Therapeutic options for mucinous ovarian carcinoma

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition

The Molecular Origin and Taxonomy of Mucinous Ovarian Carcinoma

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases

Uncovering dengue in India: morbidity estimates

Over the last few decades, reporting of dengue cases has dramatically spread over almost entire India but the disease burden is grossly under- estimated under the current surveillance system. This review based on literature searches in PubMed and Medline for the period 1961-2012 describes changing epidemiological patterns, emerging challenges to public health intervention for control of dengue transmission in India and estimates magnitude of under-reporting. The annual reported numbers in 10 selected states/Union Territories with the highest number of cases during the years 2008-2012 and the surveillance system estimated expansion factor of 8.9- 9.6 derived from Thailand and Cambodia data respectively were used for new estimates of dengue morbidity in India. The reporting incidence of dengue is as low as 4/100,000 in 2012. The estimated crude incidence of dengue for 2012 is 53/100,000 to 58.83/100,000 and the country annual health care facility based case load would be around 700,000. India needs to expand surveillance activities to non-hospitalized cases and to the distribution and abundance of Aedes aegypti throughout country and review state and local vector control activities for Aedes aegypti and Aedes albopictus. Knowledge of vector prevalence is essential to estimate the geographical distribution of dengue infection and associated disease

Comparison of several curves in the context of nonparametric regression

Consider the model y\sb{lj} = \mu\sb{l}(t\sb{j}) + \varepsilon\sb{lj}, $l = 1,..,m$ and $j = 1,..,n,$ where \varepsilon\sb{lj} are independent mean zero finite variance random variables. Under the above setting we test the hypothesesH\sb0 : \mu\sb1 (t) {=..=}\ \mu\sb{m}(t) vs H\sb{a} : \mu\sb{l}(t) are not all equal.Different procedures for testing the above hypotheses are studied. Test procedures are based on comparing estimates of the regression functions. Both smoothing spline and orthogonal series estimators are considered and the smoothing parameters are selected using Generalized Cross Validation criterion. Under some regularity conditions the asymptotic distributions of some of the test statistics are shown to be normal. Asymptotic power comparisons for the shift alternative are discussed. Comparison of regression curves in Bayesian nonparametric regression is also investigated.U of I OnlyETDs are only available to UIUC Users without author permissio

Knee joint reconstruction with modular-megaprosthesis following peri-articular tumour resection and mutilating trauma: Sri Lankan perspective on limb salvage surgery

amount of bone resected, is the most popular & readily available option for limb salvage surgery in the world. MMP can be used for reconstruction of the knee joint where the use of regular prosthesis would be impossible following peri-articular tumour resection and mutilating trauma due to greater degree of bone loss and extensive ligament damage or excision. MMP is yet an emerging concept in Sri lankan setup due to many obstacles in implementing limb salvage surgery. Methods: Six consecutive patients underwent Total Knee Arthroplasty(TKA) with MMP in SJP General Hospital within the period of 31/06/2009--31/08/2012. Primary pathology, operative details, complications following surgery and in subsequent follow-up was analyzed. Knee-Society-Knee-Score-(KSKS) determined the functional outcome of the surgery. Results: Six TKAs were for wide local excision of lower femoral osteosarcomas(n=2), chondrosarcoma(n=1) & a Giant cell tumour(n=1) with a Extensive knee trauma(n=1) and a periprosthetic fracture of previous primary TKA(n=1). Range of follow up duration was(6–24 months). No intra operative or immediate post operative complications were detected. Excellent outcome (Knee-Society-Knee-Score 80 -100) reported in all, except for the patient who underwent TKA following extensive trauma. He subsequently developed a flexion contracture with a peri-prosthetic wound infection. Conclusion: Knee joint reconstruction with MMP is a successful option in periarticular tumor resection or mutilating trauma involving the knee joint which may salvage the limb preserving a good functional outcome despite extensive ligament and bone loss.

Dengue Virus Infection in Africa

Reported incidence of dengue has increased worldwide in recent decades, but little is known about its incidence in Africa. During 1960–2010, a total of 22 countries in Africa reported sporadic cases or outbreaks of dengue; 12 other countries in Africa reported dengue only in travelers. The presence of disease and high prevalence of antibody to dengue virus in limited serologic surveys suggest endemic dengue virus infection in all or many parts of Africa. Dengue is likely underrecognized and underreported in Africa because of low awareness by health care providers, other prevalent febrile illnesses, and lack of diagnostic testing and systematic surveillance. Other hypotheses to explain low reported numbers of cases include cross-protection from other endemic flavivirus infections, genetic host factors protecting against infection or disease, and low vector competence and transmission efficiency. Population-based studies of febrile illness are needed to determine the epidemiology and true incidence of dengue in Africa

Assessing perceptions of establishing a vaccine pooled procurement mechanism for the Western Pacific Region.

This study explored the demand and interest among countries in the World Health Organization Western Pacific Region (WPR) to establish and participate in a regional vaccine pooled procurement mechanism. National counterparts affiliated with Ministries of Health that are involved in the national procurement of vaccines within the WPR were identified and invited to complete surveys. Out of 80 counterparts invited, 17 (21%) responded, representing 13 of the 27 WPR countries. Five countries expressed interest in participating in a regional pooled procurement mechanism, 3 expressed lack of interest and 5 did not respond to the question. Preferred characteristics of the procurement mechanism, included flexible participation (i.e. non-compulsory), payment in local currency before receipt of goods and a fixed price for vaccines (i.e. not tiered pricing). Vaccine pricing disparities were noted among upper middle-income and high-income countries for five of the 13 routine vaccines surveyed. Eight countries listed budget planning, quality of vaccines, timely delivery, cost-saving and payment after receipt as potential benefits of pooled procurement