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BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Zusammenfassung Hintergrund Umfangreiche Daten aus prospektiven klinischen Studien liefern einen hohen Evidenzgrad für den Einsatz von CDK4/6-Hemmern in Kombination mit einer endokrinen Therapie (CDK4/6i + ET) als Standard bei der First-Line-Behandlung von metastatischem HER2-negativen hormonrezeptorpositiven (HER2−/HR+) Brustkrebs. Reale Daten von Patientinnengruppen, die damit in der Praxis behandelt wurden, liefern Erkenntnisse über Veränderungen von Patientenmerkmalen und Prognosen im Laufe der Zeit. Methoden Die Daten wurden dem prospektiven praxisbezogenen PRAEGNANT-Register (NCT02 338 167) entnommen. Die eingeschlossenen Patientinnen hatten fortgeschrittenen primären und metastasierten HER2−/HR+ Brustkrebs. Die gewählten Therapien, das progressionsfreie Überleben und das Gesamtüberleben der jeweiligen Therapie sowie die Zeitspanne, während der die Behandlung erfolgte, werden dargelegt. Ergebnisse Nachdem CDK4/6-Hemmer erstmals im November 2016 eingesetzt wurden, stieg die Häufigkeit ihres Einsatzes schnell an. In den letzten Jahren (2018–2022) wurden ca. 70–80 % aller Patientinnengruppen mit CDK4/6-Hemmern behandelt; eine endokrine Monotherapie wurde rund 10 % und eine Chemotherapie ungefähr 15 % aller Patientinnen verabreicht. Die schlechteste Prognose hatten Patientinnen, die eine Chemotherapie erhielten. Seit Kurzem erhalten hauptsächlich Patientinnen mit guter Prognose eine endokrine Monotherapie; Patientinnen, die eine Chemotherapie erhalten, haben eine ungünstigere Prognose. Das progressionsfreie Überleben und das Gesamtüberleben von mit CDK4/6i + ET behandelten Patientinnen blieb über einen längeren Zeitraum ähnlich, obwohl sich die Patientenmerkmale änderten. Schlussfolgerung Die Behandlung mit CDK4/6i + ET entwickelte sich rasch zum First-Line-Therapiestandard für Patienten mit fortgeschrittenem Mammakarzinom. Seit der Einführung von CDK4/6i + ET wird die endokrine Monotherapie nur bei Patientinnen mit einer sehr günstigen Prognose eingesetzt, während Chemotherapie meist nur an Patientinnen verabreicht wird, die eine eher ungünstige Prognose haben. Veränderungen der Patientenmerkmale scheinen die Prognose von mit CDK4/6i + ET behandelten Patientinnen nicht zu beeinflussen.

ZusammenfassungDrahtlokalisation stellt die am häufigsten verwendete Lokalisationsmethode bei nicht palpablen Mammakarzinomen dar. Zu potenziellen Nachteilen der Technik gehören eine niedrige Rate an R0-Resektionen, die Invasivität und das Risiko der Drahtdislokation. Des Weiteren ist die Notwendigkeit einer Re-Operation mit einem erhöhten Rezidivrisiko assoziiert. Intraoperative Sonografie (IOUS) erlaubt eine direkte Visualisierung der Läsion und des Resektionsvolumens und reduziert die Rate an positiven Rändern bei palpablen und nicht palpablen Tumoren. Wir führten ein systematisches Review der Studien zur IOUS durch. Die randomisierten Studien wurden in 2 Metaanalysen ausgewertet. In nicht palpablen Mammakarzinomen zeigten 3 randomisierte Studien höhere R0- Resektionsraten im IOUS-Arm, verglichen mit Drahtlokalisation. Der signifikante Unterschied konnte in der Metaanalyse bestätigt werden (Risk Ratio 4,34, p < 0,0001, I2 = 0 %). Die meisten der 41 Kohortenstudien mit 3291 Patientinnen zeigten höhere R0-Resektionsraten und niedrigere Nachresektionsraten bei Verwendung von IOUS. Eine Metaanalyse von 3 randomisierten Studien bei palpablem Mammakarzinom zeigte signifikant höhere Raten an positiven Rändern im Palpations-Arm (Risk Ratio 2,84, p=0,0047, I2=0%). In 13 Kohortenstudien mit 942 Patientinnen mit palpablem Mammakarzinom, waren die R0-Resektionsraten meist höher und die Gewebsvolumina niedriger bei Verwendung von IOUS. IOUS ist eine sichere nicht invasive Technik zur Lokalisation von sonografisch sichtbaren Tumoren und verbessert R0-Resektionsraten bei palpablem und nicht palpablem Mammakarzinom. Sonografische Weiterbildung für Brustoperateure erscheint empfehlenswert.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles.Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423GA (p.Leu141=) and c.839+5GA variants impaired the normal splicing of TBX6 messenger RNA, c.422TC (p.Leu141Pro) and c.745GA (p.Val249Met) led to decreased protein expression, c.10CT (p.Pro4Ser) and c.400GA (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356GA (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2− HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2− HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 – 2022), about 70 – 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

Disseminated tumor cells (DTCs) in the bone marrow (BM) are known to be of prognostic value for patients with early breast cancer (EBC). In addition to histopathological features, multigene expression assays, such as the commercially available 21-gene Breast Recurrence Score® assay, have been validated for evaluating prognosis and making decisions concerning adjuvant treatment in EBC. In a previous retrospective study from our group, the 21-gene assay was shown to be associated with DTC-detection. A key endpoint of the prospective IRMA trial was to evaluate the association between Recurrence Score® (RS) result and tumor cell dissemination in patients with EBC. DTC-status and RS result were assessed in patients with ER-positive/HER2-negative EBC with 0–3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women’s Health of Tuebingen University, Germany. Patients with a high RS result (≥ 26) were more frequently DTC-positive (22.6%) than patients with a low RS result (8.6%, p=0.034). The odds for DTC-positivity increased with rising RS values (p= 0.047). We therefore confirm that a high genomic risk is associated with tumor cell dissemination into the BM. Further trials are needed to investigate whether therapeutic decisions could be further individualized by combining DTC-status and prognostic gene signature testing.

Despite tremendous progress in deciphering breast cancer at the genomic level, the pronounced heterogeneity remains a major obstacle to the advancement of novel and more effective treatment approaches. Frequent treatment failure and the development of treatment resistance highlight the need for patient-derived tumor models that reflect the individual tumors of breast cancer patients and allow a comprehensive analyses and parallel functional validation of individualized and therapeutically targetable vulnerabilities in protein signal transduction pathways. Here, we introduce the generation and application of breast cancer patient-derived 3D microtumors (BC-PDMs). Residual fresh tumor tissue specimens were collected from n = 102 patients diagnosed with breast cancer and subjected to BC-PDMs isolation. BC-PDMs retained histopathological characteristics, and extracellular matrix (ECM) components together with key protein signaling pathway signatures of the corresponding primary tumor tissue. Accordingly, BC-PDMs reflect the intertumoral heterogeneity of breast cancer and its key signal transduction properties. DigWest®-based protein expression profiling of identified treatment responder and non-responder BC-PDMs enabled the identification of potential resistance and sensitivity markers of individual drug treatments, including markers previously associated with treatment response and yet undescribed proteins. The combination of individualized drug testing with comprehensive protein profiling analyses of BC-PDMs may provide a valuable complement for personalized treatment stratification and response prediction for breast cancer.

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Figure S1. Flow chart of the data selection process for a pooled analysis of the prognostic relevance of circulating tumor cells in early breast cancer. Patients were ineligible if no valid data on CTC presence at the time of primary diagnosis as assessed using the FDA-cleared CellSearch® System were available (e.g., because of insufficient amount of blood or test failure). * A total of 3,754 patients with early breast cancer were randomized in the SUCCESS A clinical trial; however, blood samples for the enumeration of CTCs with the CellSearch® System were only collected after written informed consent from 1,994 of those patients.

Purpose: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis.Experimental Design: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I–III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months.Results: One or more CTCs were detected in 20.2% of the patients. CTC-positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P < 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47–2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49–2.40), breast cancer–specific survival (HR, 2.04; 95% CI, 1.52–2.75), and overall survival (HR, 1.97; 95% CI, 1.51–2.59).Conclusions: In patients with primary breast cancer, the presence of CTCs was an independent predictor of poor disease-free, overall, breast cancer–specific, and distant disease-free survival. Clin Cancer Res; 22(10); 2583–93. ©2016 AACR.

Table S1. Patients and study variables according to study center for the pooled analysis of circulating tumor cells in early breast cancer

Purpose Preeclampsia occurs in up to 15% of pregnancies and constitutes a major risk factor for cardiovascular disease. This observational cohort study aimed to examine the association between preeclamptic pregnancies and cardiovascular outcomes as well as primary and specialized care utilization after delivery. Methods Using statutory claims data we identified women with singleton live births between 2010 and 2017. Main outcomes included the occurrence of either hypertension or cardiovascular disease after one or more preeclamptic pregnancies, number of contacts to a general practitioner or cardiologist after delivery and prescribed antihypertensive medication. Data were analyzed using Cox proportional hazard regression models adjusted for maternal age, diabetes, dyslipidemia, and obesity. Results The study cohort consisted of 181,574 women with 240,698 births. Women who experienced preeclampsia once had an increased risk for cardiovascular (hazard ratio, HR = 1.29) or hypertensive (HR = 4.13) events. In women affected by recurrent preeclampsia, risks were even higher to develop cardiovascular disease (HR = 1.53) or hypertension (HR = 6.01). In the following years after delivery, general practitioners were seen frequently, whereas cardiologists were consulted rarely (0.3 and 2.4%). Conclusion Women affected by preeclampsia experience an increased risk of developing chronic hypertension and cardiovascular disease, especially those with recurrent preeclampsia. Future medical guidelines should take this potential risk into account.

ObjectiveGynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study’s objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease.MethodsThe German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021.ResultsA total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy.ConclusionOur study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Purpose The purpose is to analyse perioperative complications associated with the retropubic tension-free vaginal tape (TVT) procedure and their management. Methods This retrospective, monocentric cohort study included 960 women after retropubic TVT procedure performed by one surgeon from 2011 to 2016. Complications were identified up to 6 weeks after the procedure, divided into specific and general complications and classified based on the Clavien–Dindo (CD) Classification. A visit 6 weeks after the surgical procedure was attended by all patients. Results 77 complications, of which 74 occurred postoperatively and 3 intraoperatively, affecting 72 (7.5%) out of 960 women. Urinary retention and voiding problems were the most common complication. The mean age of women suffering complications was 3.4 years higher in comparison to the mean age of women without complications (p = 0.036). The Body Mass Index (BMI) of the group of women with perioperative complications had an average BMI which was 0.5 kg/m2 lower than the average BMI of the women without complications. 22 (12.8%) out of 172 women with recurrent stress incontinence had postoperative complications, of which 21 were related to the TVT. Conclusion The retropubic TVT is a surgical procedure associated with a low number of perioperative complications, even in the group of elderly and overweight women, as well as in cases of recurrent stress incontinence.

Purpose Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.

Zusammenfassung Einleitung Multigen-Assays werden zunehmend als Entscheidungshilfe für eine Chemotherapie beim Mammakarzinom verwendet. Wir stellen hier den 21-Gen-Recurrence-Score (RS) von Patientinnen mit Brustkrebs vor, die routinemäßig in Deutschland untersucht wurden. Patientinnen und Methoden 4695 Patientinnen mit hormonrezeptorpositivem und HER2-negativem Brustkrebs im Frühstadium (pT1–3, pN0–1, M0) wurden einer retrospektiven Analyse unterzogen. Bei diesen Patientinnen wurde in Deutschland zwischen November 2015 und Juli 2018 der Genexpressionstest Oncotype DX zur Ermittlung des Recurrence-Scores durchgeführt. Die Klassifikation der RS-Gruppen erfolgte gemäß der TAILORx Studie (RS: 0–10; 11–25; 26–100). Ergebnisse Von diesen Patientinnen wurden 21 % in die niedrige RS-Gruppe, 63 % in die mittlere RS-Gruppe, und 15 % in die hohe RS-Gruppe eingeteilt. 1772 (81 %) von 2175 Patientinnen im Alter von über 50 Jahren und ohne Lymphknotenbefall wurden entweder in die niedrige oder die mittlere RS-Gruppe eingeteilt. Der Prozentsatz an Patientinnen mit einem niedrigen oder mittleren RS betrug 90 % bei Patientinnen ohne Lymphknotenbefall (1284 von 1432 Patientinnen), 79 % bei Patientinnen mit einem hohen (≥ 20 %) Ki-67-Wert (1829 von 2310 Patientinnen), 86 % bzw. 70 % bei Patientinnen mit G2- bzw. G3-Tumoren (3244 von 3762 Patientinnen bzw. 368 von 522 Patientinnen), 88 % bei Patientinnen mit einem Tumordurchmesser von > 5 cm (140 von 159 Patientinnen) und 82 % bei Patientinnen ohne Lymphknotenbefall, aber mit einem hohen klinischen Risiko (1110 von 1352). Schlussfolgerung Die Verteilung des 21-Gens RS bei deutschen Patientinnen, die in der klinischen Routinepraxis getestet wurden, deutet darauf hin, dass gemäß den Ergebnissen der TAILORx-Studie die Chemotherapie bei den meisten dieser Patientinnen keinen Nutzen hat.

Zusammenfassung Einleitung Narbige Verengungen und ein Volumendefizit im Bereich der Axilla können zu einem anhaltenden Lymphödem führen und zählen zu den häufigsten Nebenwirkungen nach einer Brustkrebstherapie im Achselbereich. Ziel dieser Arbeit ist die Vorstellung einer Operationstechnik zur Reduzierung von Lymphödemen mithilfe eines Turn-Over Flaps. Material und Methoden Zwischen Oktober 2016 und Mai 2018 wurden 5 Patientinnen mit einem Lymphödem Grad 2 nach Mammakarzinomtherapie mit dieser neuen Methode behandelt. Dabei erfolgte die vollständige Entfernung der kompromittierenden Narbenstränge der Axilla, gefolgt von einer Reaugmentation der Axilla mittels Turn-Over Flap. Danach wurde bei allen Patientinnen eine Brustrekonstruktion mit einer an die thorakodorsalen Gefäße angeschlossenen Fernlappenplastik durchgeführt. Prä- und postoperativ wurden der Umfang beider Arme, die Lebensqualität und die Schmerzen gemessen. Ergebnisse Im Durchschnitt sanken die Schmerzen im ipsilateralen Arm von 6 auf 1 auf der numerischen Schmerzskala, und die Lebensqualität verbesserte sich merklich (2,8 vs. 7,0). Es zeigte sich eine deutliche Verringerung des Lymphödems, vor allem im Oberarm. Komplikationen wie sekundäre Blutungen, Infektionen oder Lappenverlust sind nicht aufgetreten. Schlussfolgerung Eine vollständige Entfernung der nach Brustkrebsbehandlungen entstandenen Vernarbungen im Bereich der Axilla und eine Reaugmentation der Axilla mittels Turn-Over Flap führten zu einer Verringerung des ipsilateralen Lymphödems und zu einer Verbesserung der Schmerzen und der Lebensqualität. Wir deuten dieses Outcome als Ergebnis der physiologischen Ausrichtung der Lymphgefäße und eines lymphknotenhaltigen Transpositionslappens. Die Reaugmentation der Axilla mittels Turn-Over Flap könnte eine wirksame, nicht mikrochirurgische Alternative zur Lymphknotentransplantation darstellen.

Uterus transplantation (UTx) is currently the only available treatment for absolute uterine factor infertility. The International Society of Uterus Transplantation (ISUTx) was formally founded in 2017 and joined the Transplantation Society as a formal section in 2021. The Third International Congress of the ISUTx was held in Tübingen, Germany, in October 2021, as a hybrid meeting, attended virtually by about 450 delegates and in person by 35 delegates. This report summarizes the Tübingen meeting and complementary topics of relevance presented at the Second ISUTx state-of-the-art webinar meeting, held in Prague, in October 2020. Main topics covered included surgical considerations, including dissection of veins in living donors and the pros and cons of minimally invasive surgery; managing immune risks; UTx during the COVID-19 pandemic; lessons learnt in the areas of imaging and cytomegalovirus infection; long-term psychological outcomes; opportunities to increase organ availability; and new horizons in UTx, including potential reuse of transplants and the utilization of robotic approaches. Implementation of an International UTx Registry was discussed and considered crucial to assure quality, safety, and further progress in UTx. Attempts made thus far have been promising.

To identify potential genetic causes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), we analyzed blood and rudimentary uterine tissue of 5 MRKH discordant monozygotic twin pairs. Assuming that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with high allele frequency in the affected tissue, low allele frequency in the blood of the affected twin, and almost absent in blood of the unaffected twin. Focusing on MRKH candidate genes, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. In addition, we conducted transcriptome analysis of affected tissue and observed perturbations largely similar to those in sporadic cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a role of estrogen in MRKH pathology. Our genome sequencing approach of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. As no clear pathogenic differences were detected, research to evaluate other regulatory layers are required to better understand the complex etiology of MRKH.

Patients with hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (eBC) with a high risk of relapse often undergo adjuvant chemotherapy. However, only a few patients will gain benefit from chemotherapy. Since classical tumor characteristics (grade, tumor size, lymph node involvement, and Ki67) are of limited value to predict chemotherapy efficacy, multigene expression assays such as the Oncotype DXThe RS result was assessed in patients with HR+/HER2- unilateral eBC with 0-3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. Therapy recommendations without knowledge of the RS result were compared to therapy recommendations with awareness of the RS result.In total, 245 patients underwent RS assessment. Without knowledge of the RS result, 92/245 patients (37.6%) would have been advised to receive chemotherapy. After RS assessment, 56/245 patients (22.9%) were advised to undergo chemotherapy. Chemotherapy was waived in 47/92 patients (51.1%) that were initially recommended to receive it. Chemotherapy was added in 11/153 patients (7.2%) that were recommended to not receive it initially.Using the RS result to guide adjuvant treatment decisions in HR+/HER2- breast cancer led to a substantial reduction of chemotherapy. In view of the results achieved in prospective studies, the RS result is among other risk-factors suitable for the individualization of adjuvant systemic therapy.

Preeclampsia is associated with a substantially increased long-term risk for cardiovascular, cerebrovascular and renal disease. It remains unclear whether and to which extent specialized medical postpartum care is sought. We aimed to assess current utilization of postpartum primary and specialized care and medication prescription behavior in women who experienced preeclampsia. This retrospective observational study based on statutory claims data included 193,205 women with 258,344 singleton live births between 2010 and 2017 in Southern Germany. Postpartum care was evaluated by analyzing and comparing the frequency of medical consultations in primary and specialized care and prescriptions for antihypertensive medication among women with and without preeclampsia up to 7.5 years after delivery. Gynecologists and general practitioners were the main health care providers for all women. Although specialized postpartum care was sought by more women after preeclampsia, the effect size indices revealed no considerable association between a history of preeclampsia and the utilization of specialized outpatient aftercare (e.g. 2% vs. 0.6% of patients with and without preeclampsia who consulted a nephrologist during the first year postpartum, r = 0.042). Preeclampsia was associated with an increased risk to take any antihypertensive medication after delivery (HR 2.7 [2.6; 2.8]). Postpartum referral to specialized outpatient care and quarterly prescriptions of antihypertensives following preeclampsia failed to match the early and rapidly increased incidence and risk of hypertension. These data highlight the missed opportunity to implement a reasonable follow-up strategy and prevention management in order to achieve long-term clinical benefits.

Purpose The rates of hysterectomy are falling worldwide, and the surgical approach is undergoing a major change. To avoid abdominal hysterectomy, a minimally invasive approach has been implemented. Due to the increasing rates of subtotal hysterectomy, we are faced with the following questions: how often does the cervical stump have to be removed secondarily, and what are the indications? Methods This was a retrospective, single-centre analysis of secondary resection of the cervical stump conducted from 2004 to 2018. Results Secondary resection of the cervical stump was performed in 137 women. Seventy-four percent of the previous subtotal hysterectomy procedures were performed in our hospital, and 26% were performed in an external hospital. During the study period, 5209 subtotal hysterectomy procedures were performed at our hospital. The three main indications for secondary resection of the cervical stump were prolapse (31.4%), spotting (19.0%) and cervical dysplasia (18.2%). Unexpected histological findings (premalignant and malignant) after subtotal hysterectomy resulted in immediate (median time, 1 month) secondary resection of the cervical stump in 11 cases. In four patients, the indication was a secondary malignant gynaecological disease that occurred more than 5 years after subtotal hysterectomy. The median time between subtotal hysterectomy and secondary resection of the cervical stump was 40 months. Secondary resection of the cervical stump was performed vaginally in 75.2% of cases, laparoscopically in 20.4% of cases and abdominally in 4.4% of cases. The overall complication rate was 5%. Conclusion Secondary resection of the cervical stump is a rare surgery with a low complication rate and can be performed via the vaginal or laparoscopic approach in most cases. The most common indications are prolapse, spotting and cervical dysplasia. If a secondary resection of the cervical stump is necessary due to symptoms, 66.6% will be performed within the first 6 years after subtotal hysterectomy.

Im Rahmen von onkologischen Operationen besteht immer die Abwagung zwischen onkologischer Sicherheit und dem Funktionserhalt. Dies gilt insbesondere bei Operationen im Becken, aufgrund der engen Lagebeziehung zur Muskulatur des Beckenbodens sowie Gefas und Nervenverlaufen. Aktuell dienen zumeist Risikomodelle, praoperative Bildgebung, die Einschatzung des Operateurs sowie der intraoperative Schnellschnitt als Entscheidungsgrundlage. Neue Bildgebungstechniken sowie Standardisierung im Schnellschnitt haben diese in den letzten Jahren deutlich verbessert. Es verbleiben jedoch weiterhin Einschrankungen durch zeitliche Verzogerung sowie erschwerte korrekte anatomische Zuordnung der zu untersuchenden Praparate. Alternative intraoperative Verfahren konnten diese Grenzen in der Zukunft uberwinden. Patientenabgeleitete Organoide haben sich in den letzten Jahren zu einem wichtigen neuen Forschungsvehikel entwickelt. Sie basieren auf Tumorstammzellen, die unter speziellen Kulturbedingungen dreidimensionale Replikate des Ursprungsgewebes formen. Damit sind sie optimal geeignet zur Testung von individuellen Systemtherapien aber auch als Validierungstechnik fur neue diagnostische Verfahren. Das durch die Deutsche Forschungsgemeinschaft geforderte Graduiertenkolleg 2543/I analysiert in einem interdisziplinaren Team das Potenzial neuer diagnostischer Methoden im Hinblick auf die intraoperative real-time Diagnostik in Erganzung zu konventionellen Schnellschnittdiagnostik

Background/aim Detection of disseminated tumor cells (DTCs) after systemic treatment predicts poor prognosis in breast cancer patients. The aim of our study was to assess the expression of stem-cell marker SOX2 on DTCs and in the primary tumor of patients treated with neoadjuvant chemotherapy (NAT). Materials and methods In 170 DTC-positive patients after NAT an additional slide of bone marrow aspirate was stained by double immunofluorescence to detect SOX2-positive DTCs. The SOX2 status of the primary tumor was assessed using the same antibody. Results The SOX2-status of DTCs was determined in 62 patients and 20 of those (32%) had SOX2 positive DTCs. The SOX2 status of DTCs was not associated with any of the clinicopathological factors. A total of 36% of the patients with a SOX2-negative tumor showed SOX2-positive persistent DTCs. Conclusion SOX2-positive DTCs can be detected in breast cancer patients after NAT, even in patients with SOX2-negative primary tumors. This suggests that these populations may have evolved independently of each other.

ZusammenfassungDie diesjährige 17. St.-Gallen(SG)-Konsensus-Konferenz zur Behandlung von Patientinnen mit frühem Mammakarzinom (SG-BCC) stand unter dem Motto „Customizing local and systemic therapies for women with early breast cancer“ und fokussierte auf die Herausforderung, die Behandlung des frühen Mammakarzinoms zielgerichteter auf die individuelle Krankheitssituation zu adaptieren. Wie schon in den vergangenen Jahren hat auch dieses Jahr eine deutsche Arbeitsgruppe führender Brustkrebsexpert*innen die Ergebnisse der internationalen SG-BCC 2021 vor dem Hintergrund der deutschen Therapieempfehlungen für den Klinikalltag in Deutschland diskutiert. Der Vergleich der SG-Empfehlungen mit den erst kürzlich aktualisierten Therapieempfehlungen der Kommission Mamma der Arbeitsgemeinschaft Gynäkologische Onkologie e. V. (AGO) sowie der S3-Leitlinie ist hilfreich, da sich das SG-BCC-Panel aus Experten unterschiedlicher Länder zusammensetzt, weshalb länderspezifische Besonderheiten in die SG-Empfehlungen einfließen können. Die deutschen Therapieempfehlungen der AGO sowie der S3-Leitlinie basieren auf der aktuellen Evidenz. Gleichwohl muss jede Therapieentscheidung immer einer Nutzen-Risiko-Abwägung für die individuelle Situation unterzogen und mit der Patientin besprochen werden.

In cancer, the complex interplay between tumor cells and the tumor microenvironment results in the modulation of signaling processes. By assessing the expression of a multitude of proteins and protein variants in cancer tissue, wide-ranging information on signaling pathway activation and the status of the immunological landscape is obtainable and may provide viable information on the treatment response. Archived breast cancer tissues from a cohort of 84 patients (no adjuvant therapy) were analyzed by high-throughput Western blotting, and the expression of 150 proteins covering central cancer pathways and immune cell markers was examined. By assessing CD8α, CD11c, CD16 and CD68 expression, immune cell infiltration was determined and revealed a strong correlation between event-free patient survival and the infiltration of immune cells. The presence of tumor-infiltrating lymphocytes was linked to the pronounced activation of the Jak/Stat signaling pathway and apoptotic processes. The elevated phosphorylation of PPARγ (pS112) in non-immune-infiltrated tumors suggests a novel immune evasion mechanism in breast cancer characterized by increased PPARγ phosphorylation. Multiplexed immune cell marker assessment and the protein profiling of tumor tissue provide functional signaling data facilitating breast cancer patient stratification.

The objective of this case series was to describe different uterus-preserving surgical approaches and outcomes in patients with complex obstructive Müllerian duct malformation caused by cervical and/or vaginal anomalies. A retrospective analysis was performed including patients undergoing uterovaginal anastomosis (n = 6) or presenting for follow-up (n = 2) at the Department for Gynecology at the University of Tuebingen between 2017 and 2022. Uterovaginal anastomosis was performed with a one-step combined vaginal and laparoscopic approach (method A), a two-step/primary open abdominal approach with primary vaginal reconstruction followed by abdominal uterovaginal anastomosis after vaginal epithelization (method B) or an attempted one-step approach followed by secondary open abdominal uterovaginal anastomosis due to reobstruction (method A/B). Patients presented at a mean age of 15 years. Two patients were treated by method A, four by method B and two by method A/B. Functional anastomosis was established in seven of eight patients, with normal vaginal length in all patients. Concerning uterovaginal anastomosis, the primary open abdominal approach with or without previous vaginal reconstruction seems to have a higher success rate with fewer procedures and should be implemented as standard surgical therapy for complex obstructive genital malformations including the cervix.

The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were analyzed in relationship to systemic treatment, circulating tumor cells (CTC) count, progression-free survival (PFS), and overall survival (OS). Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429, and CTC status (CTC-positive ≥ 5 CTC/7.5 mL) was assessed in 47 patients at baseline (BL), after the first completed cycle of a new line of systemic therapy (1C), and upon the progression of disease (PD). MiR-200a, miR-200b, and miR-141 expression was reduced at 1C compared to BL. Upon PD, all miR-200s were upregulated compared to 1C. At all timepoints, the levels of miR-200s were elevated in CTC-positive versus CTC-negative patients. Further, heightened miR-200s expression and positive CTC status were associated with poorer OS at BL and 1C. In MBC patients, circulating miR-200 family members decreased after one cycle of a new line of systemic therapy, were elevated during PD, and were indicative of CTC status. Notably, increased levels of miR-200s and elevated CTC count correlated with poorer OS and PFS. As such, both are promising biomarkers for optimizing the clinical management of MBC.

Purpose Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. Methods ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model’s overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). Results A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761–0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595–0.800) as Brier score has been calculated 0.09. Conclusions We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC.

ObjectiveMayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a rare congenital disease manifesting with aplasia or severe hypoplasia of uterine structures. Even though extensive studies have been performed, for the majority of cases the etiology remains unclear. In this study, we sought to identify genetic causes in discordant monozygotic (MZ) twins using genome sequencing of blood of both twins as well as uterine tissue of the affected twin. In addition, we profiled the endometrial transcriptome of affected twins to compare perturbations with those of sporadic MRKH cases.ResultsFirst, analyzing the data under the assumption that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with a high allele frequency in affected tissue, a low allele frequency in blood of the affected twin and almost absent in the blood of the unaffected twin. Since ACTR3B has not been reported for genitourinary anomalies before, clinical relevance of the variant needs to be clarified.Second, examining the data for candidate genes previously implied in MRKH, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. Analysis for copy number and structural variants revealed no discordant variants in the twins or variants in candidate genes or regions.Third, we conducted transcriptome analysis of affected tissue and observed widespread perturbations largely similar to those in sporadic MRKH cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a key role of estrogen in MRKH pathology.ConclusionOur study on genome sequencing of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. Nevertheless, no clear pathogenic differences in the twins or between blood and tissue samples were detected. This points towards a more complex etiology of MRKH less dependent on genetic differences and more determined by epigenetic changes or environmental factors. Our transcriptome data showed a clear overlap with gene expression data of sporadic MRKH cases, indicating that the etiology for MRKH in discordant twins and sporadic cases is largely similar.

Purpose The PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient’s quality of life) using a questionnaire. Methods 235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient’s quality of life. Results 135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients’ health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested. Conclusion This study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry.

Wire-guided localization (WGL) is the most frequently used localization technique in non-palpable breast cancer (BC). However, low negative margin rates, patient discomfort, and the possibility of wire dislocation have been discussed as potential disadvantages, and re-operation due to positive margins may increase relapse risk. Intraoperative ultrasound (IOUS)-guided excision allows direct visualization of the lesion and the resection volume and reduces positive margins in palpable and non-palpable tumors. We performed a systematic review on IOUS in breast cancer and 2 meta-analyses of randomized clinical trials (RCTs). In non-palpable BC, 3 RCTs have shown higher negative margin rates in the IOUS arm compared to WGL. Meta-analysis confirmed a significant difference between IOUS and WGL in terms of positive margins favoring IOUS (risk ratio 4.34, p0.0001, I2 = 0%). 41 cohort studies including 3291 patients were identified, of which most reported higher negative margin and lower re-operation rates if IOUS was used. In palpable BC, IOUS was compared to palpation-guided excision in 3 RCTs. Meta-analysis showed significantly higher rates of positive margins in the palpation arm (risk ratio 2.84, p = 0.0047, I2 = 0%). In 13 cohort studies including 942 patients with palpable BC, negative margin rates were higher if IOUS was used, and tissue volumes were higher in palpation-guided cohorts in most studies. IOUS is a safe noninvasive technique for the localization of sonographically visible tumors that significantly improves margin rates in palpable and non-palpable BC. Surgeons should be encouraged to acquire ultrasound skills and participate in breast ultrasound training.Drahtlokalisation stellt die am häufigsten verwendete Lokalisationsmethode bei nicht palpablen Mammakarzinomen dar. Zu potenziellen Nachteilen der Technik gehören eine niedrige Rate an R0-Resektionen, die Invasivität und das Risiko der Drahtdislokation. Des Weiteren ist die Notwendigkeit einer Re-Operation mit einem erhöhten Rezidivrisiko assoziiert. Intraoperative Sonografie (IOUS) erlaubt eine direkte Visualisierung der Läsion und des Resektionsvolumens und reduziert die Rate an positiven Rändern bei palpablen und nicht palpablen Tumoren. Wir führten ein systematisches Review der Studien zur IOUS durch. Die randomisierten Studien wurden in 2 Metaanalysen ausgewertet. In nicht palpablen Mammakarzinomen zeigten3 randomisierte Studien höhere R0-Resektionsraten im IOUS-Arm, verglichen mit Drahtlokalisation. Der signifikante Unterschied konnte in der Metaanalyse bestätigt werden (Risk Ratio 4,34, p0,0001, I2 = 0%). Die meisten der 41 Kohortenstudien mit 3291 Patientinnen zeigten höhere R0-Resektionsraten und niedrigere Nachresektionsraten bei Verwendung von IOUS. Eine Metaanalyse von 3 randomisierten Studien bei palpablem Mammakarzinom zeigte signifikant höhere Raten an positiven Rändern im Palpations-Arm (Risk Ratio 2,84, p = 0,0047, I2 = 0%). In 13 Kohortenstudien mit 942 Patientinnen mit palpablem Mammakarzinom, waren die R0-Resektionsraten meist höher und die Gewebsvolumina niedriger, bei Verwendung von IOUS. IOUS ist eine sichere nicht invasive Technik zur Lokalisation von sonografisch sichtbaren Tumoren und verbessert R0-Resektionsraten bei palpablem und nicht palpablem Mammakarzinom. Sonografische Weiterbildung für Brustoperateure erscheint empfehlenswert.