Unmet clinical needs in women with polycystic ovary syndrome in regard to mental health: a cross-sectional study.

PURPOSE: Polycystic ovary syndrome (PCOS) management has hardly been standardized until recent years. Despite the existence of a detailed, evidence-based guideline published by the European Society of Human Reproduction and Embryology (ESHRE), it remains unclear to what extent healthcare providers adhere to this guideline. Our aim is to evaluate the gynaecological medical care provided in women with PCOS, particularly in terms of mental health, from the patients' perspective. METHODS: For this cross-sectional online cohort study in women with PCOS, we designed a standardized, non-validated questionnaire covering aesthetic aspects, metabolism, menstrual cycle, reproduction, mental health, and prevention of chronic non-communicable diseases. RESULTS: Among 1879 participants, various mental health aspects were reported: body image (n = 1879), eating patterns/habits (n = 1878), and emotional well-being (n = 1874). Although nearly all women (99.7%) reported complaints on at least one session of mental health, consultation rates were low (body image 9.7%, eating patterns/habits 16.6%, emotional well-being 4.4%). Mean satisfaction with counselling on the different domains varied from moderate to fairly satisfying, with scores of 56.0 points (SD 31.7), 53.5 points (SD 32.0), and 63.7 points (SD 30.2), respectively. More complaints were associated with lower satisfaction. The overall satisfaction with the management provided by the healthcare practitioner (HCP) was low, averaging 36.5 points (SD 29.7). Consequently, most women wished for more counselling (58.9%). CONCLUSION: Women affected by PCOS are not properly managed according to ESHRE guideline in regard to mental health issues. Overall consultation rates and corresponding satisfaction with management were poor, highlighting the need for significant improvements in healthcare provision.

Unmet Clinical Needs in Women with Aesthetic Manifestations of Polycystic Ovary Syndrome: A Cross-Sectional Study.

Background: Polycystic ovary syndrome (PCOS) management has hardly been standardized until recent years. There is an accurate, evidence-based guideline published by the European Society of Human Reproduction and Embryology (ESHRE). However, it remains unclear to which extent, if at all, the guideline is followed by health care providers. The aim was to explore the subjectively perceived quality of gynecological medical care in women with PCOS suffering from aesthetic complaints. Materials and Methods: A nonvalidated questionnaire was constructed in a standardized manner covering the domains: aesthetic aspects, metabolism, menstrual cycle, reproduction, mental health, and prevention of chronic noncommunicable diseases. Results: A total of 1960 participants with aesthetic complaints, such as acne (66.2%), alopecia (43.9%), hirsutism (77.9%), or overweight/obesity (72.3%) were included. The percentage of women being counseled was low (acne 20.3%, alopecia 12.9%, hirsutism 17.5%, overweight/obesity 36.2%). Satisfaction with counseling was moderate (40.4-44.1 points). Many women tried at least one therapeutic method (75.9%), whereas only a few were counseled for therapy (acne 27.0%, alopecia 24.6%, hirsutism 24.0%, overweight/obesity 18.8%) with moderate satisfaction for hyperandrogenism (mean 55.1-59.5 points) and good satisfaction for overweight/obesity (mean 60.8 points). Overall satisfaction was rated with a mean of 30.5 points (standard deviation 27.1) on a scale from 0 to 100 and thus considered "not satisfied." Fewer complaints were significantly correlated with higher satisfaction. Most women wished for more counseling (80.8%), as well as more diagnostic (63.2%) and therapeutic options (70.2%). Conclusions: Women affected by PCOS are not properly managed according to the ESHRE guideline. Indeed, this guideline recommends comprehensive history and physical examination for clinical hyperandrogenism as well as holistic approaches in therapy, including education and counseling of patients. Still, overall consultation rates and satisfaction were poor.

The Impact of Diet on Urinary Risk Factors for Cystine Stone Formation.

Despite the importance of dietary management of cystinuria, data on the contribution of diet to urinary risk factors for cystine stone formation are limited. Studies on the physiological effects of diet on urinary cystine and cysteine excretion are lacking. Accordingly, 10 healthy men received three standardized diets for a period of five days each and collected daily 24 h urine. The Western-type diet (WD; 95 g/day protein) corresponded to usual dietary habits, whereas the mixed diet (MD; 65 g/day protein) and lacto-ovo-vegetarian diet (VD; 65 g/day protein) were calculated according to dietary reference intakes. With intake of the VD, urinary cystine and cysteine excretion decreased by 22 and 15%, respectively, compared to the WD, although the differences were not statistically significant. Urine pH was significantly highest on the VD. Regression analysis showed that urinary phosphate was significantly associated with cystine excretion, while urinary sulfate was a predictor of cysteine excretion. Neither urinary cystine nor cysteine excretion was affected by dietary sodium intake. A lacto-ovo-vegetarian diet is particularly suitable for the dietary treatment of cystinuria, since the additional alkali load may reduce the amount of required alkalizing agents.

Attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons: a cross-sectional study.

PURPOSE: To assess the attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons. METHODS: Cross-sectional electronic survey in 248 Swiss women aged 15-35 years, nationally representative for educational level. RESULTS: Most women did not worry about an age-related fertility decline. Two-thirds of women would consider using hormone therapy (HT) for menopausal symptom relief although concerns about side effects and risks were still high. Acceptance of cryopreservation of oocytes (19%) or ovarian tissue (13%) for postponing fertility or menopause was generally low, but increased (37%) if both goals could be achieved with one surgery. Cryopreservation of ovarian tissue for postponing menopause was acceptable for 22% of women. Not having a suitable partner until age 35 increased the likelihood of considering postponing fertility by cryopreservation (p < 0.001) and had a stronger impact on that decision than the factor "pursuing a career" (p < 0.001). CONCLUSION: More education on age-related fertility decline, menopause and HT (benefit-risk ratio) is needed. Furthermore, the political and socioeconomic discussion should focus on women's needs, especially on compatibility of career and family.

Serum and follicular fluid testosterone concentrations do not correlate, questioning the impact of androgen supplementation on the follicular endocrine milieu.

Basic research into a possible link between serum and follicular fluid androgen concentrations to detemine whether androgen supplementation in low responders affects follicular endocrine milieu is still lacking. Ninety-seven women (aged 28-43 years) undergoing one natural IVF cycle without any hormone stimulation were analysed. Serum and follicular fluid were collected at the time of follicle aspiration, and the concentrations of LH, total testosterone, oestradiol, dehydroepiandrosterone and anti-Mullerian hormone (AMH) were determined. Serum LH (P = 0.003) and AMH (P = 0.026) concentrations, and follicular fluid AMH (P = 0.015) decreased with increasing age. Within follicular fluid, total testosterone was correlated with oestradiol (P < 0.001) and AMH (P = 0.010); LH correlated with AMH (P = 0.005). Correlation analysis of serum and follicular fluid hormone concentrations revealed that LH, oestradiol and AMH correlated (P < 0.001), whereas testosterone did not. Testosterone serum concentrations did not correlate with other follicular fluid hormones, such as dehydroepiandrosterone, oestradiol and AMH, whereas serum LH correlated with follicular flulid AMH (P < 0.008). Follicular fluid hormone concentrations seem to be independent from serum testosterone. Therefore, it is questionable whether an increase in serum testosterone concentration by androgen supplementation could improve the follicular endocrine milieu.

[(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study.

PURPOSE: To characterise efficacy and safety of (177)Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). PATIENTS AND METHODS: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with (177)Lu-DOTATOC were analysed retrospectively. Subjects were administered (177)Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. RESULTS: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. CONCLUSION: (177)Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with impaired bone marrow or renal function, which reflects a uniquely low uptake of (177)Lu-DOTATOC by normal organs.

Centre-independent detection of non-small cell lung cancer (NSCLC) by means of classification with receiver operating characteristic (ROC)-based data transformation.

The diagnosis of non-small cell lung cancer (NSCLC) by using tumour markers needs to be improved and standardised in order to compare marker profiles from different centres. A centre-independent tool based on receiver operating characteristics (ROC) curves instead of cut-off-based approaches for NSCLC diagnosis was established. Carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) were measured in 326 NSCLC patients and 160 patients with benign lung diseases (Heidelberg, HD) and compared to 158 NSCLC patients and 128 controls from an occupational medicine high-risk cohort (Giessen, GI). The cohorts differed in tumour-stages, marker cut-offs and therefore in sensitivity for NSCLC detection. Sensitivity for CYFRA 21-1 (most sensitive marker) was 65% GI, 35% HD, for CEA: 43% GI and 35% HD. Marker-combination increased sensitivity to 53% HD resp. 73% GI, accompanied by decreasing specificity. A transfer of the cut-off-based classification methods from HD to GI and vice versa led to false classifications. Sensitivity and specificity do not change using classification methods on transformed data such as the described decision guarantee. CEA/CYFRA-combination allows a classification method transferable despite structural differences of the cohorts. Only 0.8% of the datasets showed discordance in classification. The diagnosis of NSCLC based on ROC curves eliminate centre-specific differences. Classification methods lead to an improvement in NSCLC diagnosis.

A fuzzy-classifier using a marker panel for the detection of lung cancers in asbestosis patients.

BACKGROUND: The aim of this study was to evaluate the diagnostic power of a fuzzy classifier and a marker panel (CYFRA 21-1, NSE, CRP) for the detection of lung cancers in comparison to asbestosis patients at high-risk of developing lung cancer. PATIENTS AND METHODS: A panel of four tumour markers, i.e. CEA, CYFRA 21-1, NSE, SCC and CRP, was measured in newly diagnosed lung cancer patients of different histological types and stages in comparison to asbestosis patients. In this prospective study, a fuzzy classifier was generated with the data of 216 primary lung cancer patients and 76 patients suffering from asbestosis. The patients and controls were recruited in the clinics of the University in Giessen. RESULTS: At 95%-specificity, it was possible with this tool to detect non-small cell lung cancers in 70% at stage I (n = 30), in 95% at stage II (n = 22), in 98% at stage III (n = 56), in 92% at stage IV (n = 50) and small cell lung cancers with limited disease status (n = 21) in 90.7% and with extensive disease status (n = 37) in 97.3%. In contrast, single markers had a detection rate significantly far below these. The application of the classifier was examined on an independent collective of 38 non-small cell lung cancers and 76 asbestosis patients. The latter underwent stationary rehabilitation in the clinics for occupational diseases in Bad Reichenhall or Falkenstein. The fuzzy classifier showed correct negative classification in 75 out of the 76 cancer-free asbestosis patients, which confirmed a specificity of 97.4%. The overall sensitivity for lung cancer detection in high risk populations was 73.6%. All large cell carcinomas were detected. The positive predictive value was 77.7%. The negative predictive value reached 94.8%. CONCLUSION: With the fuzzy classifier and a marker panel, a reliable diagnostic tool for the detection of lung cancers in a high risk population is available.

Decision guarantee in tumour marker analysis: a cut-off independent assessment.

BACKGROUND: The analysis of tumour markers is based on the evaluation of data in relation to defined cut-off values. Changes in the method of determination or reference study group have led to different results. Generally, fuzzy logic-based classifiers for the evaluation of tumour-marker profiles have increased sensitivity and higher specificity. Drawing from experiences with cut-off-oriented evaluation, the suggestion that diagnosis be made using a non-cut-off-based approach is discussed. PATIENTS AND METHODS: Two hundred and eighty-one consecutive patients with newly diagnosed, histologically confirmed lung cancer and a control group of 231 patients were examined. Histological classification of the tumour cases yielded 59 small cell carcinomas, 102 squamous cell carcinomas, 66 adenocarcinomas and 54 large cell carcinomas or mixed bronchial carcinomas without classification. The control group without tumours consisted of 23 healthy subjects, 125 patients with silicosis or asbestosis, 27 patients with chronic obstructive pulmonary diseases (COPD) and 56 persons suffered from inflammatory lung diseases. RESULTS: CYFRA 21-1 was the most sensitive marker with a sensitivity of 57.3% and a specificity of 94.9%. The sensitivity increased when various tumour markers were evaluated. The loss of specificity through this type of multiparametric analysis could be compensated for by using a multiparametric evaluation such as a fuzzy logic classifier. A determination of the sensitivity-adapted confidence in diagnosis should be made. The decision guarantee and the cut-off-based evaluation are qualitatively equal because the decision threshold of 0.5 corresponds by definition to the cut-off value at 95% specificity. Every cut-off-based system of classification could be restated by using the decision guarantee instead of the measured values. CONCLUSION: The evaluation based on decision guarantee has proven to be unaffected by changes in laboratory systems. The multiparametric system of classification based on decision guarantee of individual markers is self-adjusting and differences in measurement levels are eliminated if the ROC curves of the individual markers are in agreement.

Cut-off-independent tumour marker evaluation using ROC approximation.

BACKGROUND: The analysis of tumour markers is based on the evaluation of data in relation to defined cut-off values. Changes in the method of determination or reference study group have led to different results. Cut-off-independent diagnostic evaluation of laboratory parameters can avoid laboratory-based and method-derived systematic errors. The decision guarantee (DG) is an appropriate parameter that can be determined using a defined reference population and its respective receiver operating characteristic (ROC) curve. The influence of ROC differences on the determination of DG is examined. PATIENTS AND METHODS: A group of 281 consecutive patients with newly diagnosed, histologically confirmed lung cancer and a control group of 231 patients were examined. Histological classification of the tumour cases defined in 59 small-cell carcinoma, 102 squamous cell carcinomas, 66 adenocarcinomas and 54 large-cell carcinomas or mixed bronchial carcinomas without classification. The control group without tumours consisted of 23 healthy subjects, 125 patients with silicosis or asbestosis, 27 with chronic obstructive pulmonary diseases (COPD) and 56 suffering from inflammatory lung diseases. RESULTS: Cytokeratin-19 fragments (CYFRA 21-1) was the most sensitive marker with a sensitivity of 57.3% and a specificity of 94.9%. Sensitivity and specificity influence each other. Related to the ROC curve, the method described here ensured the diagnosis of lung cancer on the basis of the data collected in comparison with a reference population. Thus, it was possible to determine with statistical certainty whether the evaluation of the sample data would lead to a diagnosis of lung cancer. CONCLUSION: The DG provides the basis for a laboratory-and method-independent support for a diagnosis including fairer information about the reference population in the data analysis.

Improved sensitivity in the diagnosis of gastro-intestinal tumors by fuzzy logic-based tumor marker profiles including the tumor M2-PK.

The aim of this study was to improve diagnostic efficiency in the detection of gastro-intestinal cancers by using fuzzy logic modeling in combination with a tumor marker panel (CEA, CA72-4, CA19-9) including Tumor M2-PK. In this prospective study histologically confirmed colorectal (n=247), esophageal (n=86) and gastric cancer (n=122) patients were investigated and compared to control (n=53) persons without any malignant diseases. Tumor M2-PK was measured in plasma with an ELISA (ScheBoBiotech, Germany); all other markers were measured in sera (Roche, Germany). At 95% specificity, tumor detection was possible by the best single marker in colorectal cancer patients in 48% (Tumor M2-PK), in gastric cancers in 61% (CA72-4) and in esophageal cancers in 56% (Tumor M2-PK). A fuzzy logic rule-based system employing a tumor marker panel increased sensitivity significantly in colorectal cancers (p<0. 001) to 63% (Tumor M2-PK and CEA), in gastric cancers (p<0.001) to 81% (Tumor M2-PK and CA 72-4) and in esophageal cancers (p<0.02) to 74% (Tumor M2-PK and CA72-4). Adding a third marker further improved the sensitivity only marginally. Fuzzy logic analysis has proven to be more powerful than measurement of single markers alone or combinations using multiple logistic regression analysis of the markers. Therefore, with the fuzzy logic method and a tumor marker panel (including Tumor M2-PK), a new diagnostic tool for the detection of gastro-intestinal cancers is available.

Differential diagnosis of pleural effusions by fuzzy-logic-based analysis of cytokines.

Pleural effusions can be caused by highly different underlying diseases and are characterized by complex interactions of various local and circulating cells as well as numerous soluble parameters like interleukins (IL). Knowledge about this complex network could help to indicate underlying disease. Therefore, we have investigated immunoreactive concentrations of IL-4, IL-6, IL-11, IL-15, IL-17, IL-18, and tumor necrosis factor-alpha (TNF-alpha) in pleural effusions and peripheral blood from patients with tuberculosis, bronchial carcinoma and other carcinomas as well as congestive heart failure (CHF) and pneumonias. To determine the value of cytokine measurement for differential diagnosis, statistical and fuzzy-logic methods were applied. Quantitative analysis showed high concentrations of IL-6 and IL-11 only in pleural effusions. IL-15, IL-17, IL-18 and TNF-alpha could be detected also in blood plasma. Lowest amounts were detected in CHF indicating the non-inflammatory origin of effusions. Statistical analysis did not provide evidence for diagnostic relevance of singular cytokines. Fuzzy-logic analysis was able to assign patients to the correct diseases with 80% accuracy using IL-6 and IL-15 measurement. Our results confirm the pathogenetic role of these cytokines in pleural effusions. Fuzzy-logic-based procedures may help to characterize and distinguish effusions of unknown origin even in small patient groups.

Fuzzy logic-based tumor marker profiles including a new marker tumor M2-PK improved sensitivity to the detection of progression in lung cancer patients.

In lung cancer patients tumor markers are used for disease monitoring. The goal of this study was to improve diagnostic efficiency in the detection of tumor progression in lung cancer patients by using fuzzy logic modeling in combination with a tumor marker panel (Tumor M2-PK, CYFRA 21-1, CEA, NSE and SCC). Thirty-three small cell lung cancers (SCLC) and 69 consecutive inoperable patients (40 squamous and 29 adenocarcinomas) were included in a prospective study. The changes of blood levels of tumor markers as well as their analysis by fuzzy logic modelling were compared to the clinical evaluation of response vs. non-response to therapy. Clinical monitoring was evaluated according to the standard criteria of the WHO. Tumor M2-PK was measured in plasma with an ELISA (ScheBo Biotech, Germany) and all other markers in sera (Roche, Germany). At a 90% specificity, the respective best single marker found the following fraction of all patients who had tumor progression clinically detected: in SCLC with NSE 52%, in adenocarcinoma with CYFRA 21-1 89% and in squamous carcinoma with SCC 65%. A fuzzy logic rule-based system employing a tumor marker panel increased the sensitivity in small cell carcinomas to 73% with the marker combination NSE/CEA and to 63% with the marker combination NSE/Tumor M2-PK, respectively. In squamous carcinomas an improvement of sensitivity is also observed using the marker combination of SCC/Tumor M2-PK (Sensitivity: 81%) or SCC/CEA (Sensitivity: 71%). By using the fuzzy logic method and the marker combination CYFRA 21-1/CEA as well as CYFRA 21-1/Tumor M2-PK, the detection of lung cancer progression was possible in all adenocarcinomas. With the fuzzy logic method and a tumor marker panel (including the new marker Tumor M2-PK), a useful diagnostic tool for the detection of progression in lung cancer patients is available.

Fuzzy logic-based tumor-marker profiles improved sensitivity in the diagnosis of lung cancer.

BACKGROUND: The aim of this study was to improve the diagnostic efficiency of tumor markers in the diagnosis of lung cancer, by the mathematical evaluation of a tumor marker profile employing fuzzy logic modelling. METHODS: A panel of four tumor markers, i.e., carcinoembryonic antigen (CEA), cytokeratin 19 antibody (CYFRA 21-1), neuron-specific enolase (NSE), squamous cell carcinoma-related antigen (SCC) and, additionally, C-reactive protein (CRP), was measured in 175 newly diagnosed lung cancer patients with different histological types and stages. Results were compared with those in 120 control subjects, including 27 with chronic obstructive pulmonary diseases (COPD), 65 with pneumoconiosis, and 11 persons with acute inflammatory lung diseases. A classificator was developed using a fuzzy-logic rule-based system. RESULTS: Application of the fuzzy-logic rule-based system to the tumor marker values of CYFRA 21-1, NSE, and CRP yielded an increase in sensitivity of approximately 20%, i.e., 92%, compared with that of the best single marker, CYFRA 21-1(sensitivity, 72%). The corresponding specificity was 95%. The fuzzy classificator significantly improved the sensitivity of the tumor marker panel in stages I and IIIa for non-small-cell lung cancer, as well as in "limited disease" status for small-cell lung cancer. Also, the diagnosis of other stages of lung cancer was enhanced. CONCLUSION: Fuzzy-logic analysis was proven to be more powerful than the measurement of single markers alone or combinations using multiple logistic regression analysis of all markers. Therefore, fuzzy logic offers a promising diagnostic tool to improve tumor marker efficiency.