Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures.

Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.

Basic Gynecologic Ultrasound Examination (Level I): DEGUM, ÖGUM, and SGUM Recommendations. / Qualitätsanforderungen an gynäkologische Ultraschall-Untersuchungen der DEGUM-Stufe I: Empfehlungen der DEGUM, ÖGUM und SGUM.

Ultrasound has become an essential diagnostic tool in gynecology, and every practicing gynecologist must be able to differentiate normal from pathologic findings, such as benign or malignant pelvic masses, adnexal torsion, pelvic inflammation disease, endometriosis, ectopic pregnancies, and congenital uterine malformations at least on a basic level. A standardized approach to the correct settings of the ultrasound system, the indications for gynecologic ultrasound investigations, and the sonographic appearance of normal anatomy and common pathologic findings in the standard planes are important prerequisites for safe and confident clinical management of gynecologic patients. Based on current publications and different national and international guidelines, updated DEGUM, ÖGUM, and SGUM recommendations for the performance of basic gynecologic ultrasound examinations were established.

Prevalence and Infant Mortality of Major Congenital Malformations Stratified by Birthweight.

BACKGROUND: Low birthweight and major congenital malformations (MCMs) are key causes of infant mortality. OBJECTIVES: The aim of this study was to explore the prevalence of MCMs in infants with low and very low birthweight and analyze the impact of MCMs and birthweight on infant mortality. METHODS: We determined prevalence and infant mortality of 28 life-threatening MCMs in very-low-birthweight (<1,500 g, VLBW), low-birthweight (1,500-2,499 g, LBW), or normal-birthweight (≥2,500 g, NBW) infants in a cohort of 2,727,002 infants born in Germany in 2006-2017, using de-identified administrative data of the largest statutory public health insurance system in Germany. RESULTS: The rates of VLBW, LBW, and NBW infants studied were 1.3% (34,401), 4.0% (109,558), and 94.7% (2,583,043). MCMs affected 0.5% (13,563) infants, of whom >75% (10,316) had severe congenital heart disease. The prevalence (per 10,000) of any/cardiac MCM was increased in VLBW (286/176) and LBW (244/143), as compared to NBW infants (38/32). Infant mortality rates were significantly higher in infants with an MCM, as opposed to infants without an MCM, in each birthweight group (VLBW 28.5% vs. 11.5%, LBW 16.7% vs. 0.9%, and NBW 8.6% vs. 0.1%). For most MCMs, observed survival rates in VLBW and LBW infants were lower than expected, as calculated from survival rates of VLBW or LBW infants without an MCM, and NBW infants with an MCM. CONCLUSIONS: Infants with an MCM are more often born with LBW or VLBW, as opposed to infants without an MCM. Many MCMs carry significant excess mortality when occurring in VLBW or LBW infants.

Quality Requirements for gynecological ultrasound examinations of DEGUM level II - Recommendations of the Sections/Working Groups Gynecology and Obstetrics of DEGUM, ÖGUM and SGUM. / Qualitätsanforderungen an die gynäkologischen Ultraschalluntersuchungen der DEGUM Stufe II ­ Empfehlungen der Sektionen/Arbeitskreise Gynäkologie und Geburtshilfe der DEGUM, ÖGUM und SGUM.

Gynecological sonography is the central and most frequently used technical examination method used by gynecologists. Its focus is on the clarification of masses of the uterus and the adnexa, fertility diagnosis, clarification of bleeding disorders and chronic and acute pelvic problems, pelvic floor and incontinence diagnosis as well as the differential diagnosis of disturbed early pregnancy. The indication for diagnostic and therapeutic interventions, preoperative planning and postoperative controls are largely based on the findings of gynecological sonography. These examinations are particularly dependent on the experience of the examiner.Based on the proven multi-stage concept of obstetric diagnostics, gynecological sonography should primarily be performed by an experienced and specialized examiner in patients for whom the initial gynecological examinations have not yet led to a sufficient assessment of the findings. So that the expert status required for this has an objective basis, the Gynecology and Obstetrics Section of DEGUM in cooperation with ÖGUM and SGUM implemented the option of acquiring DEGUM Level II for gynecological sonography. The effectiveness of the care in the multi-level concept depends on the quality of the ultrasound examination at level I. Quality requirements for the basic examination and the differentiation between the basic and further examination have therefore already been defined by DEGUM/ÖGUM. The present work is intended to set out quality requirements for gynecological sonography of DEGUM level II and for the correspondingly certified gynecologists.Common pathologies from gynecological sonography and requirements for imaging and documentation are described.

Immune Heterogeneity Between Primary Tumors and Corresponding Metastatic Lesions and Response to Platinum Therapy in Primary Ovarian Cancer.

CD3+ and CD8+ lymphocytes are well known prognostic markers in primary ovarian cancer. In contrast, the predictive value of the immune infiltrate concerning treatment response and the involvement of immune heterogeneity between primary and metastatic lesions are poorly understood. In this study, the immune infiltrate of 49 primary tumors and 38 corresponding lesions in the omentum (n = 23) and the peritoneum (n = 15) was immunohistochemically analyzed and correlated with clinicopathological factors and platinum-sensitivity. Immune heterogeneity was observed between paired primary and metastatic lesions for all immune cell phenotypes. The stromal immune infiltrate was higher in the omental lesions than in the primary tumors, which was reflected by CD45 (p=0.007), CD3 (p=0.005), CD8 (p=0.012), and PD-1 (programmed cell-death protein 1) (p=0.013). A higher stromal infiltrate of both CD45+ and CD3+ cells in the omental lesions was associated with the detection of lymph node metastasis (CD45, p=0.018; CD3, p=0.037). Platinum-sensitive ovarian cancers revealed a higher intratumoral CD8+ infiltrate in the peritoneal lesions compared to the primary tumors (p=0.045). In contrast, higher counts of stromal PD-1+ cells in the peritoneal lesions have been associated with reduced platinum-sensitivity (p=0.045). Immune heterogeneity was associated with platinum response and might represent a selection marker for personalized therapy.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Number 032/034-OL, April 2018) - Part 2 with Recommendations on the Therapy and Follow-up of Endometrial Cancer, Palliative Care, Psycho-oncological/Psychosocial Care/Rehabilitation/Patient Information and Healthcare Facilities.

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose Using evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patient's quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal extent of surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy if required. An evidence-based optimal use of different therapeutic modalities should improve the survival rates and quality of life of these patients. This S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources included reviews of evidence, which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one part of the guideline. Identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then subsequently modified during structured consensus conferences and/or additionally amended online using the DELPHI method, with consent between members achieved online. The guideline report is freely available online. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of endometrial cancer including precancers and early endometrial cancer as well as recommendations on palliative medicine, psycho-oncology, rehabilitation, patient information and healthcare facilities to treat endometrial cancer. The management of precancers of early endometrial precancerous conditions including fertility-preserving strategies is presented. The concept used for surgical primary therapy of endometrial cancer is described. Radiotherapy and adjuvant medical therapy to treat endometrial cancer and uterine carcinosarcomas are described. Recommendations are given for the follow-up care of endometrial cancer, recurrence and metastasis. Palliative medicine, psycho-oncology including psychosocial care, and patient information and rehabilitation are presented. Finally, the care algorithm and quality assurance steps for the diagnosis, therapy and follow-up of patients with endometrial cancer are outlined.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) - Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer.

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patient's quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online. Recommendations Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids.

BACKGROUND: Targeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients. METHODS: Tumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture. Similarly, spheroids were also generated from established HER2 negative breast cancer cell lines T-47D, MCF7, HCC1143, and HCC1937 to compare treatment efficacy of heterogeneous cell populations from patient tumor tissue with homogeneous cell lines. Spheroids were treated in vitro with guideline-recommended compounds. Treatment mediated impact on cell survival was subsequently quantified using an ATP assay. RESULTS: Differences were observed in the metabolic activity of the untreated spheroids, whereby cell lines consistently achieved higher values compared to tissue spheroids (p < 0.001). A higher number of cells per spheroid correlated with a higher basal metabolic activity in tissue-derived spheroids (p < 0.01), while the opposite was observed for cell line spheroids (p < 0.01). Recurrent tumors showed a higher mean vitality (p < 0.01) compared to primary tumors. Except for taxanes, treatment efficacy for most tested compounds differed significantly between breast cancer tissue spheroids and breast cancer cell lines. Overall a high variability in treatment response in vitro was seen in the tissue spheroids regardless of the tested substances. A greater response to anthracycline/docetaxel was observed for hormone receptor negative samples (p < 0.01). A higher response to 5-FU (p < 0.01) and anthracycline (p < 0.05) was seen in high grade tumors. Smaller tumor size and negative lymph node status were both associated with a higher treatment efficacy to anthracycline treatment combined with 5-FU (cT1/2 vs cT3/4, p = 0.035, cN+ vs cN-, p < 0.05). CONCLUSIONS: The tissue spheroid model reflects current guideline treatment recommendations for HER2 negative breast cancer, whereas tested cell lines did not. This model represents a unique diagnostic method to select the most effective therapy out of several equivalent treatment options.

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients.

BACKGROUND: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). METHODS: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. RESULTS: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. CONCLUSION: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.

Role of Helicobacter pylori infection in iron deficiency during pregnancy.

OBJECTIVE: We investigated the possible role of Helicobacter pylori infection in iron deficiency during pregnancy in a large group of mothers in Germany after the birth of their baby under special consideration of iron supplementation. STUDY DESIGN: All women who were delivered of their baby between November 2000 and November 2001 at the Department of Gynecology and Obstetrics at the University of Ulm, Germany, were recruited for the study. Hemoglobin levels at various points of time during pregnancy were obtained from the mothers' health charts. Current H pylori infection was determined by 13 C-urea breath test. We used multiple linear regression analyses to assess the impact of infection status on hemoglobin level at the beginning of pregnancy and on hemoglobin change during pregnancy. RESULTS: Twenty-three percent of the 898 mothers had a H pylori infection, and 20% of the mothers had a hemoglobin level below 12 g/dL at the beginning of pregnancy. Compared with uninfected mothers, mothers with H pylori infection had a lower mean hemoglobin level at the beginning of pregnancy (-0.25 g/dL; 95% CI, -0.49, -0.003) and a more unfavorable change in hemoglobin level during pregnancy (-0.14 g/dL; 95% CI, -0.38, 0.10). CONCLUSION: This study supports a possible moderate, but still relevant, independent role of H pylori infection in iron deficiency during pregnancy.

Helicobacter pylori infection and the occurrence and severity of gastrointestinal symptoms during pregnancy.

OBJECTIVE: We investigated the possible role of Helicobacter pylori infection in the occurrence and severity of gastrointestinal symptoms during pregnancy in a large group of mothers after delivery. STUDY DESIGN: Between November 2000 and November 2001, mothers were recruited after delivery at the Department of Gynecology and Obstetrics at the University of Ulm. Present H pylori infection was determined by (13)C-urea breath test. Associations between gastrointestinal symptoms during pregnancy (sickness, vomiting, increased saliva production, heartburn) and H pylori infection were quantified by crude and adjusted odds ratios with 95% CI. RESULTS: Twenty-three percent of the 898 mothers had a current H pylori infection. Eighty-four percent of the mothers reported at least one of the evaluated gastrointestinal symptoms, and 30% of the mothers reported at least one physician visit because of the severity of these symptoms. None of the analyzed gastrointestinal symptoms showed an association to a current H pylori infection after an adjustment for the covariates, even after a virulence marker of H pylori infection was taken into account. CONCLUSION: This study does not support an involvement of H pylori infection in the generation of gastrointestinal symptoms during pregnancy.

Asymptomatic adnexal masses: correlation of FDG PET and histopathologic findings.

PURPOSE: To analyze asymptomatic adnexal masses at positron emission tomography (PET) with fluorodeoxyglucose (FDG) in correlation with histopathologic findings and evaluate FDG PET for assessing malignancy in comparison with transvaginal B-mode and Doppler ultrasonography (US) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: Ninety-nine patients underwent static FDG PET of the abdomen. US scans were evaluated according to sonomorphologic scoring systems. Resistance index of tumor blood vessels was calculated. Transverse and sagittal T1-weighted MR images obtained before and after intravenous administration of gadopentetate dimeglumine with a fat-saturation technique and T2-weighted MR images were acquired at 1.5 T. Adnexal mass malignancy was first assessed with each modality and then with a combination of the three techniques. Final diagnosis was made with histopathologic evaluation. RESULTS: FDG PET depicted seven of 12 malignant and 66 of 87 benign asymptomatic adnexal tumors. False-negative PET results were obtained in five of seven stage pT1a cystadenocarcinomas and tumors of low malignant potential but not in advanced-stage ovarian carcinomas. Small moderately intense FDG accumulations in the lower pelvis were caused by benign adnexal tumors or gastrointestinal activity in 21 of 27 cases. The overall sensitivities and specificities were 58% (95% CI: 27.7, 84.8) and 76% (95% CI: 65.5, 84.4), respectively, for FDG PET; 92% (95% CI: 61.5, 99.8) and 60% (95% CI: 48.7, 70.1), respectively, for US; 83% (95% CI: 51.6, 97.7) and 84% (95% CI: 74.5, 90.9), respectively, for MR imaging; and 92% (95% CI: 61.5, 99.8) and 85% (95% CI: 75.8, 91.8), respectively, for the combination of three modalities. CONCLUSION: Since the sensitivity of US is as high as that of PET, MR imaging, and the combination of three modalities, it remains the method of choice for diagnosis and assessment of asymptomatic adnexal masses.

Acute respiratory failure and short-term outcome after premature rupture of the membranes and oligohydramnios before 20 weeks of gestation.

OBJECTIVES: To study the effect of premature rupture of membranes and oligohydramnios before 20 weeks of gestation (PROM20) on acute respiratory morbidity and on short-term outcome in infants with a gestational age >or=24 weeks. STUDY DESIGN: A historic cohort study was performed of all infants born after PROM20 with a gestational age greater-than-or-equal24 weeks between 1990 and 1999. Control infants were matched for year of birth, gestational age, and birth weight. RESULTS: PROM20 infants had an increased acute respiratory morbidity (higher ventilator settings and increased incidence of hypoxemia, hypercapnia, and pulmonary hypertension) and a trend to more air leaks. Although not statistically different, PROM20 infants had more complications (neonatal survival, 68% vs 95%; severe intracranial hemorrhage, 31% vs 6%; chronic lung disease in surviving infants, 46% vs 17%). The relative risk for combined morbidity (death, intracranial hemorrhage, chronic lung disease) was increased (3.0, P =.019) when compared with matched control infants. However, 31% of the surviving PROM20 infants were discharged without apparent morbidity. CONCLUSIONS: Expectant treatment in women with PROM20 and present neonatal intensive care has improved the survival of PROM20 infants despite severe initial respiratory failure. However, chronic morbidity still occurred.