Barrett's Esophagus: Emerging Knowledge and Management Strategies

The incidence of esophageal adenocarcinoma (EAC) has increased exponentially in the last 3 decades. Barrett's esophagus (BE) is the only known precursor of EAC. Patients with BE have a greater than 40 folds higher risk of EAC compared with the general population. Recent years have witnessed a revolution in the clinical and molecular research related to BE. However, several aspects of this condition remain controversial. Data regarding the true prevalence of BE have varied widely. Recent studies have suggested a lower incidence of EAC in nondysplastic BE (NDBE) than previously reported. There is paucity of prospective data showing a survival benefit of screening or surveillance for BE. Furthermore, the ever-increasing emphasis on healthcare cost containment has called for reexamination of the screening and surveillance strategies for BE. There is a need for identification of reliable clinical predictors or molecular biomarkers to risk-stratify patients who might benefit the most from screening or surveillance for BE. Finally, new therapies have emerged for the management of dysplastic BE. In this paper, we highlight the key areas of controversy and uncertainty surrounding BE. The paper discusses, in detail, the current literature about the molecular pathogenesis, biomarkers, histopathological diagnosis, and management strategies for BE

Ex-vivo drug screening of surgically resected glioma stem cells to replace murine avatars and provide personalise cancer therapy for glioblastoma patients [version 1; peer review: 2 approved]

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas

Findings from the Peutz-Jeghers Syndrome Registry of Uruguay

Background: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Methods: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. Results and discussion: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. Conclusion: The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation

The revised Bethesda guidelines: extent of utilization in a university hospital medical center with a cancer genetics program

<p>Abstract</p> <p>Background</p> <p>In 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution.</p> <p>Methods</p> <p>All HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients' electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution.</p> <p>Results</p> <p>A total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling.</p> <p>Conclusion</p> <p>This retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.</p

Improvement in quality of life measures in patients with refractory hepatitis C, responding to re-treatment with Pegylated interferon alpha -2b and ribavirin

Abstract Background In this paper, we report the health related quality of life (HRQOL) data from patients with hepatitis C viral infection (HCV) who were refractory to prior therapy and had re-treatment with a combination of Pegylated interferon alpha-2b and ribavirin. We hypothesized that the HRQOL will improve in those patients who attain sustained viral response similar to naïve patients undergoing treatment for HCV. Methods HRQOL data was obtained from 152 patients enrolled into a randomized study for re-treatment of HCV refractory to prior therapy with interferon alpha-2b in combination with ribavirin. The treatment protocol was for 48 weeks and had a high and low dose arm. The HRQOL data was collected at baseline, weeks 24 and 48 of treatment, and at 24 week follow-up after treatment. A repeated measures statistical model was used for comparing the HRQOL domain scores between the responders and non-responders and the treatment groups. The responders and non-responders were also compared to the age and sex adjusted national mean scores. Results Twenty-five of the 152 (17%) patients achieved a sustained viral response. At baseline, HRQOL is lower in HCV patients compared to national norms. The norm based HRQOL domain scores for the different domains of the SF-36 instrument were as follows: physical functioning = 47.13, role-physical = 46.87, bodily pain = 48.00, general health = 44.01, vitality = 45.39, social functioning = 47.05, role-emotional = 48.88, mental health = 48.76, physical component score 43.26 and mental component score = 46.17. The scores decreased during therapy in those who would be responders and non-responders, but the pattern of change was different. During the treatment, the HRQOL domain scores of responders decrease notably in the domain of vitality. At week 48 vitality scores were worst in responders. 5 of the 8 domain scores were lower compared to baseline in non-responders. At 24 weeks post treatment follow up, HRQOL in those refractory patients who respond to re-treatment tended to be better than the national average in the domains of vitality (p = .06), social functioning (p = .06) and role-emotional (p = .03) while the non-responders improved their scores in domains of physical function and bodily pain. Conclusion We conclude that patients who are to be responders and non-responders behave differently in terms of the HRQOL domain scores when re-treated with a combination of interferon alpha 2b and ribavirin. The responders sustained a significant decrease in the domain score of vitality while 5 of the 8 domain scores decrease in non-responders at the end of treatment. At the end of follow up, in responders, the HRQOL score tended to be better than the national average notably in the domains of role-emotional, vitality and social functioning. On the other hand, in non-responders, the domain scores of physical function improve, while that of role-emotional worsened.</p