Collaborations in gynecologic oncology education and research in low- and middle- income countries: Current status, barriers and opportunities.

Eighty-five percent of the incidents and deaths from cervical cancer occur in low and middle income countries. In many of these countries, this is the most common cancer in women. The survivals of the women with gynecologic cancers are hampered by the paucity of prevention, screening, treatment facilities and gynecologic oncology providers. Increasing efforts dedicated to improving education and research in these countries have been provided by international organizations. We describe here the existing educational and research programs that are offered by major international organizations, the barriers and opportunities provided by these collaborations and hope to improve the outcomes of cervical cancer through these efforts.

Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation.

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.

International models of investigator-initiated trials: implications for Japan.

BACKGROUND: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials. MATERIALS: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world. RESULTS: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval. CONCLUSIONS: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.

Insulin-requiring diabetes in Ethiopia: associations with poverty, early undernutrition and anthropometric disproportion.

BACKGROUND/OBJECTIVES: Most insulin-requiring diabetes patients in Ethiopia have an atypical form of the disease, which resembles previous descriptions of malnutrition-related diabetes. As so little is known about its aetiology, we have carried out a case-control study to evaluate its social and nutritional determinants. SUBJECTS/METHODS: Men and women with insulin-requiring diabetes (n=107), aged 18-40 years, were recruited in two centres, Gondar and Jimma, 750 km northwest and 330 km southwest of the capital, Addis Ababa, respectively. Controls of similar age and sex (n=110) were recruited from patients attending other hospital clinics. RESULTS: Diabetes was strongly associated with subsistence farming, odds ratio=3.5 (95% confidence interval: 1.5-7.8) and illiteracy/low levels of education, odds ratio=4.0 (2.0-8.0). Diabetes was also linked with a history of childhood malnutrition, odds ratio=5.5 (1.0-29.0) the mother's death during childhood, odds ratio=3.9 (1.0-14.8), and markers of poverty including poorer access to sanitation (P=0.004), clean water (P=0.009), greater overcrowding (P=0.04), increased distance from the clinic (P=0.01) and having fewer possessions (P=0.01). Compared with controls, people with diabetes had low mid upper arm circumference, body mass index (BMI) and fat/lean body mass (P<0.01). In addition, men with the disease tended to be shorter, were lighter (P=0.001), with reduced sitting height (P=0.015) and reduced biacromial (P=0.003) and bitrochanteric (P=0.008) diameters. CONCLUSIONS: Insulin-requiring diabetes in Ethiopia is strongly linked with poor education and markers of poverty. Men with the disease have associated disproportionate skeletal growth. These findings point towards a nutritional aetiology for this condition although the nature of the nutritional deficiency and its timing during growth and development remains obscure.

Insulin-requiring diabetes in rural Ethiopia: should we reopen the case for malnutrition-related diabetes?

AIMS/HYPOTHESIS: We evaluated the incidence of insulin-requiring diabetes in a rural area of sub-Saharan Africa. METHODS: Health surveillance data from a chronic disease programme in two zones of Ethiopia, Gondar and Jimma, were studied. The two zones have a population of more than 5,000,000 people. RESULTS: In Gondar Zone (1995-2008) and Jimma Zone (2002-2008) 2,280 patients presented with diabetes, of whom 1,029 (45%) required insulin for glycaemic control at diagnosis. The annual incidence of insulin-requiring diabetes was 2.1 (95% CI 2.0-2.2) per 100,000 and was twice as high in men (2.9 per 100,000) as in women (1.4 per 100,000). In both sexes incidence rates peaked at the age of 25 to 29 years. Incidence rates in the urban areas of Gondar and Jimma were five times higher than in the surrounding rural areas. Patients with insulin-requiring diabetes from rural and urban areas had a very low BMI and most were subsistence farmers or unemployed. CONCLUSIONS/INTERPRETATION: The typical patient with diabetes in rural Ethiopia is an impoverished, young adult male with severe symptoms requiring insulin for glycaemic control. The low incidence rates in rural compared with urban areas suggest that many cases of this disease remain undiagnosed. The disease phenotype encountered in this area of Africa is very different from the classical type 1 diabetes seen in the West and most closely resembles previous descriptions of malnutrition-related diabetes, a category not recognised in the current WHO Diabetes Classification. We believe that the case for this condition should be reopened.

National Cancer Institute-United States strategy regarding intraperitoneal chemotherapy for ovarian cancer.

On the basis of three large randomized phase III trials, the National Cancer Institute (NCI) issued a Clinical Announcement in January 2006 recommending that women with optimally debulked stage III ovarian cancer and their physicians consider a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. The combination of IV and IP chemotherapy is associated with a clinically significant benefit in survival, although it does also confer an increased risk of toxicity compared to IV chemotherapy alone. The NCI Clinical Announcement was issued as part of a broader educational campaign, designed in conjunction with professional societies, cancer centers, Clinical Trials Cooperative Groups, and cancer advocacy organizations. The further development of IP chemotherapy in ovarian cancer requires additional clinical and translational research.

Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A.

AIMS/HYPOTHESIS: Atherosclerosis, which occurs prematurely in individuals with diabetes, incorporates vascular smooth muscle cell (VSMC) chemotaxis. Glucose, through protein kinase C-beta(II) signalling, increases chemotaxis to low concentrations of platelet-derived growth factor (PDGF)-BB. In VSMC, a biphasic response in PDGF-beta receptor (PDGF-betaR) level occurs as PDGF-BB concentrations increase. The purpose of this study was to determine whether increased concentrations of PDGF-BB and raised glucose level had a modulatory effect on the mitogen-activated protein kinase/extracellular-regulated protein kinase pathway, control of PDGF-betaR level and chemotaxis. METHODS: Cultured aortic VSMC, exposed to normal glucose (NG) (5 mmol/l) or high glucose (HG) (25 mmol/l) in the presence of PDGF-BB, were assessed for migration (chemotaxis chamber) or else extracted and immunoblotted. RESULTS: At concentrations of PDGF-BB <540 pmol/l, HG caused an increase in the level of PDGF-betaR in VSMC (immunoblotting) versus NG, an effect that was abrogated by inhibition of aldose reductase or protein kinase C-beta(II). At higher concentrations of PDGF-BB (>540 pmol/l) in HG, receptor level was reduced but in the presence of aldose reductase or protein kinase C-beta(II) inhibitors the receptor levels increased. It is known that phosphatases may be activated at high concentrations of growth factors. At high concentrations of PDGF-BB, the protein phosphatase (PP)2A inhibitor, endothall, caused an increase in PDGF-betaR levels and a loss of biphasicity in receptor levels in HG. At higher concentrations of PDGF-BB in HG, the chemoattractant effect of PDGF-BB was lost (chemotaxis chamber). Under these conditions inhibition of PP2A was associated with a restoration of chemotaxis to high concentrations of PDGF-BB. CONCLUSION/INTERPRETATION: The biphasic response in PDGF-betaR level and in chemotaxis to PDGF-BB in HG is due to PP2A activation.

Demographic, clinical, and treatment trends among women diagnosed with vulvar cancer in the United States.

OBJECTIVE: Describe the treatment and survival patterns among a population-based sample of vulvar cancer patients diagnosed in the United States in 1999. METHODS: Cases were identified for the National Cancer Institute's Patterns of Care Study (POC) using the Surveillance, Epidemiology, and End Results Program (SEER). A stratified random sample of non-Hispanic white, non-Hispanic black, and Hispanic women age 20 years and older was selected from cases reported by 11 SEER registries. Analyses of the association between vulvar cancer and key demographic, clinical, and hospital characteristics by stage were performed. Cox proportional hazards was used to estimate the odds of death due to cancer. All estimates were weighted, and analyses were conducted with SUDAAN. RESULTS: Ninety percent of cases were diagnosed with in situ or early-stage invasive disease. Older patients were more likely to present at advanced stages. Twenty-five percent of women with Stage III-IV vulvar cancer received chemotherapy plus radiation. We noted widespread use of radical local excision among women with Stage I/II cancer, but 46-54% with invasive disease underwent a radical or total vulvectomy. Factors associated with cancer death were limited to age and stage. Women 75 years and older were at higher risk compared to women aged 20-49 years and the risk of death increased with advancing stage. CONCLUSIONS: Vulvar cancer is diagnosed at early stages. Late-stage disease is associated with a significant increase in mortality. Radical surgery was still commonly performed in 1999. Radiation was more common in women diagnosed at late stage, while the use of chemoradiation remained limited.

Clinical trials in gynecological cancer.

The Gynecologic Cancer Intergroup is comprised representatives from international gynecological cancer trials organizations, which collaborate in multicenter studies to answer the clinical challenges in gynecological cancer. This review article highlights the key clinical questions facing clinical trialists over the next decade, the information and infrastructure resources available for trials, and the methods of trial development. We cover human papillomavirus (HPV)-associated neoplasia, including cervical cancer, together with endometrial cancer, ovarian cancer, and vulvar cancer. Infrastructure for clinical trials includes a database for trials, templates for protocol development, patient educational material, and financial support for clinical trials. Other critical issues include support from government and charities and government regulations.

Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men.

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Progress in ovarian cancer research: proceedings of the 5th Biennial Ovarian Cancer Research Symposium.

Ovarian cancer remains the most lethal gynecological malignancy. The 5th Biennial Symposium overviewed the progress of ovarian cancer research over the last few years. Molecularly based technologies have allowed the identification of multiple biomarkers to aid in ovarian cancer diagnosis and treatment. Furthermore, data analysis systems evaluating the behavior of these markers have been designed. Therapeutic use of ovarian cancer protein markers has been fueled by the development of animal models that more closely simulate the pathogenesis of ovarian cancer, and multiple new therapies are being developed that may have impact against the disease. Finally, the design of clinical trials both for ovarian cancer treatment and prevention are key in advancing the science of ovarian cancer into the clinic. The need for strategies that would optimize patient participation in clinical trials is paramount.

Acute respiratory distress syndrome in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies.

Inborn errors of metabolism have not previously been recognized as a risk factor for acute respiratory distress syndrome (ARDS). We report this complication in four patients with defects of the mitochondrial trifunctional protein (MTP). This enzyme catalyses three steps in the beta-oxidation of long-chain fatty acids. Three of the patients were homozygous for the 'common' 1528G>C mutation in the alpha-subunit of the MTP, giving rise to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The fourth patient did not carry this mutation but had severely decreased activities of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase. One patient died and histology in this patient showed severe interstitial pulmonary fibrosis. The other three patients recovered after being ventilated for up to 6 months. The high frequency of ARDS in patients with MTP defects suggests that this inborn error may be a risk factor for ARDS.

Diabetes-induced activation of protein kinase C inhibits store-operated Ca2+ uptake in rat retinal microvascular smooth muscle.

AIMS/HYPOTHESIS: To assess the effects of diabetes-induced activation of protein kinase C (PKC) on voltage-dependent and voltage-independent Ca2+ influx pathways in retinal microvascular smooth muscle cells. METHODS: Cytosolic Ca2+ was estimated in freshly isolated rat retinal arterioles from streptozotocin-induced diabetic and non-diabetic rats using fura-2 microfluorimetry. Voltage-dependent Ca2+ influx was tested by measuring rises in [Ca2+]i with KCl (100 mmol/l) and store-operated Ca2+ influx was assessed by depleting [Ca2+]i stores with Ca2+ free medium containing 5 micromol/l cyclopiazonic acid over 10 min and subsequently measuring the rate of rise in Ca2+ on adding 2 mmol/l or 10 mmol/l Ca2+ solution. RESULTS: Ca2+ entry through voltage-dependent L-type Ca2+ channels was unaffected by diabetes. In contrast, store-operated Ca2+ influx was attenuated. In microvessels from non-diabetic rats 20 mmol/l D-mannitol had no effect on store-operated Ca2+ influx. Diabetic rats injected daily with insulin had store-operated Ca2+ influx rates similar to non-diabetic control rats. The reduced Ca2+ entry in diabetic microvessels was reversed by 2-h exposure to 100 nmol/l staurosporine, a non-specific PKC antagonist and was mimicked in microvessels from non-diabetic rats by 10-min exposure to the PKC activator phorbol myristate acetate (100 nmol/l). The specific PKCbeta antagonist LY379196 (100 nmol/l) also reversed the poor Ca2+ influx although its action was less efficacious than staurosporine. CONCLUSION/INTERPRETATION: These results show that store-operated Ca2+ influx is inhibited in retinal arterioles from rats having sustained increased blood glucose and that PKCbeta seems to play a role in mediating this effect.

Interaction of glucose and long chain fatty acids (C18) on antioxidant defences and free radical damage in porcine vascular smooth muscle cells in vitro.

AIMS/HYPOTHESIS: Abnormalities of glucose and fatty acid metabolism in diabetes are believed to contribute to the development of oxidative stress and the long term vascular complications of the disease; therefore the interactions of glucose and long chain fatty acids on free radical damage and endogenous antioxidant defences were investigated in vascular smooth muscle cells. METHODS: Porcine vascular smooth muscle cells were cultured in 5 mmol/l or 25 mmol/l glucose for 10 days. Fatty acids, stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2) and alpha-linolenic acid (18:3) were added with defatted bovine serum albumin as a carrier for the final three days. RESULTS: Glucose (25 mmol/l) alone caused oxidative stress in the cells as evidenced by free radical-mediated damage to DNA, lipids, and proteins. The addition of fatty acids (0.2 mmol/l) altered the profile of free radical damage; the response was J-shaped with respect to the degree of unsaturation of each acid, and oleic acid was associated with least damage. At a lower concentration alpha-linolenic acid (0.01 mmol/l) was markedly different in that, when added to 25 mmol/l glucose it resulted in a decrease in free radical damage to DNA, lipids and proteins. This was accompanied by a marked increase in antioxidant and glutathione concentrations as well as by increased gene expression is of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione synthesis. CONCLUSIONS/INTERPRETATION: The results clearly show that glucose and fatty acids interact in the production of oxidative stress in vascular smooth muscle cells.

Follow up of fetal outcome in cases of maternal phenylketonuria in Northern Ireland.

BACKGROUND: Maternal phenylketonuria (PKU) can result in multiple congenital anomalies. In Northern Ireland, the prevalence of PKU is relatively high at 1 in 4000. OBJECTIVE: To assess the outcome of 39 pregnancies in 20 mothers. RESULTS: Dietary control was established before conception in 17 pregnancies (44%). Five mothers with hyperphenylalaninaemia had 11 pregnancies. There were no congenital anomalies in this group, and all appear to be developing normally. Fifteen women with classical PKU had 28 pregnancies. One pregnancy ended in a first trimester miscarriage. Twelve out of 27 (44%) completed pregnancies produced babies with a congenital anomaly and/or developmental delay. CONCLUSIONS: Most problems occurred when dietary control was not established until after the 2nd trimester. As the cohort of young women with treated PKU is growing steadily, maternal PKU is going to become an even greater cause for concern.