Spontaneous hypoglycemia: should we mind the gap? Long-term follow-up of healthy people who met Whipple's triad criteria.

CONTEXT: Patients discharged as "healthy" with the symptoms of spontaneous hypoglycemia, commonly known as Whipple's triad, need more attention. OBJECTIVE: Characterization and long-term follow-up of symptom development in patients with spontaneous hypoglycemia discharged as "healthy". The objective was to ascertain whether any conditions related to the symptoms were diagnosed during the follow-up period. METHODS: Retrospective analysis of patient data and evaluation of a specific questionnaire on the development of symptoms of spontaneous hypoglycemia. In addition, patient questionnaires were evaluated and primary care physicians were asked about possible diseases not recorded at baseline that occurred during the follow-up period. SETTING: Center for Endocrinology, Diabetology, and Osteology at the University Hospital Marburg, Inpatient Department, Germany. PATIENTS: All patients who presented to our center for the 72-hour fast between 2005 and 2018 and were discharged without an internal medicine diagnosis were included. INTERVENTIONS: Survey by questionnaire, via telephone interview. MAIN OUTCOME MEASURES: Patient-reported information on current symptoms compared to original symptoms, diagnosis of insulinoma or diabetes mellitus during follow-up, matched with primary care physician data, and metabolic and biometric data such as body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA IR), insulin sensitivity Matsuda Index (ISI-M), and area under the curve. RESULTS: A total of 41 datasets were evaluated at baseline and 38 patients were followed for an average of approximately 10 years. In total, 61% of respondents still reported the same symptoms as at baseline. No insulinoma was missed in these patients. Only two of the 38 patients developed diabetes mellitus. CONCLUSION: The high percentage of patients who are discharged as "healthy" and still have symptoms after many years is disturbing. It is possible that the symptoms are not due to low blood glucose. We urge caution with use of the term "healthy". We advocate a multidisciplinary therapeutic approach after an organic cause of hypoglycemia has been ruled out. Psychosomatic treatment seems to be useful. In addition, more research should be conducted on this topic.

Axillary lymph node status and invasive lobular breast cancer : Analysis of the Clinical Tumor Register of the AGO Austria.

BACKGROUND: Invasive lobular carcinoma (ILC) represents the second most common type of invasive breast cancer (BC). Although ILC generally have good prognostic properties (positive estrogen receptor, ER, low tumor grade), they are generally diagnosed at a more advanced stage. The data on the axillary lymph node status in ILC compared to invasive ductal carcinoma (IDC) are considered controversial. Therefore, the aim of this study was to compare the pathological node stage (pN) between ILC and IDC in an Austria-wide register. METHODS: Data of the Clinical Tumor Register (Klinisches TumorRegister, KTR) of the Austrian Association for Gynecological Oncology (AGO) were retrospectively analyzed. Patients with primary early BC, invasive lobular or ductal, diagnosed between January 2014 and December 2018, and primary surgery were included. A total of 2127 tumors were evaluated and compared in 2 groups, ILC n = 303, IDC n = 1824. RESULTS: A total of 2095 patients were analyzed in the study. In the multivariate analysis, pN2 and pN3 were observed significantly more frequently in ILC compared with IDC (odds ratio, OR 1.93; 95% confidence interval, CI 1.19-3.14; p = 0.008 and OR 3.22; 95% CI: 1.47-7.03; p = 0.003; respectively). Other factors associated with ILC were tumor grades 2 and 3, positive ER, and pathological tumor stage (pT) 2 and pT3. In contrast, concomitant ductal carcinoma in situ, overexpression of the human epidermal growth factor receptor 2 (HER2), and a moderate and high proliferation rate (Ki67) were found less frequently in ILC. CONCLUSION: The data show an increased risk of extensive axillary lymph node metastasis (pN2/3) in ILC.

Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial.

BACKGROUND: The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL. METHODS: This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4-6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535. FINDINGS: 110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion -0·016, 95% CI -0·15 to -0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups. INTERPRETATION: Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment. FUNDING: Austrian Science Fund and Austrian Gynaecological Oncology group.

Austria-based real-world data on bevacizumab in newly diagnosed epithelial ovarian cancer.

BACKGROUND: Front-line maintenance therapy with bevacizumab demonstrates high efficacy and safety in epithelial ovarian cancer, as already shown in large phase III trials; however, the corresponding study populations are often not fully representative of patients in clinical routine. In this Austria-based multicenter study, we aimed to explore the real-world outcomes of bevacizumab use in front-line treatment of ovarian cancer, including patients with comorbidities and poor performance status. PATIENTS: This study is an open label single arm multicenter noninterventional trial and included patients with newly diagnosed advanced epithelial ovarian cancer, who were treated with platinum-based chemotherapy and were candidates for receiving bevacizumab according to the product label. Data collection started in the third quarter of 2012 and ended in the third quarter of 2018. RESULTS: In this study 50 patients were included and 575 adverse events were reported for 90% of the patients. The majority of the adverse events were mild (47%) or moderate (37%). The most common adverse events were hypertension (60%), anemia (48%), leukopenia (42%), thrombocytopenia (36%), neutropenia (36%) and proteinuria (26%). A relation to bevacizumab was documented only for 10.3% of all adverse events. In almost 50% of all adverse events, no intervention was needed and bevacizumab treatment had to be interrupted only in 3.3% of all adverse events. The median progression-free survival was 1.3 years (95% CI 1.1-1.8). CONCLUSION: The routine use of front-line bevacizumab for advanced ovarian cancer is associated with high efficacy comparable with that obtained in randomized phase III clinical trials; however, hypertension and proteinuria were reported significantly more often in our Austria-based real-world population.

Inmunización en personal de salud / Immunization in health care workers

Resumen Justificación: la inmunoprofilaxis del personal sanitario conlleva múltiples propósitos que engloban tanto la protección de los pacientes como de los funcionarios mismos, y redunda en un claro beneficio para el empleador. En particular, la protección de pacientes inmunocomprometidos y con bajo potencial de desarrollar respuestas vacunales efectivas es de suma importancia. Programas de inmunización sistemática del personal de salud pueden reducir el riesgo de enfermedad, minimizar el impacto de accidentes laborales con materiales infecciosos y mantener la fuerza de trabajo indemne en los centros médicos durante los brotes estacionales de algunas infecciones. Objetivos: concatenar los esquemas de vacunación recomendados actualmente para los funcionarios que laboran en centros de salud y ofrecer una guía adaptada a la realidad epidemiológica nacional. Métodos: se efectuó una revisión no sistemática de bibliografía médica publicada en Internet entre 1990 y 2018, concerniente a vacunación de empleados sanitarios. De igual manera, se compararon los respectivos esquemas de inmunización vigentes en América y Europa. Conclusiones: la trasmisión de enfermedades infecciosas en los centros sanitarios es un problema de salud pública frecuentemente no reconocido, pero sustancial, que pone en riesgo tanto a los usuarios como al personal de estas instituciones. La inmunización de los trabajadores sanitarios es una estrategia fundamental para prevenir y contener la diseminación de agentes infecciosos a nivel hospitalario. Esta medida puede crear "inmunidad de rebaño" para proteger a pacientes y funcionarios que no se hayan vacunado o no puedan generar inmunidad suficiente contra determinados patógenos. Además, la vacunación de los empleados de salud constituye un punto de referencia para motivar las inmunizaciones en los demás segmentos de la población.

Abstract Background: Immune prophylaxis in health care personnel induces multiple positive effects that include protection for patients, as well as for employees and results with a clear benefit for the employers. Especially in immunological compromised patient groups and individuals who present a diminished potential to develop immunity to vaccination, contagion prevention is of highest importance. Systematic immunization programs can help to lower disease risks, minimize impact of occupational accidents related to handling of contagious materials and maintain the intactness of workforce in medical centers during periods of seasonal infection outbreaks. Objectives: this article resumes the present recommended schemes for vaccination of health care personnel and concludes them in a guideline adapted to the country´s epidemiologic reality. Methods: a non-systematic revision of medical literature related to immunization of health care personnel, published online between 1990 and 2018, was realized. In the same manner, a comparison of active vaccination schemes existing in Europe and the United States of America has been executed. Conclusion: the transmission of infectious diseases in health care installations represents a frequently ignored problem which substantially elevates the infection risk of patients as well as of health care personnel. The vaccination of health care personnel represents the easiest to imply and most effective strategy to inhibit this kind of transmission of infectious diseases. As well, this measure can create a "herd immunity" protecting patients and health care personnel who are not vaccinated or in conditions where they can not develop sufficient immunity against infectious agents. Furthermore, the immunization of the health care workers represents a reference and an example of motivation to other parts of the population.

Risk of endometrial cancer in asymptomatic postmenopausal patients with thickened endometrium: data from the FAME-Endo study: an observational register study.

PURPOSE: To evaluate the risk for endometrial cancer (EC) in a large series of asymptomatic patients with thickened endometrium at ultrasound examination based on previously published data of a theoretical cohort. METHODS: In a prospective register study, a total of 1024 women with thickened endometrium in ultrasound examination undergoing histological diagnosis by dilation, hysteroscopy and curettage were evaluated. 124 patients were excluded due to current medication with tamoxifen and/or presence of HNPCC leaving 900 patients for further analysis. RESULTS: Mean [standard deviation (SD)] age of patients was 65.6 (8.6) years. Mean (SD) endometrial thickness was 11.9 (5.8) mm. 32 and 6 cases of EC and complex endometrial hyperplasia with atypia were found, respectively. In the univariate analysis, a statistically significant association between endometrial thickness, current use of antihypertensive medication, number of deliveries, and the presence of endometrial fluid in preoperative vaginal ultrasound (p < 0.05) with EC was found. A multivariate logistic regression model incorporating these parameters showed a statistically significant independent association of endometrial thickness, number of deliveries, and the presence of endometrial fluid in preoperative vaginal ultrasound (p < 0.05), but not current use of antihypertensive medication, with EC. Using a cut-off of the endometrial thickness of > 11 mm, the risk for "EC alone" and "EC and complex endometrial hyperplasia with atypia combined" was found to be 6.7% and 7.9%, respectively. CONCLUSIONS: Our data compare favorably to a theoretical cohort suggesting a clinically reasonable cut-off of > 11 mm endometrial thickness to discriminate between "normal" and "pathological". The data regarding "risk for endometrial cancer" can be used for counseling affected women.

Vacunación en adultos / Vaccination in adults

ResumenIntroducción:cada año, miles de adultos mueren por causa de enfermedades prevenibles mediante vacunación. Sin embargo, la aplicación de vacunas en adultos es muy baja a nivel mundial por múltiples razones, incluyendo los altos costos de implementación.Objetivos:discutir las recomendaciones nacionales e internacionales de inmunización de personas mayores de 18 años, incluyendo las poblaciones con alto riesgo de adquirir infecciones inmunoprevenibles y resumirlas en un esquema recomendado para vacunación de adultos en general, y personas con elevado nivel de riesgo.Métodos:se efectuó una revisión no sistemática de bibliografía médica y científica publicada entre 2000 y 2017, concerniente a vacunación en adultos. Así mismo, se compararon los esquemas de inmunización vigentes en América y Europa.Conclusiones:las recomendaciones para vacunación en adultos se basan principalmente en edad, condiciones médicas subyacentes, estilo de vida, inmunizaciones previas, características epidemiológicas locales y viajes. La necesidad de aplicar un esquema de vacunación adecuado a la población general y a poblaciones con factores de riesgo, representa una medida de gran importancia en un sistema de salud funcional. En este sentido, la adecuada asesoría e información provenientes del personal de salud constituyen un predictor clave en la inmunización de adultos.

AbstractIntroduction:Every year thousands of adults die from vaccine preventable disease worldwide. Nevertheless, the vaccine application rates maintain in relative low levels for multiple reason, including high costs of the implementation of vaccination programs.Objectives:Discuss national and international existing immunization schemes for adult persons, including high risk populations for the acquisition of immune preventable infections and resume this knowledge in vaccination schemes for adults in general and high risk populationMethods:A nonsystematic revision of medical and scientific literature related to adult vaccination topics from the years 2000 to 2017 was performed. As well, a comparison between actual vaccination schemes from American and European countries has been realized.Conclusion:Vaccination recommendations are based in multiple factors like age, individual medical history, lifestyle, formerly applied vaccinations, local epidemiologic criteria end traveling activity.The application of adequate vaccination scheme for both, adults in general and an adaptation for persons with elevated risk factors, represents a crucial element for effective health system. Therefore, the adequate assessing and information provided by medical personnel represents a key factor in successful vaccination and disease prevention.

AGO Austria recommendation on screening and diagnosis of Lynch syndrome (LS).

PURPOSE: This manuscript reports the consensus recommendations on screening and diagnosis of Lynch syndrome (LS) in patients with endometrial or ovarian cancer as well as on possible preventive measures in effectively LS-diagnosed women. The recommendations are issued by the Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) of the Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) after consultation of the most recent and relevant literature and following deliberation by the Genetic Task-Force convoked May, 2015 by the AGO Council. RESULTS AND CONCLUSION: The Austrian AGO recommends immunohistochemical tissue screening for type-I and type-II endometrial cancers in all patients below the age of 70 years, and for all endometrioid and clear-cell ovarian cancers independently of the patient's age. If needed immunohistochemistry should be complemented by tissue MLH1 promotor hypermethylation testing and/or microsatellite instability (MSI) analysis. The diagnosis LS requires confirmation through identification of a germline mutation by a molecular genetic examination in the mismatch repair genes using the patient's blood. This should be performed without preceding tissue screening when in LS-associated cancer patients the family history fulfills the Amsterdam II or the revised Bethesda criteria. In LS-diagnosed women, the age for prophylactic surgery should be set flexibly based on an informed consent. Regarding the monitoring of these women, chemo-preventive measures as well as screening procedures either to avoid or to early detect LS-related tumors are discussed with a special light on their specific limitations.

Vacunación de pacientes adultos receptores de trasplante de células madre hematopoyéticas: Perspectiva de Costa Rica / Vaccination of adult patients receiving hematopoietic stem cell transplantation: Perspective of Costa Rica

In this article the present recommendations for immunization of adult patients who received hematopoietic stem cell transplantation -a common procedure in therapy of many types of hematological diseases and serious inborn defects of the immune system- are reviewed and discussed. Patients that undergo this kind of transplantation procedure exhibit, compared to the general population, an elevated susceptibility of immune-preventable infections, due to loss of the humoral and cellular protective immunity. A revaccination strategy for transplanted patients can result in a significant diminution of morbidity and mortality related to the treatment of these diseases. Few data are published about the duration and magnitude of the vaccination response in this specific population of patients. Moreover, deviation from international guidelines recommendations for post-transplant immune prophylaxis can be observed frequently, partly as a result of the absence of specific vaccines in some countries. Multiple factors as intensity of the pharmacologic immune suppression, myeloablative regimen, administration of monoclonal and polyclonal antibodies, duration of the post-transplant period or the presence of graft-versus-host disease (GVHD), can influence the immune response and establish special considerations for certain biological agents, as observed in case of living attenuated virus composed vaccines. This conditions are responsible for the fact that an optimal time point for vaccination of transplanted patients remains not clearly defined. More specific studies about the underlying immunological mechanisms during immunocompromised periods are necessary to understand better the immunogenicity and security of existing vaccines. The development of innovative vaccines as well can induce certain advances in the post-transplant therapy.

El presente artículo revisa las recomendaciones actuales para la inmunización de pacientes adultos que han recibido trasplante de células madre hematopoyéticas, procedimiento común en la terapia de muchas patologías hematológicas y defectos congénitos del sistema inmune. Los pacientes que reciben este tipo de tratamiento son más susceptibles a infecciones inmunoprevenibles que la población general debido a la pérdida de la inmunidad protectora tanto humoral como celular con posterioridad al trasplante. De esta manera, la revacunación de los receptores de trasplante representa una estrategia importante para reducir la morbilidad y mortalidad asociadas con esas enfermedades. Sin embargo, se conoce poco sobre la duración y magnitud de la respuesta inmunológica generada por las vacunas en esta población. Además, aunque existen guías internacionales consensuadas en inmunoprofilaxis post-trasplante, frecuentemente ocurren desviaciones en las prácticas recomendadas por múltiples motivos, incluyendo la no disponibilidad de ciertas vacunas en algunos sistemas de salud. Factores como la intensidad de la inmunosupresión farmacológica, el régimen mieloablativo empleado, la administración de anticuerpos monoclonales y policlonales, la duración de la fase neutropénica en el período posterior al trasplante y la presencia de enfermedad injerto versus hospedero (graft-versus-host disease, GVHD) pueden influenciar la respuesta inmunitaria y establecer consideraciones especiales para ciertos agentes como es el caso de las vacunas compuestas por virus vivos atenuados. Estas condiciones contribuyen a que el momento oportuno de inicio de las inmunizaciones en los receptores de trasplante aún no se encuentre bien definido. Se requieren más estudios específicos acerca de los mecanismos inmunológicos subyacentes durante los estados de inmunocompromiso para entender mejor la inmunogenicidad y seguridad de las vacunas existentes en dichos contextos. El desarrollo de vacunas innovadoras puede también inducir avances en la terapia post-trasplante.

[Vaccination of adult patients receiving hematopoietic stem cell transplantation: Perspective of Costa Rica]. / Vacunación de pacientes adultos receptores de trasplante de células madre hematopoyéticas: Perspectiva de Costa Rica.

In this article the present recommendations for immunization of adult patients who received hematopoietic stem cell transplantation -a common procedure in therapy of many types of hematological diseases and serious inborn defects of the immune system- are reviewed and discussed. Patients that undergo this kind of transplantation procedure exhibit, compared to the general population, an elevated susceptibility of immune-preventable infections, due to loss of the humoral and cellular protective immunity. A revaccination strategy for transplanted patients can result in a significant diminution of morbidity and mortality related to the treatment of these diseases. Few data are published about the duration and magnitude of the vaccination response in this specific population of patients. Moreover, deviation from international guidelines recommendations for post-transplant immune prophylaxis can be observed frequently, partly as a result of the absence of specific vaccines in some countries. Multiple factors as intensity of the pharmacologic immune suppression, myeloablative regimen, administration of monoclonal and polyclonal antibodies, duration of the post-transplant period or the presence of graft-versus-host disease (GVHD), can influence the immune response and establish special considerations for certain biological agents, as observed in case of living attenuated virus composed vaccines. This conditions are responsible for the fact that an optimal time point for vaccination of transplanted patients remains not clearly defined. More specific studies about the underlying immunological mechanisms during immunocompromised periods are necessary to understand better the immunogenicity and security of existing vaccines. The development of innovative vaccines as well can induce certain advances in the post-transplant therapy.

Prophylactic long-acting granulocyte-colony stimulating factors (G-CSF) in gynecologic malignancies: an oncologic expert statement.

We reviewed the status of the use of the prophylactic long-acting granulocyte colony-stimulating factors (G-CSFs) pegfilgrastim and lipegfilgrastim in gynecologic malignancies. Long-acting G-CSFs should not be used in weekly regimens. Filgrastim is not indicated in patients with febrile and/or severe neutropenia after administration of long-acting G-CSF in the same cycle. One study has shown a moderate effect on febrile neutropenia of ciprofloxacin when co-administered with pegfilgrastim. There is broad evidence from meta-analyses that pegfilgrastim effectively reduces severe neutropenia. In parallel, its adverse effects have been studied extensively. All-cause mortality was significantly reduced by pegfilgrastim. The glycopegylated long-acting G-CSF, lipegfilgrastim has demonstrated antineutropenic efficacy similar to that of pegfilgrastimin in one breast cancer study. In another pivitol non-small cell lung cancer study, impaired survival was observed in the lipegfilgrastim group during the first 30 days of study. The European Medicines Agency claimed more profound safety data to be provided for lipegfilgrastim by 2017.

AGO Austria recommendations for genetic testing of patients with ovarian cancer.

In Austria, 700 women are diagnosed every year with ovarian carcinoma. Approximately 15% of the patients with epithelial ovarian cancer have a germline mutation in the BRCA1 or BRCA2 genes. The increased incidence of breast and/or ovarian cancer in genetically related family members has given rise to the term "hereditary breast and ovarian cancer syndrome" (HBOC). Some 25-55% of these in-family diseases are attributed to germline mutations of BRCA1 or BRCA2, and approximately 5-10% to other known tumor predisposition syndromes. The remaining persons may carry mutations in as yet unidentified genes. HBOC caused by BRCA1 and BRCA2 mutations is an autosomal dominant disorder with high penetrance. BRCA1 and BRCA2 encode for so-called tumor suppressor proteins. Inherited functional mutations of these genes cause loss of function of the respective allele. Loss of function of the second allele causes complete loss of the corresponding protein and facilitates the development of a malignancy.The Association of Gynecologic Oncology recommends that testing for a germline mutation in BRCA1 or BRCA2 should be offered to all patients with epithelial ovarian cancer. When mutations in BRCA1, BRCA2, or other cancer-susceptibility genes have been identified, patients with ovarian carcinoma can be treated with new, innovative therapies. This recommendation is intended as a standard guideline for genetic testing of patients with an ovarian carcinoma.

Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle.

Gonadotropin-releasing hormone (GnRH) controls mammalian reproduction via the hypothalamic-pituitary-gonadal (hpg) axis, acting on gonadotrope cells in the pituitary gland that express the GnRH receptor (GnRHR). Cells expressing the GnRHR have also been identified in the brain. However, the mechanism by which GnRH acts on these potential target cells remains poorly understood due to the difficulty of visualizing and identifying living GnRHR neurons in the central nervous system. We have developed a mouse strain in which GnRHR neurons express a fluorescent marker, enabling the reliable identification of these cells independent of the hormonal status of the animal. In this study, we analyze the GnRHR neurons of the periventricular hypothalamic nucleus in acute brain slices prepared from adult female mice. Strikingly, we find that the action potential firing pattern of these neurons alternates in synchrony with the estrous cycle, with pronounced burst firing during the preovulatory period. We demonstrate that GnRH stimulation is sufficient to trigger the conversion from tonic to burst firing in GnRHR neurons. Furthermore, we show that this switch in the firing pattern is reversed by a potent GnRHR antagonist. These data suggest that endogenous GnRH acts on GnRHR neurons and triggers burst firing in these cells during late proestrus and estrus. Our data have important clinical implications in that they indicate a novel mode of action for GnRHR agonists and antagonists in neurons of the central nervous system that are not part of the classical hpg axis.

Carboplatin and nonpegylated liposomal doxorubicin in primary advanced or recurrent endometrial cancer: a phase 2 trial conducted by AGO Austria.

OBJECTIVE: Recurrent/advanced endometrial carcinoma carries a poor prognosis. Chemotherapy usually consists of cisplatin/doxorubicin and paclitaxel or the doublet of carboplatin and paclitaxel.We report on final results of the Austrian phase 2 AGO trial of nonpegylated doxorubicin citrate and carboplatin in 39 patients with primary advanced or relapsed endometrial cancer. The main primary end point is response rate, and the main secondary end point is feasibility. METHODS: Thirty-nine patients received 60 mg/m nonpegylated doxorubicin citrate and carboplatin (area under the curve, 5) every 3 weeks for 6 to 9 cycles or until progression. Best response during therapy, progression-free survival, and the toxicity profile were recorded. RESULTS: Thirteen patients (33%) had primary advanced disease, and 26 patients (67%) had recurrent disease. Seventy-five percent of the tumors were adenocarcinomas, 15% were serous carcinomas, and 5% were clear cell and mixed müllerian carcinomas. We observed 1 complete response (3%) and 16 partial responses (41%) in the intention-to-treat population. The median progression-free survival was 7.2 months, and the median overall survival was 14.7 months. Overall, 177 cycles were administered; the mean number of cycles per patient was 4.5. Ten percent of patients received 9 cycles of chemotherapy, and 44% of patients received 6 cycles of chemotherapy. Grade 3/4 neutropenia occurred in 17%, grade 3/4 anemia in 5%, and grade 3/4 thrombopenia in 12% of the cycles. In 6% of the cycles, febrile neutropenia was noticed. Grade 3/4 nausea was seen in 5% of cycles. One patient (3%) experienced cardiac toxicity and had a reduction in the left ventricular ejection fraction to below 50%. CONCLUSIONS: The reported combination demonstrates considerable activity and should be evaluated further.

Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: analysis of the CALYPSO trial.

OBJECTIVE: The role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis. METHODS: Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery. RESULTS: Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001). CONCLUSION: SCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential.

Imaging calcium responses in GFP-tagged neurons of hypothalamic mouse brain slices.

Despite an enormous increase in our knowledge about the mechanisms underlying the encoding of information in the brain, a central question concerning the precise molecular steps as well as the activity of specific neurons in multi-functional nuclei of brain areas such as the hypothalamus remain. This problem includes identification of the molecular components involved in the regulation of various neurohormone signal transduction cascades. Elevations of intracellular Ca(2+) play an important role in regulating the sensitivity of neurons, both at the level of signal transduction and at synaptic sites. New tools have emerged to help identify neurons in the myriad of brain neurons by expressing green fluorescent protein (GFP) under the control of a particular promoter. To monitor both spatially and temporally stimulus-induced Ca(2+) responses in GFP-tagged neurons, a non-green fluorescent Ca(2+) indicator dye needs to be used. In addition, confocal microscopy is a favorite method of imaging individual neurons in tissue slices due to its ability to visualize neurons in distinct planes of depth within the tissue and to limit out-of-focus fluorescence. The ratiometric Ca(2+) indicator fura-2 has been used in combination with GFP-tagged neurons. However, the dye is excited by ultraviolet (UV) light. The cost of the laser and the limited optical penetration depth of UV light hindered its use in many laboratories. Moreover, GFP fluorescence may interfere with the fura-2 signals. Therefore, we decided to use a red fluorescent Ca(2+) indicator dye. The huge Stokes [corrected] shift of fura-red permits multicolor analysis of the red fluorescence in combination with GFP using a single excitation wavelength. We had previously good results using fura-red in combination with GFP-tagged olfactory neurons. The protocols for olfactory tissue slices seemed to work equally well in hypothalamic neurons. Fura-red based Ca(2+) imaging was also successfully combined with GFP-tagged pancreatic ß-cells and GFP-tagged receptors expressed in HEK cells. A little quirk of fura-red is that its fluorescence intensity at 650 nm decreases once the indicator binds calcium. Therefore, the fluorescence of resting neurons with low Ca(2+) concentration has relatively high intensity. It should be noted, that other red Ca(2+)-indicator dyes exist or are currently being developed, that might give better or improved results in different neurons and brain areas.

Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain.

GnRH signaling regulates reproductive physiology in vertebrates via the hypothalamic-pituitary-gonadal axis. In addition, GnRH signaling has been postulated to act on the brain. However, elucidating its functional role in the central nervous system has been hampered because of the difficulty in identifying direct GnRH signaling targets in live brain tissue. Here we used a binary genetic strategy to visualize GnRH receptor (GnRHR) neurons in the mouse brain and started to characterize these cells. First, we expressed different fluorescent proteins in GnRHR neurons and mapped their precise distribution throughout the brain. Remarkably, neuronal GnRHR expression was only initiated after postnatal day 16, suggesting peri- and postpubertal functions of GnRH signaling in this organ. GnRHR neurons were found in different brain areas. Many GnRHR neurons were identified in areas influencing sexual behaviors. Furthermore, GnRHR neurons were detected in brain areas that process olfactory and pheromonal cues, revealing one efferent pathway by which the neuroendocrine hypothalamus may influence the sensitivity towards chemosensory cues. Using confocal Ca(2+) imaging in brain slices, we show that GnRHR neurons respond reproducibly to extracellular application of GnRH or its analog [D-TRP(6)]-LH-RH, indicating that these neurons express functional GnRHR. Interestingly, the duration and shape of the Ca(2+) responses were similar within and different between brain areas, suggesting that GnRH signaling may differentially influence brain functions to affect reproductive success. Our new mouse model sets the stage to analyze the next level of GnRH signaling in reproductive physiology and behavior.

Clinical consequences of the Calypso trial showing superiority of PEG-liposomal doxorubicin and carboplatin over paclitaxel and carboplatin in recurrent ovarian cancer: results of an Austrian gynecologic oncologists' expert meeting.

The Calypso trial showed an improved progression-free survival with PEG-liposomal doxorubicin (PLD) and carboplatin (P) as compared with the standard regimen paclitaxel (PCLTX) and P in the second- or third-line treatment of platinum-sensitive epithelial ovarian cancer [1]. A panel of Austrian gynecologic oncologists discussed the clinical consequences of the data from the Calypso study for the routine practice. PLD + P had a significantly lower rate of alopecia and neuropathy than the taxane regimen, both toxicities which compromise the quality of life. Due to possible significant thrombocytopenia, the blood counts of patients undergoing PLD + P therapy should be monitored weekly. Patients receiving PLD/P are at higher risk of nausea and vomiting. Palmoplantar erythrodysesthesia (hand-foot syndrome) is a significant toxicity of PLD + P most prevalent after the third or fourth cycle. Prophylaxis consists of avoiding pressure on feet and hands and other parts of the body. Similarly, prophylaxis of mucositis seems important and includes avoiding consumption of hot, spicy and salty foods and drinks. Mouth dryness should be avoided. Premedication with antiemetics and dexamethasone dissolved in 5% glucose is done to prevent hypersensitivity to PLD. In conclusion, the therapeutic index is more favorable for PLD + P than for PCTX + P.

Pros and cons of intraperitoneal chemotherapy in the treatment of epithelial ovarian cancer.

Development of the pros and cons of intraperitoneal (IP) chemotherapy in the treatment of epithelial ovarian cancer based on the most prominent data published on the evolution of IP chemotherapy and on experience with this therapeutic strategy in clinical routine. The literature published on IP chemotherapy in ovarian cancer between 1970 and 2008 was identified systematically by computer-based searches in MEDLINE and the Cochrane Library. Furthermore, a preliminary analysis of data recorded during an observational nationwide multicenter study of the Austrian AGO on IP-IV chemotherapy using the GOG-172 treatment regimen was performed. The literature review unequivocally revealed a significantly greater toxicity for IP than for intravenous (IV) cisplatin-based chemotherapy. However, according to a Cochrane meta-analysis, IP-IV administration of chemotherapy is associated with a 21.6% decrease in the risk for death. In agreement with earlier reports, the most frequently mentioned side-effects in the Austria-wide observational study were long-lasting neurotoxicity, abdominal pain, fatigue, gastrointestinal and metabolic toxicities, and catheter-related complications. Most of these toxicities were identified as mirroring the toxicity profile of high-dose IV cisplatin (>or=100 mg/m(2)). In some patients, the classic IP-IV regimen with cisplatin/paclitaxel was changed to an alternative schedule comprising carboplatin AUC 5 (d1) and weekly paclitaxel 60 mg/m(2) (d1, 8, 15) completely administered via the IP route. This treatment was better tolerated and quality of life was significantly less compromised. However, neutropenia and thrombocytopenia were the limiting side-effects of this IP regimen. In cases where optimal cytoreduction with residual disease