J.A. Rauh-Hain

Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis

BACKGROUND Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown. METHODS We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality. RESULTS Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]). CONCLUSIONS Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.

Sequential Changes in Antiangiogenic Factors in Early Pregnancy and Risk of Developing Preeclampsia

Concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) increase in maternal blood with the approach of clinical preeclampsia. Although alterations in these circulating antiangiogenic factors herald the signs and symptoms of preeclampsia, in vitro studies suggest they may also play a role in regulating early placental cytotrophoblast functions. Early pregnancy changes in sFlt1 and sEng may thus identify women destined to develop preeclampsia. We performed a nested case-control study of 39 women who developed preeclampsia and 147 contemporaneous normotensive controls each with serum collected in the first (11 to 13 weeks of gestation) and second (17 to 20 weeks) trimesters. Whereas levels of sFlt1 and sEng at 11 to 13 weeks were similar between cases and controls (sFlt1: 3.5±0.3 ng/mL versus 3.0±0.1, P=0.14; sEng 6.9±0.3 ng/mL versus 6.6±0.2, P=0.37, respectively), at 17 to 20 weeks both were elevated in the women destined to develop preeclampsia (sFlt1: 4.1±0.5 ng/mL versus 3.1±0.1, P<0.05; sEng, 6.4±0.4 ng/mL versus 5.2±0.1, P<0.01). Women who developed preterm (<37 weeks) preeclampsia demonstrated even greater sequential changes: difference [delta{d}] between second and first trimester levels: dsFlt1, 0.63±0.91 ng/mL in preterm PE versus 0.05±0.15 in controls; dsEng, 0.73±0.77 ng/mL versus −1.32±0.18, P<0.01. Similar findings were noted in a cross-sectional analysis of specimens collected from the Calcium for Preeclampsia Prevention Study. In conclusion, sequential changes in antiangiogenic factors during early pregnancy may be useful for predicting preterm preeclampsia.

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. To date, there is no preoperative technique that reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resultant intraperitoneal dissemination of tumor. The objective of this study was to assess the impact of intraperitoneal morcellation on the outcomes of patients with ULMS.

Risk for developing gestational diabetes in women with twin pregnancies

Objective. To examine the risk of developing gestational diabetes mellitus (GDM) in women with twin compared with singleton pregnancies. Research design and methods. We examined a cohort of 23,056 pregnant women who gave birth to a live infant between 1 September 1998 and 31 December 2006, 553 of whom had twin pregnancy. The primary exposure was twin versus singleton pregnancy, and the primary outcome was the development of GDM. Standard univariate analyses were performed, as were multivariable analysis with logistic regression to control for potential confounding variables. GDM was diagnosed using criteria of the National Diabetes Data Group. Results. Patients with twin pregnancies had a higher rate of GDM when compared with singleton pregnancies (3.98%vs. 2.32%; p = 0.01). In a multiple regression analysis after adjusting for age, race/ethnicity, body mass index, maximal systolic and diastolic blood pressure, smoking and parity, twin pregnancy was associated with an approximately two-fold increase in risk for developing GDM (OR 2.2, 95% CI 1.4–3.6). In a stratified analysis, women between the ages of 25 and 30 years and African-American women had the highest risk of developing GDM in twin pregnancies. When compared with twins of non-diabetic mothers, twins of gestational diabetics had a higher rate of admission to the neonatal intensive care unit (37%vs. 52%; p = 0.05), had longer hospitalisation (8 ± 0.5 vs. 16 ± 4 days; p = 0.01) and higher rate for respiratory distress syndrome (7%vs. 27%; p = 0.001). Conclusion. There is a significant increase in the incidence of GDM in twin pregnancies versus singleton pregnancies. The risk is highest in African-American and young women.

Progress and remaining challenges for cancer control in Latin America and the Caribbean

Cancer is one of the leading causes of mortality worldwide, and an increasing threat in low-income and middle-income countries. Our findings in the 2013 Commission in The Lancet Oncology showed several discrepancies between the cancer landscape in Latin America and more developed countries. We reported that funding for health care was a small percentage of national gross domestic product and the percentage of health-care funds diverted to cancer care was even lower. Funds, insurance coverage, doctors, health-care workers, resources, and equipment were also very inequitably distributed between and within countries. We reported that a scarcity of cancer registries hampered the design of credible cancer plans, including initiatives for primary prevention. When we were commissioned by The Lancet Oncology to write an update to our report, we were sceptical that we would uncover much change. To our surprise and gratification much progress has been made in this short time. We are pleased to highlight structural reforms in health-care systems, new programmes for disenfranchised populations, expansion of cancer registries and cancer plans, and implementation of policies to improve primary cancer prevention.

Endometrial stromal sarcoma: a systematic review.

OBJECTIVE: To summarize available studies with respect to evaluation and management of patients with endometrial stromal sarcoma and undifferentiated endometrial sarcoma. DATA SOURCES: We conducted an electronic search of research articles published in English between January 1, 1981, and January 1, 2013, using MEDLINE, PubMed, and ClinicalTrials.gov (www.clinicaltrials.gov) databases. METHODS OF STUDY SELECTION: Of the 115 studies initially identified, 86 were chosen after limiting the review to those articles focusing on endometrial stromal sarcoma and crossreferencing to eliminate duplication. Review articles were excluded. Of the 86 studies meeting eligibility criteria, 84 were retrospective, one was a prospective phase II trial, and one was a phase III randomized study. Data were extracted systematically. Each of the reviewers assessed the quality of each study independently. TABULATION, INTEGRATION, AND RESULTS: Data were abstracted using standard abstraction templates to summarize study findings. Given the rarity of this tumor, we report available data with respect to epidemiology, pathogenesis, prognostic factors, and treatment. Endometrial stromal sarcoma and undifferentiated endometrial sarcoma comprise an estimated 1% of all uterine cancers and less than 10% of all uterine mesenchymal neoplasms. Hysterectomy and bilateral salpingo-oophorectomy is the cornerstone of treatment for early-stage (I or II) disease. Surgical resection when feasible may also be appropriate for patients presenting with advanced-stage tumors. The value of adjuvant therapy for early-stage disease remains unproven. Hormone therapy continues to be the most efficacious treatment modality for patients with advanced-stage or recurrent disease. CONCLUSION: Endometrial stromal sarcoma and undifferentiated endometrial sarcoma are rare tumors. Surgical resection is appropriate for patients with early-stage (I or II) disease and those with resectable, advanced-stage (III or IV) tumors. Hormone therapy may be appropriate in treating advanced and recurrent disease.

Understanding barriers to cervical cancer screening among Hispanic women

OBJECTIVE We investigated issues affecting Papanicolaou smear screening access, health services utilization, acculturation, social networking, and media venues most conducive to acquiring health information among Hispanics. STUDY DESIGN Self-identified Hispanics were surveyed. Participants were stratified based on age, time living in the United States, and Papanicolaou screening frequency. RESULTS Of 318 participants, Hispanics aged 30 years or older and living in the United States less than 5 years prefer speaking Spanish. Women with 5 or more lifetime Papanicolaou smears were 1.610 times more likely to have lived in the United States 5 or more years, 1.706 times more likely to speak a second language, and 1.712 times less likely to need a translator during their health care encounter. CONCLUSION Age and years living in the United States may be independent risk factors for participation in Papanicolaou screening programs. Social difficulties inherent to acculturation inform health behavior and translate to health disparity among Hispanics. Our results may help design federally funded and community-level programs.

Utility of pre-operative serum CA-125 in the management of uterine papillary serous carcinoma

OBJECTIVE To evaluate the usefulness of pre-operative serum CA-125 in the management of women diagnosed with uterine papillary serous carcinoma (UPSC). We hypothesized that elevated pre-operative levels of serum CA-125 correlate with higher disease stage and poorer prognosis. METHODS Patients diagnosed with UPSC and managed in our institution were identified over a period of 10 years, 1995 to 2005. All required information were extracted from their records. The nonparametric test applied for comparison of data included Kruskal Wallis H-test and Man-Whitney U-test. The chi(2) test and Spearman correlation test were used to examine the association of serum CA-125 with different parameters. Receiver operator characteristic curves (ROC) were used to quantify marker performance. Recurrence and survival were analyzed using Kaplan-Meier method. Multivariate analyses were performed with a Cox proportional regression method. RESULTS A total of 41 patients met the study criteria. Mean pre-operative serum CA-125 levels were significantly higher in patients with stage IV (1150+/-1297 U/mL), compared with stage III (181+/-232 U/mL; P<0.001), stage II (22+/-9; P<0.001), and stage I (14+/-1; P<0.001). CA-125 correlated strongly with stage (r=0.68, P<0.001). On the ROC, a cut-off of 35 IU/mL provided the best sensitivity and specificity (78% vs. 100% respectively) for extra-uterine disease. Disease free survival (DFS) and overall survival (OS) were longer in patients with CA-125<35 U/mL compared with CA-125>or=35 U/mL [median DFS not reached during study vs. 21.2 months (P=0.009), and median OS not reached during study vs. 25 months, (P=0.0001) respectively]. Multivariate regression model showed CA-125 as the only variable associated with survival (P=0.05). CONCLUSION Pre-operative serum CA-125 levels correlate with stage of disease in patients with UPSC. This may be important for management planning, prognostication and counseling in these women.

Advances in the management of recurrent endometrial cancer.

Objective:Endometrial carcinoma is the most common malignancy of the female reproductive tract. Although most cases are diagnosed at an early stage, endometrial carcinoma carries a poor prognosis when it recurs after previous definitive treatment or when diagnosed at an advanced stage. The purpose of this review is to summarize the contemporary management of recurrent endometrial carcinoma. Methods:A literature review was conducted on the management of advanced, recurrent, or metastatic endometrial cancer to determine the best evidence to support the roles of surgery, radiation, and medical therapy. Results:Radiation therapy (RT) has a role in the treatment of a local or regional recurrence, especially in the patient who has not had prior RT. For selected patients who experience a loco-regional recurrence and who have been treated with RT, pelvic exenteration may be an option. Those patients with metastatic disease are not curable and should be considered for palliative chemotherapy. The data support the use of carboplatin and paclitaxel as an acceptable alternative to cisplatin-based regimens. For women who progress after first-line treatment, the options are limited. Current clinical trials are evaluating the role of angiogenesis inhibitors and molecularly targeted therapy (including the mammalian target of rapamycin inhibitors and multitargeted tyrosine kinase inhibitors) with the aim of identifying other novel agents that can be exploited for treatment of advanced disease. Conclusions:The treatment of women with advanced, recurrent, or metastatic endometrial cancer represents an unmet need in oncology. Robust clinical trials are required to explore how to improve on therapy. The incorporation of molecularly targeted agents has the potential to improve outcomes for women who require treatment in both the first-line and second-line settings.

Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma.

Ovarian clear cell adenocarcinoma (OCCA) is a unique biological subtype of epithelial ovarian cancer, with a similar gene profile to renal cell carcinoma (RCC). Sunitinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with proven antitumor activity in RCC and a rational biological option for treatment of OCCA. A 60-year-old woman presented with recurrent and refractory stage IA OCCA, after 9 years of remission. Sunitinib was initiated as fifth-line chemotherapy, associated with cystic degeneration of liver metastasis and a short downward trend in her CA125 level. Recurrent and refractory OCCA may respond to Sunitinib. Clinical trials are needed to objectively confirm these findings, as benefit may be limited in patients with extensively pretreated tumors