Registry Study of the Working Group on Cervical Pathology and Colposcopy (AGCPC) on the Diagnostic Algorithm for the New Cervical Cancer Screening - Initial Data.

Introduction: For the first time since 1971, new regulations were introduced for cervical cancer screening as an organized cancer screening guideline (oKFE-RL) starting 1 January 2020. From the age of 20, a cytological smear test is performed annually, and from the age of 35, so-called co-testing (cytology and test for high-risk HPVs) is performed every three years. In case of abnormalities, the algorithm is used as the basis for investigation. According to this diagnostic algorithm, even so-called low-risk groups receive early colposcopic evaluation. This approach has been heavily debated and serves as the basis for this registry study. Methods: All patients who presented to the centers for a colposcopy as part of the diagnostic algorithm were included after signing an informed consent form. The following findings were obtained: Medical history, colposcopy, histology, and cytology findings, as well as possible therapies and their findings. The aim was to evaluate the frequency of the target lesions cervical intraepithelial neoplasia (CIN) 2+/CIN 3+ in the respective groups. Result: A total of 4763 patients were enrolled in the study from July 2020 to October 2022. As a referral diagnosis, HPV persistence (HPV: human papillomavirus) with group I was determined in 23.9% (1139), HPV persistence with group II-a in 2.1% (100), II-p (ASC-US) in 11.2% (535), and II-g (AGC endocervical NOS) in 1.3% (64). III-p (ASC-H) and III-g (AGC endocervical favor neoplastic) were found in 9.4% (447) and 2.2% (107), respectively, IIID1 (LSIL) in 19% (906), IIID2 (HSIL, moderate dysplasia) in 18.9% (898), IVa-p (HSIL, severe dysplasia) in 10.7% (508), IVa-g (AIS) in 0.7% (31), IVb-p (HSIL with features suspicious for invasion) and IVb-g (AIS with features suspicious for invasion) in 0.3% (15), 0.1% (6), and 7 with suspected invasion V-p (squamous cell carcinoma)/V-g (endocervical adenocarcinoma) (0.1%). In the IVa-p group (HSIL, severe dysplasia), 67.7% had CIN 2+ and 56.5% had CIN 3+, adenocarcinoma in situ (AIS), and adenocarcinoma. If the histology of the excised tissue specifically based on the colposcope findings was also evaluated, CIN 2+ was found in 79.7% of cases, and CIN 3+ in 67.3% of cases. In IIID2 (HSIL, moderate dysplasia), CIN 2+ was detected in 50.9%, and CIN 3+/AIS in 28.3%. After evaluating patients who underwent surgery immediately, this increased to 53.0% for CIN 2+ and 29.3% for CIN 3+/AIS. In IIID1 (LSIL), CIN 2+ was detected in 27.4% and CIN 3+/AIS in 11.7%, and in II-p (ASC-US), CIN 2+ was detected in 23.4% and CIN 3+ and AIS in 10.8%, and in II-g (AGC endocervical NOS), CIN 2+ was detected in 34.4% and CIN 3+ in 23.4%. In the HPV persistence/II-a and I group, 21% showed CIN 2+, and 12.1% showed CIN 3+ and AIS, and 13% showed CIN 2+ and 5.9% showed CIN 3+ and AIS. In patients who were HPV-negative and had further diagnostics performed on the basis of cytologic smear alone, 27.9% had CIN 2+, and 14.1% had CIN 3 and AIS. Discussion: In a synopsis of the present findings of our initial data of the registry study on the new cervical cancer screening, according to the organized early cancer screening guideline (oKFE-RL), we could show that the target lesion CIN 3+ and AIS is detected unexpectedly frequently in a not insignificant proportion, especially in the cytological low-risk group. Currently, we cannot answer whether this can reduce the incidence and mortality of cervical carcinoma, but this could be an initial indication of this and will be reviewed in further long-term evaluations.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer.

OBJECTIVE: To study how genetics may play a role in determining risk of chemotherapy-related amenorrhea (CRA) in young women with breast cancer. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENT(S): Premenopausal women ≤45 years of age enrolled in one of these three trials were included if they had at least one menstrual case report form after chemotherapy ended and if they were of European ancestry. Forms during and up to 3 months after receipt of GnRH agonist were excluded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association of single-nucleotide polymorphisms with post-chemotherapy menstruation adjusted for trial and arm, age, tamoxifen use, and nodal status. RESULT(S): The median age of the 1,168 women was 41 years (range 19-45). Among these, 457 (39%) never resumed menses after chemotherapy. Older age, tamoxifen use, and node-negative disease were associated with increased risk of CRA. Adjusting for these, rs147451859, in an intron of PPCDC (phosphopantothenoylcysteine decarboxylase), and rs17587029, located 5' upstream of RPS20P11 (ribosomal protein S20 pseudogene 11), were associated with post-chemotherapy menstruation. CONCLUSION(S): Genetic variation may contribute to risk of CRA. Better prediction of who will experience CRA may inform reproductive and treatment decision making in young women with cancer.

Differential prognostic relevance of patho-anatomical factors among different tumor-biological subsets of breast cancer: Results from the adjuvant SUCCESS A study.

OBJECTIVES: In breast cancer, large tumor size, positive nodal stage and a triple-negative tumor subtype are associated with reduced survival, but the interactions between these prognostic factors are not well understood. MATERIAL AND METHODS: Here we re-evaluated the impact of tumor size, nodal stage and tumor subtype on disease-free survival (DFS), overall survival (OS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) in a retrospective analysis using data from the adjuvant SUCCESS A trial. Subgroup analyses were conducted to assess whether the effect of tumor size and nodal stage on survival depended on tumor subtype. RESULTS: Increasing tumor size, higher nodal stage and triple negative breast cancer (TNBC) were associated with unfavorable prognosis (all p < 0.001). There was no significant interaction between tumor subtype and tumor size (p > 0.5 for all four survival endpoints), but we found significant interactions between tumor subtype and nodal stage (p < 0.05 for all four survival endpoints), with no differences in survival among tumor subtypes for patients with pN0 tumors (all p > 0.05) and pronounced differences in survival among tumor subtypes for patients with positive nodal stage (all p < 0.001). CONCLUSIONS: This analysis confirms tumor size, nodal stage and tumor subtype as independent prognostic factors in high-risk early breast cancer. Nodal-positive patients with TNBC had a considerably worse outcome compared to nodal-positive patients with another tumor subtype. This underlines the importance for early detection particularly for patients with TNBC. TRIAL REGISTRATION: EudraCT 2005-000490-21; ClinicalTrials.gov Identifier: NCT02181101.

Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment.

PURPOSE: Several studies have provided evidence on the prognostic relevance of circulating tumor cells (CTCs) detected before and after chemotherapy regarding overall survival (OS) and progression-free survival (PFS) in early breast cancer (EBC). We provide data on the prevalence of CTCs 2 and 5 years after primary diagnosis in a cohort of patients with EBC. METHODS: The SUCCESS study is a multicenter, prospective, randomized trial comparing PFS in primary breast cancer patients undergoing one of two adjuvant chemotherapy regimens followed by 2 versus 5 years of treatment with zoledronate. CTCs from patients without signs of breast cancer recurrence were analyzed in peripheral blood using the FDA cleared CellSearch® System (Veridex, USA) 2 and 5 years after primary diagnosis. RESULTS: CTCs were detected at 2 and 5 years after primary diagnosis in 96 (16.7%) and 47 (8.2%) of the 574 patients, respectively. There were no associations between CTC status and patient and tumor characteristics or treatment regimens. In 442 (77.0%) patients, no CTCs were detected at either of the two time points, and in 11 patients (1.9%), CTCs were found at both 2 and 5 years after primary diagnosis. In 85 (14.8%) patients, CTCs were present 2 years after primary diagnosis but not after 5 years, while 36 (6.3%) patients had CTCs in their blood only at the 5-year follow-up. CONCLUSIONS: In patients with EBC, CTCs can be detected even 5 years after primary diagnosis without clinical signs of disease recurrence.

Influence of Prognostic Factors on Lymph Node Involvement in Endometrial Cancer: A Single-Center Experience.

OBJECTIVE: The requirement for and extent of lymphadenectomy in endometrial cancer is still controversial. Clinicopathological prognostic factors could be helpful to predict lymph node involvement and avoid therefore unnecessary lymphadenectomy. The aim of this study was to investigate which factors can predict lymph node involvement and how lymph node metastases are distributed in the pelvic and para-aortic regions. METHODS: This retrospective analysis was performed by analyzing data from patients with endometrial cancer treated with standard surgery and lymphadenectomy at the Department of Gynecology and Obstetrics of the University Hospital Ulm in 2000 to 2013. RESULTS: One hundred twenty-five patients received pelvic lymphadenectomy with a median of 25 removed nodes, and 111 patients additionally received para-aortic lymphadenectomy with a median of 12 removed nodes. Metastatic lymph nodes were found in 24.8% of the patients, and a multivariate logistic regression showed that lymphovascular space invasion, histological type, and tumor stage significantly and independently predicted lymph node involvement. Of the 111 patients with both pelvic and para-aortic lymphadenectomy, 18 (16.2%) patients had metastatic para-aortic nodes, and 3 (2.7%) patients had isolated positive para-aortic lymph nodes without involvement of pelvic lymph nodes. DISCUSSION: Lymphovascular space invasion, histological type, and tumor stage are significant predictors of lymph node involvement in endometrial cancer. In patients at high risk of nodal involvement, lymphadenectomy should be performed systematically up to the renal vein. Large and carefully designed prospective studies are needed to evaluate patient cohorts for which a complete lymphadenectomy provides a survival benefit. In the future, the increasing use of sentinel node biopsy may facilitate a more personalized treatment of patients with endometrial cancer.

Value of endometrial thickness assessed by transvaginal ultrasound for the prediction of endometrial cancer in patients with postmenopausal bleeding.

PURPOSE: Histological confirmation of endometrial cancer by dilatation/curettage (D/C) in women with postmenopausal bleeding (PMB) can be challenging due to anesthesiological and/or surgical risks. Thus, less invasive methods for diagnostics are required to identify patients with minimal risk for endometrial cancer (EC) to avoid unnecessary surgical intervention. The objective of this single-center cohort study was to assess the diagnostic validity of transvaginal ultrasound (TVUS) measurements of endometrial thickness (ET) in patients with PMB for the detection of EC. METHODS: A retrospective analysis of data from patients presenting between January 2005 and August 2014 at the Department of Obstetrics and Gynecology, University Hospital Ulm, Germany, with PMB and subsequent D/C was performed. Complete data with TVUS documentation of ET and histological results of tissue samples were available from 254 patients. In addition, data on age, body mass index (BMI), ASA-score, diabetes, hypertension, and hematological laboratory values (for a smaller subsample) were recorded. To identify independent risk factors, a multivariate logistic regression with endometrial cancer as binary response variable (yes/no) was performed. Diagnostic efficacy data for different ET cutoff points (≤1 to ≤26 mm) were obtained by a receiver operator characteristic (ROC) curve analysis. RESULTS: The multivariate logistic regression revealed a significant independent predictive value for age and ET. However, none of the analyzed ET cutoff points showed optimal diagnostic validity, as all cutoff points with sensitivity rates above 90% (≤1 to ≤5 mm) had false positive rates of 70% and higher. CONCLUSIONS: There is no ET cutoff point that provides good diagnostic accuracy and/or reliably excludes the presence of endometrial cancer in patients with PMB. Thus, our data analysis supports the actual German approach of histological evaluation of any PMB to confirm or exclude EC.

Survey of compartment syndrome of the lower extremity after gynecological operations.

PURPOSE: This study was aimed to investigate incidence, circumstances and consequences of acute compartment syndrome (CS) of the lower extremity after gynecological operations in lithotomy position by collecting data from departments of Obstetrics and Gynecology in Germany. DESIGN: Retrospective observational study. SETTING: Departments of Obstetrics and Gynecology in the area of North Rhine (Germany) METHODS: A 24-item questionnaire was sent to 168 gynecological departments. In addition, cases anonymously reported to the Expert Committee for Medical Malpractice Claims of the Medical Association of North Rhine between 2002 and 2012 were analyzed. MAIN OUTCOME MEASURE: Incidence of acute CS after gynecological operations. RESULTS: A total of 59 questionnaires (35 %) were returned for analysis, reporting 21 cases of CS. Based on the collected data, we calculated an incidence of postoperative CS ranging between 0.067 % and 0.28 %. All reported cases of postoperative CS occurred after surgeries in lithotomy position, 57.1 % of cases occurred after laparoscopic procedures and 76.2 % after procedures longer than 4 h. Overall, 61.0 % of departments do not routinely inform about the risk of this complication when they get patients' informed consent. Reported prevention strategies were inconsistent and ranged from none to multiple measures. CONCLUSION: CS is a complication clearly associated with long lasting gynecological operations in Lithotomy position. Despite a relatively high incidence, so far no guidelines on perioperative management and medicolegal aspects exist and preventive measures are heterogeneous among institutions. The need for guidelines and recommendations by an expert committee has been identified.

Compartment syndrome after gynecologic operations: evidence from case reports and reviews.

Compartment syndrome (CS) of the lower leg is a rare but severe complication of operations in the lithotomy (LT) position after urologic, gynecologic and general surgery. A delay in diagnosis and treatment can lead to loss of function and even life-threatening complications. The pathophysiology is still not fully understood but it is believed that ischemia as a result of increased compartment pressure and decreased perfusion pressure may lead to CS. The type of leg support and the intraoperative hypotension have been discussed as risk factors but evidence is mainly based on case reports and expert opinion. Studies suggest that time spent in the LT position and the addition of head-down tilt are associated with CS. As these positions are routinely applied during various gynecologic procedures, forensically CS has to be considered as a specific complication of gynecologic surgery in the LT position. Despite the low incidence there is a need for prospective studies and guidelines for its prevention. Sixteen case reports describing 19 cases of CS following gynecologic surgery in lithotomy position were found during a literature search. This review is based on 14 of these case reports (17 cases), which describe a postoperative compartment syndrome in a previously healthy leg. We summarize the reported cases and literature on CS after gynecologic procedures in order to increase awareness among medical staff and to give careful recommendations regarding perioperative management based on available information.