Development and Validation of the Asia-Pacific Proximal Colon Neoplasia Risk Score.

BACKGROUND & AIMS: Patients found to be at high risk of advanced proximal neoplasia (APN) after flexible sigmoidoscopy screening should be considered for colonoscopy examination. We developed and validated a scoring system to identify persons at risk for APN. METHODS: We collected data from 7954 asymptomatic subjects (age, 50-75 y) who received screening colonoscopy examinations at 14 sites in Asia. We randomly assigned 5303 subjects to the derivation cohort and the remaining 2651 to the validation cohort. We collected data from the derivation cohort on age, sex, family history of colorectal cancer, smoking, drinking, body mass index, medical conditions, and use of nonsteroidal anti-inflammatory drugs or aspirin. Associations between the colonoscopic findings of APN and each risk factor were examined using the Pearson χ2 test, and we assigned each participant a risk score (0-15), with scores of 0 to 3 as average risk and scores of 4 or higher as high risk. The scoring system was tested in the validation cohort. We used the Cochran-Armitage test of trend to compare the prevalence of APN among subjects in each group. RESULTS: In the validation cohort, 79.5% of patients were classified as average risk and 20.5% were classified as high risk. The prevalence of APN in the average-risk group was 1.9% and in the high-risk group was 9.4% (adjusted relative risk, 5.08; 95% CI, 3.38-7.62; P < .001). The score included age (61-70 y, 3; ≥70 y, 4), smoking habits (current/past, 2), family history of colorectal cancer (present in a first-degree relative, 2), and the presence of neoplasia in the distal colorectum (nonadvanced adenoma 5-9 mm, 2; advanced neoplasia, 7). The c-statistic of the score was 0.74 (95% CI, 0.68-0.79), and for distal findings alone was 0.67 (95% CI, 0.60-0.74). The Hosmer-Lemeshow goodness-of-fit test statistic was greater than 0.05, indicating the reliability of the validation set. The number needed to refer was 11 (95% CI, 10-13), and the number needed to screen was 15 (95% CI, 12-17). CONCLUSIONS: We developed and validated a scoring system to identify persons at risk for APN. Screening participants who undergo flexible sigmoidoscopy screening with a score of 4 points or higher should undergo colonoscopy evaluation.

Management of Chronic Hepatitis B: Knowledge and Practices of Physicians in Pakistan.

BACKGROUND: In Pakistan, approximately 4.5 million people are afflicted with chronic hepatitis B (CHB). The compliance with hepatitis B virus (HBV) management guidelines is still unknown. This was the first study from Pakistan in which the knowledge and practices of treating physicians were compared with three standardized guidelines (Asia Pacific Association for the Study of the Liver (APASL) 2012/European Association for the Study of the Liver (EASL) 2012/American Association for the Study of Liver Diseases (AASLD) 2009). METHODS: A cross-sectional study was conducted during 2014-2015 at four tertiary care teaching hospitals of Karachi, Pakistan. The study participants were internists, gastroenterologist, senior residents who were involved in the management of CHB patients. All participants were offered to fill the study questionnaire. RESULTS: A total of 179 physicians (103 residents, 76 consultants) participated. Mean age of participant was 35 ± 9.3 years. Approximately one-third of them followed AASLD (27.3%) and EASL (24.0%) guidelines. Entecavir, tenofovir or Peg IFN ∞ 2a were considered as first line therapy by 43%, 38.5% and 30.2% respectively. However, 17.9% preferred entecavir with tenofovir for rescue therapy, 25.7% and 23.5% preferred tenofovir or entecavir as both first line and rescue therapy respectively. Serum HBV DNA, alanine transaminase levels were used to monitor during oral antivirals therapy by 45.3%. hepatocellular carcinoma screening was considered for all HBV cases by 51.4% using ultrasound (55.3%) and alfa fetoprotein (52.5%) every 6 months.Overall 40.2% participants had poor knowledge about indication of liver biopsy, treatment initiation and antiviral prophylaxis. Significant association was found between grades of knowledge and gender, age group, designation and specialty (P < 0.05). Younger physicians, consultants (age 25-40 years) and those who were practicing gastroenterology/hepatology were more likely to have higher knowledge scores in compliance with the guidelines as compared to others. CONCLUSION: Our study highlighted the gaps in knowledge and practices in managing CHB patients according to guidelines. Efforts to improve knowledge, refresher courses and appropriate coordination between gastroenterologists and internal medicine physicians could enable management and follow-up of patients with CHB effectively.

Risk of Colorectal Neoplasia in Individuals With Self-Reported Family History: A Prospective Colonoscopy Study from 16 Asia-Pacific Regions.

OBJECTIVES: We tested the hypothesis that the risk of colorectal cancer (CRC), advanced colorectal neoplasia (ACN), and colorectal adenoma among screening participants with different first-degree relatives (FDRs) affected by CRC was similar. METHODS: A multi-center, prospective colonoscopy study involving 16 Asia-Pacific regions was performed from 2008 to 2015. Consecutive self-referred CRC screening participants aged 40-70 years were recruited, and each subject received one direct optical colonoscopy. The prevalence of CRC, ACN, and colorectal adenoma was compared among subjects with different FDRs affected using Pearson's χ2 tests. Binary logistic regression analyses were performed to evaluate the risk of these lesions, controlling for recognized risk factors including age, gender, smoking habits, alcohol drinking, body mass index, and the presence of diabetes mellitus. RESULTS: Among 11,797 asymptomatic subjects, the prevalence of CRC was 0.6% (none: 0.6%; siblings: 1.1%; mother: 0.5%; father: 1.2%; ≥2 members: 3.1%, P<0.001), that of ACN was 6.5% (none: 6.1%; siblings: 8.3%; mother: 7.7%; father: 8.7%; ≥2 members: 9.3%, P<0.001), and that of colorectal adenoma was 29.3% (none: 28.6%; siblings: 33.5%; mother: 31.8%; father: 31.1%; ≥2 members: 38.1%, P<0.001). In multivariate regression analyses, subjects with at least one FDR affected were significantly more likely to have CRC (adjusted odds ratio (AOR)=2.02-7.89), ACN (AOR=1.55-2.06), and colorectal adenoma (AOR=1.31-1.92) than those without a family history. The risk of CRC (AOR=0.90, 95% confidence interval (CI) 0.34-2.35, P=0.830), ACN (AOR=1.07, 95% CI 0.75-1.52, P=0.714), and colorectal adenoma (AOR=0.96, 95% CI 0.78-1.19, P=0.718) in subjects with either parent affected was similar to that of subjects with their siblings affected. CONCLUSIONS: The risk of colorectal neoplasia was similar among subjects with different FDRs affected. These findings do not support the need to discriminate proband identity in screening participants with affected FDRs when their risks of colorectal neoplasia were estimated.

A Risk-Scoring System Combined With a Fecal Immunochemical Test Is Effective in Screening High-Risk Subjects for Early Colonoscopy to Detect Advanced Colorectal Neoplasms.

BACKGROUND & AIMS: Age, sex, smoking, and family history are risk factors for colorectal cancer in Asia. The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to identify subjects with a high risk for advanced neoplasm (AN). We tested an algorithm that combined APCS scores with fecal immunochemical test (FIT) in colorectal cancer screening. METHODS: We performed a multicenter prospective study, enrolling asymptomatic individuals older than 40 years old in 12 Asia-Pacific regions from December 2011 to December 2013. APCS scores were calculated for each individual (0-1 = low risk [LR], 2-3 = medium risk [MR], and 4-7 = high risk [HR] for AN). LR and MR subjects were offered FIT and referred for early colonoscopies if FIT results were positive. HR subjects were offered colonoscopies. The proportions of subjects with ANs were determined for each group based on colonoscopy findings; odd ratios for LR and MR subjects were calculated compared to LR individuals. We calculated the sensitivity of the APCS-FIT algorithm in identifying subjects with AN. RESULTS: A total of 5657 subjects were recruited: 646 subjects (11.4%) were considered LR, 3243 subjects (57.3%) were considered MR, and 1768 subjects (31.3%) were considered HR for AN. The proportions of individuals with an AN in these groups were 1.5%, 5.1%, and 10.9%, respectively. Compared with LR group, MR and HR subjects had a 3.4-fold increase and a 7.8-fold increase in risk for AN, respectively. A total of 70.6% subjects with AN (95% confidence interval: 65.6%-75.1%) and 95.1% subjects with invasive cancers (95% confidence interval: 82.2%-99.2%) were correctly instructed to undergo early colonoscopy examination. CONCLUSIONS: The APCS scoring system, which is based on age, sex, family history, and smoking, is a useful tool for determining risk for colorectal cancer and advanced adenoma in asymptomatic subjects. Use of the APCS score-based algorithm in triaging subjects for FIT or colonoscopy can substantially reduce colonoscopy workload.

Endoscopic ultrasonography: Challenges and opportunities in the developing world.

Endoscopic ultrasonography (EUS) has become a vital diagnostic modality for the evaluation of mediastinal lymphadenopathy, pancreatic cysts and masses, anorectal pathology, subepithelial gastrointestinal lesions, and for the staging of many gastrointestinal and pulmonary malignancies. Establishing a EUS program in a developing country presents many challenges. Doing so in Pakistan has led to the identification of the following challenges: initial investment, ongoing costs (particularly fine needle aspiration needle costs), awareness and cytopathology. Endoscopic ultrasonography has revolutionized aspects of the practice of gastroenterology and oncology in the West. This technique is becoming increasingly available in the developing world, where it poses unique challenges to its practice. These challenges include those relating to service initiation and maintenance costs, physician awareness, and on-site cytopathology access. If these issues are anticipated and addressed in ways appropriate to local circumstances, obstacles to the institution of EUS programs can be overcome.

Barriers to colorectal cancer screening in the developing world: The view from Pakistan.

Colorectal cancer screening has become a defining concern of current gastroenterological practice in many Western nations. This same focus does not exist in many developing countries, including Pakistan. There is a need to develop a model for the developing world. Here are several areas that need to be pursued: (1) epidemiological research; (2) physician and public education; (3) training of gastroenterologists, especially female ones; (4) less expensive and more culturally acceptable screening options (fecal occult blood testing); and (5) cost-effectiveness analyses. Gastroenterologists in developing countries need to step up to educate people and promote, where possible and in keeping with local conditions, the prevention and early diagnosis of colorectal cancer.

Are medical ethics universal or culture specific.

In our society and culture where family is of utmost importance, sometimes I wonder how much of a doctor's duty is to the patient and how much is to the whole family. As a medical student, I remember being told by my professors that we should treat the patient as a whole and not focus on just one problem or organ system. Similarly when practicing medicine in Pakistan, one cannot treat the patient alone and ignore the family. How much should relatives' wishes be taken into account when dealing with a patient Don't patients have a right to their medical information When, how, and by whom can that right be waived What role does culture play when debating medical ethics.

Seizures during pegylated interferon and ribavirin therapy for chronic Hepatitis C: observations from the WIN-R trial.

BACKGROUND: Seizures are reported as an uncommon side effect of interferon therapy. AIM: To determine the frequency and presentation of seizures occurring during pegylated interferon-α (PEG-IFNα) and ribavirin therapy for chronic hepatitis C. METHODS: Patients were identified using data from the WIN-R trial database, a US multicenter study comparing fixed (800 mg) versus weight-based (800 to 1400 mg) daily dosing of ribavirin in combination with PEG-IFNα-2b (1.5 µg/kg/wk). RESULTS: Of the 4913 enrolled patients, 8 (0.16%) had a seizure. Three patients had a grand mal seizure and the seizure type was unknown in 5 patients. At the time of seizure, 6 patients were taking antidepressants (including 3 on bupropion), 1 was hyponatremic, and 1 had consumed a significant amount of alcohol. One patient had a history of seizures. Neuroimaging and electroencephalographic studies were negative. Antiepileptic medications were continued in the patient with a history of seizures and initiated in 1 patient. PEG-IFNα-2b plus ribavirin therapy was continued in 2 patients following seizure and neither experienced a recurrent seizure. CONCLUSIONS: Seizures occur infrequently in patients receiving PEG-IFNα-2b plus ribavirin, and appear to be associated with other risk factors including antidepressant use.

Prognostic significance of hepatitis C virus RNA detection by transcription-mediated amplification with negative polymerase chain reaction during therapy with peginterferon alpha and ribavirin.

The lower limit of detection of most polymerase chain reaction (PCR) assays for hepatitis C virus (HCV) RNA is 50 IU/ml, compared to 5 IU/ml for the transcription-mediated amplification (TMA) method. We retrospectively reviewed 57 patients to assess the predictive value of a positive TMA in the setting of a negative PCR during antiviral therapy. Patients were divided into (1) PCR-/TMA+ (discordant; n=21) and (2) PCR-/TMA-(concordant; n=36). Sustained virologic response (SVR) was decreased in the discordant group (48% vs. 75%; P=0.04). In discordant patients, SVR was more frequent in patients who had one positive TMA than in those who had two or more positive TMAs or one positive TMA and recurrent HCV RNA detectability by PCR during treatment (78% vs. 25%; P=0.03). Breakthrough occurred more frequently in discordant patients (24% vs. 3%; P=0.02). A positive TMA on two or more occasions in patients who have become PCR-negative on therapy indicates a high likelihood of treatment failure.

Treatment of relapsers after combination therapy for chronic hepatitis C.

Sustained virologic response rates are significantly higher in patients who have relapsed after a previous course of therapy compared with patients who did not respond. A meta-analysis of combination therapy in patients who failed IFN monotherapy reported SVR rates of 52% in relapsers to prior therapy and 16% in nonresponders. Similarly, relapsers after combination standard IFN and RBV therapy have higher SVR rates than combination of therapy nonresponders when treated with pegylated interferon and ribavirin. For this reason, patients who relapse after a previous course of therapy should be considered potential candidates for retreatment. Factors that have been associated with SVR in these patients include genotype non-I, low viral loads, and lesser degrees of fibrosis. The course of treatment in all patients who have relapsed after prior therapy should be reviewed to identify possible reasons for failure to achieve an SVR. In particular, optimal dosing of PEG IFN and RBV and the occurrence and timing of treatment dose reductions during prior therapy should be reviewed. The reasons for dose reduction should be addressed before initiating another course of therapy in an effort to optimize the chance for a SVR. Patients who had dose reduction for depression, anemia, or neutropenia, should be considered for antidepressants, erythropoietin, or, if neutropenia is severe, granulocyte colony stimulating factor therapy, respectively, during retreatment. Prolongation of therapy beyond 48 weeks in patients with relapse after a standard course of PEG IFN and RBV may offer a chance of SVR. Novel agents currently in development, including protease and polymerase inhibitors, may prove to be therapeutic options for these patients in the future.

A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C.

OBJECTIVES: The efficacy of combination therapy with pegylated interferon (PEG IFN) alpha plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established. METHODS: Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN alpha-2b 1.5 microg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN alpha-2b 1.0 microg/kg per wk plus RBV 1,000-1,200 mg per day (Regimen B, n = 161) for 48 wks. RESULTS: Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18%vs 13%, p= 0.21), in 8% of the combination therapy nonresponders (10%vs 6%, p= 0.35), in 21% of the IFN monotherapy nonresponders (16%vs 27%, p= 0.35), and in 42% of the combination therapy relapsers (50%vs 32%, p= 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels >or=100,000 copies/mL (21%vs 5%, p= 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14%vs 33%, p= 0.01), and African Americans had lower SVR than Caucasians (4%vs 18%, p= 0.01). CONCLUSION: Combination therapy with PEG IFN alpha-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.

Interferon alfa-2b [correction of alpha-2b]and ribavirin for patients with chronic hepatitis C and normal ALT.

OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]. METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.

Treatment of relapsers after combination therapy for chronic hepatitis C.

A significant number of patients with chronic hepatitis C relapse after treatment. As therapy for CHC has improved over the last decade, the issue of retreating patients who did not achieve a sustained virologic response with previous treatment regimens frequently arises. Several studies have assessed the efficacy of pegylated interferon (IFN) and ribavirin (RBV) combination therapy in IFN and RBV therapy relapsers. Patients who have relapsed after therapy have significantly higher SVR rates than those who are nonresponders to therapy and should be considered candidates for retreatment. Predictors of a favorable response to therapy in naïve patients appear to also predict response to therapy in patients who have relapsed previously.