphocytic infiltrates, and perivascular ischemic lesions. Identical T-cell clones were identified in the duodenum, stomach, lymph nodes, and spleen. This patient had an unusual neurological disorder related to a vasculopathy, probably mediated by a circulating neoplastic clone of activated T cells.

EBV-associated colitis mimicking IBD in an immunocompetent individual

Background. A 30-year-old immunocompetent male with an unremarkable medical history presented with 2 months of lower abdominal bloating and loose, bloody, mucoid bowel movements. He was clinically suspected to have IBD. Due to the progression of his symptoms, he ultimately required hospitalization for further investigation and care.Investigations. Full medical history and physical examination, routine blood analyses, stool studies, hepatitis serologic tests, abdominal CT, colonoscopy, PCR analysis and light microscopy and immunoperoxidase staining of colonic biopsy samples.Diagnosis. Epstein–Barr virus (EBV)-associated lymphoproliferative disorder with diffuse colonic involvement (EBV colitis) in an immunocompetent adult.Management. Inpatient supportive care.

The American College of Gastroenterology and the 80% by 2018 Colorectal Cancer Initiative: A Multifaceted Approach to Maximize Screening Rates

The American College of Gastroenterology and the 80% by 2018 Colorectal Cancer Initiative: A Multifaceted Approach to Maximize Screening Rates

Factors Associated With Guideline-recommended KRAS Testing in Colorectal Cancer Patients: A Population-based Study.

Objectives: Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States. Methods: SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). &khgr;2 tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status. Results: KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P<0.0001). Among those who received testing, there was no significant difference in survival by mutated versus wild-type KRAS. Five percent of stage I-III cases received testing. Conclusions: Wide variation in documented KRAS testing for stage IV CRC patients exists among SEER registries. Age remained highly significant in multivariate models, suggesting that it plays an independent role in the patient and/or provider decision to be tested. Further research is needed to determine drivers of variation in testing, as well as reasons for testing in stage I-III cases where it is not recommended.

Factors Associated With the Performance of Extended Colonic Resection vs. Segmental Resection in Early-Onset Colorectal Cancer: A Population-Based Study

OBJECTIVES:Early-onset colorectal cancer (CRC) incidence rates are rising. This group is susceptible to heritable conditions (i.e., Lynch syndrome (LS)) and inflammatory bowel disease (IBD) with high metachronous CRC rates after segmental resection. Hence, extended colonic resection (ECR) is often performed and considered generally in young patients. As there are no population-based studies analyzing resection extent in early-onset CRC, we used CDC Comparative Effectiveness Research (CER) data to assess state-wide operative practices.METHODS:Using CER and Louisiana Tumor Registry data, all CRC patients aged ≤50 years, diagnosed in Louisiana in 2011, who underwent surgery in 2011–2012 were retrospectively analyzed. Prevalence of, and the factors associated with operation type (ECR including subtotal/total/proctocolectomy vs. segmental resection) were evaluated.RESULTS:Of 2,427 CRC patients, 274 were aged ≤50 years. In all, 234 underwent surgery at 53 unique facilities and 6.8% underwent ECR. Statistically significant ECR-associated factors included age ≤45 years, polyposis, synchronous/metachronous LS-associated cancers, and IBD. Abnormal microsatellite instability (MSI) was not ECR-associated. ECR was not performed in sporadic CRC.CONCLUSIONS:ECR is performed in the setting of clinically obvious associated high-risk features (polyposis, IBD, synchronous/metachronous cancers) but not in isolated/sporadic CRC. However, attention must be paid to patients with seemingly lower risk characteristics (isolated CRC, no polyposis), as LS can still be present. In addition, the presumed sporadic group requires further study as metachronous CRC risk in early-onset sporadic CRC has not been well-defined, and some may harbor undefined/undiagnosed hereditary conditions. Abnormal MSI (LS risk) is not associated with ECR; abnormal MSI results often return postoperatively after segmental resection has already occurred, which is a contributing factor.

Invited comment on Warrier et al.: hereditary colorectal cancer screening and management practices by colorectal surgeons

Despite a low survey response rate of 10 % and the potential for non-response bias, the Warrier study in this month’s issue raises significant issues about genetic evaluation and surgical management in young patients suspected of having hereditary colorectal cancer (CRC)/ polyposis syndromes [1]. Perhaps most important is the fact that there is great heterogeneity among colorectal surgeons in the preoperative, operative and postoperative management practices of these patients. For example, in patients with CRC under age 50 without a family history of CRC, 33.1 % of surgeons would proceed to definitive surgery without a preoperative genetic evaluation, while 48.9 % would request some form of tumor analysis to help risk stratify the patient. In this latter group, there was again significant heterogeneity with differing practices regarding the ordering of microsatellite instability (MSI), immunohistochemistry (IHC) or combination (MSI/IHC) testing. The key question, which is not answered by this study, is what underlies the difference in approach among surgeons. As the National Comprehensive Cancer Network (NCCN) guidelines recommend mismatch repair (MMR) protein testing in all patients with CRC under the age of 50, regardless of family history, it would be important to distinguish whether the surveyed physicians are not aware of this recommendation or simply disagree with the recommendation and chose not follow it [2]. The former may signify a lack of provider education. With the later, it would be important to ascertain the physician-related factors associated with medical decision making in this highrisk patient group (e.g., the belief that there is an inadequate evidence base upon which to build a recommendation). Alternatively, there may be patient-related factors, including patient preference, insurance status and concerns of being labeled as having a genetic disease, which can either facilitate or impede effective management. For example, with regard to patient preference, some individuals may be unwilling to wait for tumor analysis or formal genetic testing results and desire surgery immediately. Clearly, in all cases, an important goal should be to better understand the driving forces and obstacles that underlie medical decision making. This will help create standardized patient care practices and may ultimately optimize clinical outcomes. Also of particular interest in the study was provider reliance on family history to decide which patients would be eligible for preoperative genetic testing, to determine extent of colonic resection and to guide postoperative surveillance. Unfortunately, this approach has many pitfalls as a significant proportion of patients may have de novo mutations and hence will lack a family history of cancer [3]. In addition, although it has been traditionally accepted that Lynch syndrome patients develop cancer in their forties, recent evidence has shown that the average age of diagnosis may be in the early sixties [4]. Hence, penetrance can vary widely, and some family members may not live long enough to manifest the malignant phenotype. This, of course, would make reliance on family history fraught with difficulty. Finally, it should be noted that gastroenterologists can play a key role in the preoperative work-up of young patients with colorectal cancer. Although colorectal surgeons perform large numbers of diagnostic preoperative J. Karlitz (&) Tulane University School of Medicine, New Orleans, LA, USA e-mail: jkarlitz@tulane.edu

KRAS Testing, Tumor Location, and Survival in Patients With Stage IV Colorectal Cancer: SEER 2010–2013

Purpose:KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%-46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS-mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22-1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05-1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study.