Molecular Guided Treatments in Gynecologic Oncology: Analysis of a Real-World Precision Cancer Medicine Platform.

INTRODUCTION: Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. PATIENTS AND METHODS: In this single-center, real-world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next-generation sequencing panel and immunohistochemistry (IHC). RESULTS: In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). CONCLUSION: Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. IMPLICATIONS FOR PRACTICE: Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy-refractory gynecologic malignancy to offer molecular-based treatment concepts.

Resistance exercise and breast cancer-related lymphedema-a systematic review update and meta-analysis.

BACKGROUND: The purpose of this systematic review update and meta-analysis was to analyze resistance exercise (RE) intervention trials in breast cancer survivors (BCS) regarding their effect on breast cancer-related lymphedema (BCRL) status and upper and lower extremity strength. METHODS: Systematic literature search was conducted utilizing PubMed, MEDLINE, and Embase databases. Any exercise intervention studies-both randomized controlled and uncontrolled-which assessed the effects of RE on BCRL in BCS in at least one intervention group published between 1966 and 31st January 2020 were included. Included articles were analyzed regarding their level of evidence and their methodological quality using respective tools for randomized and nonrandomized trials of the Cochrane collaboration. Meta-analysis for bioimpedance spectroscopy (BIS) values as well as upper and lower extremity strength was conducted. RESULTS: Altogether, 29 studies were included in the systematic review. Results of six studies with altogether twelve RE intervention groups could be pooled for meta-analysis of the BCRL. A significant reduction of BCRL after RE was seen in BIS values (95% CI - 1.10 [- 2.19, - 0.01] L-Dex score). Furthermore, strength results of six studies could be pooled and meta-analysis showed significant improvements of muscular strength in the upper and lower extremities (95% CI 8.96 [3.42, 14.51] kg and 95% CI 23.42 [11.95, 34.88] kg, respectively). CONCLUSION: RE does not have a systematic negative effect on BCRL and, on the contrary, potentially decreases it.

Lymph node ratio in inguinal lymphadenectomy for squamous cell vulvar cancer: Results from the AGO-CaRE-1 study.

OBJECTIVE: Lymph node ratio (LNR) can predict treatment outcome and prognosis in patients with solid tumors. Aim of the present analysis was to confirm the concept of using LNR for assessing outcome in patients with vulvar cancer after surgery with inguinal lymphadenectomy in a large multicenter project. METHODS: The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival. RESULTS: In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of >0% < 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P < .001), advanced tumor stage (P < .001), high tumor grade (P < .001), and deep stromal invasion (P < .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%, >0% < 20%, and ≥20%, respectively (P < .001, P < .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01-14.98, P < .001), FIGO stage (HR 1.41, 95%-CI 1.18-1.69, P < .001), and patient's performance status (HR 1.59, 95%-CI 1.39-1.82, P < .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64-28.78, P < .001), and performance status (HR 1.72, 95%-CI 1.44-2.07, P < .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models. CONCLUSIONS: In women with vulvar cancer LNR appears to be a consistent, independent prognostic parameter for both PFS and OS and allows patient stratification into three distinct risk groups. In survival analyses, LNR outperformed nodal status and number of positive nodes.

Co-expressed genes enhance precision of receptor status identification in breast cancer patients.

PURPOSE: Therapeutic decisions in breast cancer patients crucially depend on the status of estrogen receptor, progesterone receptor and HER2, obtained by immunohistochemistry (IHC). These are known to be inaccurate sometimes, and we demonstrate how to use gene-expression to increase precision of receptor status. METHODS: We downloaded data from 3241 breast cancer patients out of 36 clinical studies. For each receptor, we modelled the mRNA expression of the receptor gene and a co-gene by logistic regression. For each patient, predictions from logistic regression were merged with information from IHC on a probabilistic basis to arrive at a fused prediction result. RESULTS: We introduce Sankey diagrams to visualize the step by step increase of precision as information is added from gene expression: IHC-estimates are qualified as 'confirmed', 'rejected' or 'corrected'. Additionally, we introduce the category 'inconclusive' to spot those patients in need for additional assessments so as to increase diagnostic precision and safety. CONCLUSIONS: We demonstrate a sound mathematical basis for the fusion of information, even if partly contradictive. The concept is extendable to more than three sources of information, as particularly important for OMICS data. The overall number of undecidable cases is reduced as well as those assessed falsely. We outline how decision rules may be extended to also weigh consequences, being different in severity for false-positive and false-negative assessments, respectively. The possible benefit is demonstrated by comparing the disease free survival between patients whose IHC could be confirmed versus those for which it was corrected.

Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints.

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.

Disclosures, conflict of interest, and funding issues in urogynecology articles: a bibliometric study.

INTRODUCTION AND HYPOTHESIS: The ethical behavior of authors, editors, and journals is increasingly placed in the spotlight, by both the public and the research community. Disclosures and conflict of interest (COI) statements of publishing authors represent one important aspect. We aimed to unravel the current management of disclosures, COI, and funding statements in the subspecialty urogynecology. METHODS: A bibliometric study was carried out. We included six journals that published urogynecology articles between January and December 2013. All original articles, reviews, and opinion articles were assessed for the presence of disclosure/COI and funding statements. Information given on the official disclosure form was compared with information given in the final article (International Urogynecology Journal). RESULTS: All journals investigated require disclosure and funding statements in their instructions to authors. Of the 434 articles included, almost all contained a disclosure statement (98-100 %). Funding statements were present in 41-100 % of articles, indicating a difference in journal type (50 % on average among urogynecology journals; 75 % on average among general gynecology journals). The main source of funding was "grants" (58 %), followed by "none" (16 %), "industry" (16 %), and lastly "hospital/university" (10 %). Disclosure statements in the article were identical to the official disclosure form in 80 % (IUJ). CONCLUSIONS: Disclosure/COI statements were included in almost all urogynecology articles investigated. Their content, however, is sometimes incomplete and should possibly be monitored more closely by journals and authors. Despite universal requirements of journals, the reporting of funding seems inconsistent. This issue in addition to the completeness of disclosures should be given more attention.

Phase II study of fulvestrant 250 mg/month in patients with recurrent or metastatic endometrial cancer: a study of the Arbeitsgemeinschaft Gynäkologische Onkologie.

OBJECTIVES: The aim of this study is to evaluate the activity and toxicity of fulvestrant, a pure estrogen receptor antagonist in patients with advanced or recurrent endometrial cancer, expressing estrogen and/or progesterone receptors (ER/PR). METHODS: Eligible patients with advanced or recurrent endometrial cancer not amenable to curative surgery and/or radiotherapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 12 weeks. Therapy was continued until disease progression, death, intolerable side effects or end of study. Response was assessed in patients with at least one target lesion according to WHO-criteria. RESULTS: Thirty-five patients were enrolled in this study and received at least one injection of fulvestrant (intention to treat-population, ITT). Twenty six patients received the intended 3 injections of fulvestrant (per protocol population, PP). There was no complete response but 4 partial responses (11.4% ITT) and 8 stable diseases. The median time to progression was 2.3 months (ITT). Overall survival was 13.2 months (ITT). Treatment was well tolerated. CONCLUSIONS: Fulvestrant at a dose of 250 mg IM every 4 weeks has marginal activity and good tolerability in patients with ER and/or PR positive advanced or recurrent endometrial cancer. A loading dose strategy and the use of 500 mg/4 weeks might improve the efficacy of this treatment.

Diagnosis and Therapy of Female Urinary Incontinence. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 015/091, January 2022): Part 2 with Recommendations on Interventional/Surgical Therapy of Overactive Bladder, Surgical Treatment of Stress Urinary Incontinence and Diagnosis and Therapy of Iatrogenic Urogenital Fistula.

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the surgical treatment of female patients with stress urinary incontinence and urge incontinence. Specific solutions for the diagnostic workup and treatment of uncomplicated and complicated urinary incontinence are discussed. The diagnostics and surgical treatment of iatrogenic urogenital fistula are presented.

Diagnosis and Therapy of Female Urinary Incontinence. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/091, January 2022): Part 1 with Recommendations on Diagnostics and Conservative and Medical Treatment.

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, etiology, classification, symptoms, diagnostics, and treatment of female patients with urinary incontinence. Specific solutions for the diagnostic workup and appropriate conservative and medical therapies for uncomplicated and complication urinary incontinence are discussed.

Female Pelvic Floor Dysfunction Continues to Negatively Impact Quality-of-Life during the COVID-19 Lockdown.

The COVID-19 pandemic led to dramatical changes in elective medical care. We analysed its impact on patients with female pelvic floor dysfunction during the 6 weeks of lockdown in Austria. A cross-sectional study was conducted: All 99 women who presented at the urogynaecologic outpatient clinic of the Medical University of Vienna with pelvic organ prolapse (POP) or urinary incontinence (UI) from December 2019 up to the lockdown in March 2020 were included and contacted. 97% of these women (96 participants) agreed to participate in the survey conducted to asses pelvic floor related quality of life (QoL) through telephone- interrogation. The mean age was 59 ± 14.8 years, the POP group consisted of 42 women while the UI group included 54 women. Most participants (83% of POP and 81% of UI cases) stated that their female pelvic floor dysfunction had remained equally relevant or had become even more significant during the lockdown. Associated symptoms and psychological strain also maintained their relevance during the lockdown (UI: p = 0.229; POP: p = 0.234). Furthermore, 97% of all interviewed women indicated to be strongly willing to continue their treatment. A generalised linear model regression revealed no clinical or demographic risk factors for psychological strain during the lockdown (p > 0.05). Our results demonstrate that women's QoL remains significantly impaired by their pelvic-floor disorders even during a worldwide crisis such as COVID-19. Therefore, elective disciplines such as urogynaecology urgently require novel and innovative strategies for continued patient care even in times of a lockdown.

Surgical Assessment of Tissue Quality during Pelvic Organ Prolapse Repair in Postmenopausal Women Pre-Treated Either with Locally Applied Estrogen or Placebo: Results of a Double-Masked, Placebo-Controlled, Multicenter Trial.

The aim of this prospective randomized, double-masked, placebo-controlled, multicenter study was to analyze the surgeon's individual assessment of tissue quality during pelvic floor surgery in postmenopausal women pre-treated with local estrogen therapy (LET) or placebo cream. Secondary outcomes included intraoperative and early postoperative course of the two study groups. Surgeons, blinded to patient's preoperative treatment, completed an 8-item questionnaire after each prolapse surgery to assess tissue quality as well as surgical conditions. Our hypothesis was that there is no significant difference in individual surgical assessment of tissue quality between local estrogen or placebo pre-treatment. Multivariate logistic regression analysis was performed to identify independent risk factors for intra- or early postoperative complications. Out of 120 randomized women, 103 (86%) remained for final analysis. Surgeons assessed the tissue quality similarity in cases with or without LET, representing no statistically significant differences concerning tissue perfusion, tissue atrophy, tissue consistency, difficulty of dissection and regular pelvic anatomy. Regarding pre-treatment, the rating of the surgeon correlated significantly with LET (r = 0.043), meaning a correct assumption of the surgeon. Operative time, intraoperative blood loss, occurrence of intraoperative complications, total length of stay, frequent use of analgesics and rate of readmission did not significantly differ between LET and placebo pre-treatment. The rate of defined postoperative complications and use of antibiotics was significantly more frequent in patients without LET (p = 0.045 and p = 0.003). Tissue quality was similarly assessed in cases with or without local estrogen pre-treatment, but it seems that LET prior to prolapse surgery may improve vaginal health as well as tissue-healing processes, protecting these patients from early postoperative complications.

Cervical Cancer Screening: Comparison of Conventional Pap Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or Cotesting Strategies.

BACKGROUND: Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study. METHODS: The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated. RESULTS: In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%-95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00-1.21; PCR: 1.07, 95% CI, 1.00-1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99-1.00). NNC was highest for Pap cotesting. CONCLUSIONS: Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals. IMPACT: HPV stand-alone screening offers a better balance of benefits and harms than cotesting.See related commentary by Wentzensen and Clarke, p. 432.

Overactive bladder: Is there a link to the metabolic syndrome in men?

It is becoming increasingly clear that a variety of metabolic, cardiovascular, and endocrine factors contribute to male pelvic health. In particular, a growing body of evidence suggests a relationship between lower urinary tract symptoms, benign prostatic hyperplasia, overactive bladder, erectile dysfunction, and the metabolic syndrome. This article explores these relationships, focusing on the role of the autonomic nervous system and hyperinsulinemia, together with their implications for urological practice.

Obesity in Gynecologic Oncology.

The decades-long global obesity epidemic has resulted in steady increase in the incidence of obesity-related malignancies. The associated diagnostic and therapeutic implications present a clinical challenge for gynecologic oncology treatment strategies. Recent studies have provided solid evidence for an independent, linear, positive correlation between a pathologically increased body mass index and the probability of developing endometrial or postmenopausal breast cancer. The pathogenesis is complex and the subject of current research. Proposed causes include pathologically increased serum levels of sexual steroids and adiponectin, obesity-induced insulin resistance, and systemic inflammatory processes. The scientific evidence for an association between obesity and other gynecological malignancies is, however, less solid. The clinical relevance of obesity as a risk factor for epithelial ovarian cancer, cervical cancer and vulvar cancer appears to be negligible. Nevertheless, obesity appears to have a negative impact on prognosis and oncologic outcomes for all gynecological cancers. Whether or not this effect can be interpreted as correlative or causal is still a subject of ongoing debate.

The role of transforming growth factor-ß (TGF-ß1) in postmenopausal women with pelvic organ prolapse: An immunohistochemical study.

OBJECTIVE: Aim of the study was to investigate the expression of transforming growth factor-ß1 (TGF-ß1), a key regulator of the extracellular matrix composition, in the uterosacral ligaments (USLs) of women with pelvic organ prolapse (POP) compared with controls. We hypothesized that the expression pattern of TGF-ß1 differs between postmenopausal women with or without POP. METHODS: Under ethical approval, USL samples were obtained from postmenopausal women undergoing vaginal hysterectomy for stage two or greater pelvic organ prolapse (cases, n = 70) and from postmenopausal women without pelvic organ prolapse undergoing vaginal hysterectomy for benign indications (controls, n = 30). Immunohistochemical staining was performed from paraffin embedded tissue using anti-TGF-ß1 antibodies. The expression of TGF-ß1 was evaluated by the pathologist, who was blinded to all clinical data. RESULTS: The expression of TGF-ß1 was similar in patients with symptomatic POP (89 % positive) and in controls (90 % positive) without any signs of prolapse (p = 0.091). Age-adjusted analysis did not significantly alter these results. Regarding POP-Q stages, TGF-ß1 was significantly more frequently expressed in severe prolapse cases compared to moderate/mild cases (POP-Q stage IV versus POP-Q stage II and III; p = 0.001). No significant association could be detected between TGF-ß1 expression and age, BMI and parity in cases with POP (p > 0.05). As published previously, advanced patients' age as well as early menopausal age remained independent risk factors associated with POP in multiple logistic regression analysis (p = 0.001; p = 0.02). CONCLUSION: Although our study detected POP-Q stage related alterations in USL composition and TGF-ß1 expression, there was no significant difference in the expression of TGF-ß1 in cases with or without prolapse.

Uterus Preservation in Case of Vaginal Prolapse Surgery Acts as a Protector against Postoperative Urinary Retention.

BACKGROUND: The aim of this study was to identify clinical risk factors for increased post-void residual (PVR) volumes in patients undergoing vaginal prolapse surgery and to find out whether uterus preservation or prolapse hysterectomy influences the incidence of postoperative urinary retention. METHODS: This retrospective study included women who presented with pelvic organ prolapse (POP) and planned prolapse surgery between January 2017 and July 2019. PVR was assessed postoperatively and increased amounts were defined as incomplete voiding with residual urine volume greater than 150 mL. RESULTS: Increased PVR at the first postoperative day occurred in 31.8% (56/176). Body mass index (BMI) was significantly lower in patients with increased PVR after pelvic floor surgery compared to patients with normal PVR amounts (p = 0.040). Furthermore, during multiple logistic regression analysis, low BMI (p = 0.009) as well as prolapse hysterectomy (p = 0.032) turned out to be the strongest risk factors associated with increased PVR volume. CONCLUSION: This is the first study identifying prolapse hysterectomy as an independent risk factor for increased PVR after surgical prolapse repair. Our results might be helpful in counseling patients prior to surgery and underline the option of uterus preservation during prolapse surgery in selected cases.

Microarray Normalization Revisited for Reproducible Breast Cancer Biomarkers.

Precision medicine for breast cancer relies on biomarkers to select therapies. However, the reliability of biomarkers drawn from gene expression arrays has been questioned and calls for reassessment, in particular for large datasets. We revisit widely used data-normalization procedures and evaluate differences in outcome in order to pinpoint the most reliable reprocessing methods biomarkers can be based upon. We generated a database of 3753 breast cancer patients out of 38 studies by downloading and curating patient samples from NCBI-GEO. As gene-expression biomarkers, we select the assessment of receptor status and breast cancer subtype classification. Each normalization procedure is applied separately, and biomarkers are then evaluated for each patient. Differences between normalization pipelines are quantified as percentages of patients having outcomes different for each pipeline. Some normalization procedures lead to quite consistent biomarkers, differing only in 1-2% of patients. Other normalization procedures-some of them have been used in many clinical studies-end up with distrusting discrepancies (10% and more). A good deal of doubt regarding the reliability of microarrays may root in the haphazard application of inadequate preprocessing pipelines. Several modes of batch corrections are evaluated regarding a possible improvement of receptor prediction from gene expression versus the golden standard of immunohistochemistry. Finally, we nominate those normalization methods yielding consistent and trustable results. Adequate bioinformatics data preprocessing is key and crucial for any subsequent statistics to arrive at trustable results. We conclude with a suggestion for future bioinformatics development to further increase the reliability of cancer biomarkers.

The prognostic value of four interleukin-1 gene polymorphisms in Caucasian women with breast cancer: a multicenter study.

BACKGROUND: The proinflammatory cytokine interleukin-1 (IL-1) is known to play an important role in the carcinogenesis of breast cancer. Although IL-1 gene polymorphisms were reported to be associated with increased risk of breast cancer, their influence on survival of Caucasian breast cancer patients remains to be shown. METHODS: We studied the influence of four common gene polymorphisms (IL1A -889C/T, IL1B -511C/T, IL1B +3953E1/E2, and IL1RN long/2) of the IL-1 family on survival in 262 Caucasian patients with breast cancer by univariate and multivariate survival analysis. The combined effect of the four gene polymorphisms on overall survival was studied by haplotype analysis. RESULTS: In the present study 38 cases of cancer related death and a median time of follow-up (range) of 55.3 (0.4-175.8) months was observed. IL1RN 2/2 (homozygous mutant) gene polymorphism was associated with shortened disease free and overall survival in a univariate (p = 0.001 and p = 0.01, respectively) and multivariate analysis (p = 0.002, Odds Ratio [95% Confidence Interval] = 3.6 [1.6-8.0] and p = 0.05, Odds Ratio = 3.0 [1.1-9.3], respectively). Presence of the homozygous mutant genotype of the IL1A -889 and IL1B +3953 gene polymorphism was associated with overall survival in the univariate (p = 0.004 and p = 0.002, respectively), but not in the multivariate analysis. No association was observed between all possible haplotype combinations and overall survival. CONCLUSION: Carriage of the mutant alleles of IL1RN was independently associated with shortened disease free and overall survival rates in Caucasian patients with breast cancer.

Signet Ring Cell Carcinoma of the Lung: A Diagnostic Pitfall in Pregnancy.

Lung cancer during pregnancy represents a rare disease. In this case report, we present a patient at advanced and metastasized stage of signet ring cell carcinoma who presented in the 22nd week of gestation.

Contralateral prophylactic mastectomy in women with breast cancer without a family history or genetic predisposition : Consensus statement from the Austrian Gynecologic Oncology Working Group of the Austrian Society of Obstetrics and Gynecology.

The working group recommends against contralateral prophylactic mastectomy (CPM) in women with breast cancer without a family history or genetic predisposition with unilateral breast cancer. This is based on the low risk of developing contralateral breast cancer, the lack of a survival benefit, the increased risk of surgical complications, and the lack of benefit on quality of life.