Adjuvant radiotherapy and local recurrence in vulvar cancer - a subset analysis of the AGO-CaRE-1 study.

BACKGROUND: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. PATIENTS AND METHODS: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. RESULTS: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). CONCLUSION: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors.

Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review.

This meta-analysis and systematic review investigated evidence of the effect of oral micronutrient supplementation on male fertility. Following searches of PubMed, Ovid/Ovid Medline(r) and Embase, 18 randomized, double-blind, placebo-controlled trials were included in the meta-analysis (seven studies) and/or the systematic review (12 studies). The meta-analysis showed significant improvement in semen parameters for selenium (200µg/day and 100µg/day) (standard mean difference [SMD] 0.64 for oligozoospermia, 1.39 for asthenozoospermia), L-carnitine (2 g/day) and acetyl-L-carnitine (LAC; 1 g/day) combined (SMD 0.57 for asthenozoospermia), and co-enzyme Q10 (200 and 300 mg/day) (SMD 0.95 for oligozoospermia, 1.48 for asthenozoospermia, 0.63 for teratozoospermia). The systematic review identified promising data for supplementation with 66 mg/day zinc combined with folic acid (5 mg/day), and the polyunsaturated fatty acids eicosapentaenoic acid (EPA; 1.12 g/day) and docosahexaenoic acid (DHA; 0.72 g/day). Pregnancy rate was evaluated in a limited number of trials (four in the meta-analysis, three in the systematic review). This analysis suggests supplementation with selenium (alone or combined with N-acetylcysteine), co-enzyme Q10 and the combinations L-carnitine + acetyl-L-carnitine, folic acid + zinc and EPA + DHA is beneficial in the treatment of male infertility. Because of the small number of available studies and low number of participants, further well-designed clinical studies are needed to obtain a better overview of efficient methods of treating male infertility.

Epidemiology of injuries in outdoor and indoor hockey players over one season: a prospective cohort study.

OBJECTIVES: To determine the incidence and characteristics of hockey ('field hockey') injuries over the course of one outdoor and indoor season. Comparisons of female versus male players, outdoor versus indoor season and match versus practice were performed. METHODS: Female and male teams of the first, second, third, regional and youth divisions were recruited among a local hockey association in Northern Germany, and followed over an indoor and an outdoor season. Exposure times and location, type, severity and cause of injuries during practice and matches were documented by the coaches or medical staff and collected weekly. Prevalence and incidence rates were calculated. RESULTS: Of the 232 players (mean±SD age 20.7±4.7 years, 68.1% male, 31.9% first division), 84 players (36.2%) suffered 108 new injuries during the season. The overall incidence rate was 3.7 injuries per 1000 player hours (95% CI 3.0 to 4.4). The injury incidence was lower in practice (2.7 per 1000 player practice hours, 95% CI 2.0 to 3.3) than in matches (9.7 per 1000 player match hours, 95% CI 6.8 to 12.7), and was similar for female and male players as well as during the outdoor and the indoor season. Most injuries affected the lower limb (thigh, knee and ankle) and occurred without contact (58.3%). Severe injuries (n=34; 31.5%) were predominantly located at the knee and hand/finger. CONCLUSION: Hockey players have a high prevalence and incidence of injuries, especially at the lower limb.

Restoration of hip architecture with bipolar hemiarthroplasty in the elderly: does it affect early functional outcome?

INTRODUCTION: Reconstruction of the anatomic architecture correlates with functional outcome in patients receiving elective total hip arthroplasty. In theory similar rules should apply for bipolar hemiarthroplasty in femoral neck fractures. The influence of anatomic restoration after bipolar hemiarthroplasty on short-term clinical and functional outcome is explored in this study. PATIENTS AND METHODS: Patients receiving bipolar hemiarthroplasty for intracapsular femoral neck fractures between 2010 and 2012 were included into a retrospective cohort study. Radiologic and functional outcome parameters were recorded during the acute care phase and geriatric rehabilitation. Postoperative mobilization data were recorded and co-morbidities documented for each case. Outcome parameters were obtained during geriatric rehabilitation: Barthel index, Tinetti score, Timed up and go test, Mini-Mental State Examination. The FO-ratio (ratio of femoral offset to the body weight lever arm), HC-ratio (ratio of the height of the hip center to the pelvic height) and the BWLA ratio (ratio of the body weight lever arm to the pelvic height) were obtained from postoperative radiographs. RESULTS: A total of 193 patients with a median age of 84 (IQR = 78-94, 72% female) were analyzed. The in-hospital mortality rate was 5.7%. There was a high proportion of patients with prior co-morbidities (96% with at least one co-morbidity). During rehabilitation the Barthel index improved significantly (p < 0.001) from 40 to 55. The median Tinetti score on rehabilitation discharge was 15.5 (IQR = 10-19.5). The patients significantly improved in the timed up and go test from a median of 22 to 19 s. A significant difference (p < 0.001) was found comparing the FO ratios of the operated vs. non-operated side. None of the radiographic measures, representing the reconstructed anatomic hip geometry, significantly influenced the clinical and geriatric outcome. CONCLUSIONS: Applying the short-term functional outcome scores used in this study, optimized anatomic restoration in hemiarthroplasty may not be a major influencing factor in a cohort of elder, multi-morbid patients.

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

Risk for Pelvic Metastasis and Role of Pelvic Lymphadenectomy in Node-Positive Vulvar Cancer-Results from the AGO-VOP.2 QS Vulva Study.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

Detection and clinical relevance of early disseminated breast cancer cells depend on their cytokeratin expression pattern.

The factors determining the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients are largely unknown. Here we compared the specificity and clinical performance of two antibodies frequently used for DTC detection. Reactivities of antibodies A45-B/B3 (A45) and AE1/AE3 (AE) for selected cytokeratins (CK) were assessed by 2-DE Western Blot analysis. Using these antibodies bone marrow aspirates from 391 breast cancer patients (M(0), pT1-3, pN0-3) were screened for the presence of DTC. To obtain prognostic information, patients were followed up over a median of 83 months for time to relapse and 99 months for time to death. Among the analyzed CK, AE detected CK5, CK7, CK8, and CK19, whereas A45 recognized CK7 and CK18. In total, 24 of 391 patients (6.1%) were DTC-positive for A45, and 41 (10.5%) for AE. Although concordance between the two antibodies was 84.4%, overlap among positive cases was only 3.2%. DTC-positivity with AE and A45 was more frequent in patients of higher nodal status (P=0.019 and P=0.036, respectively). Nearly all patients with A45-positive DTC had hormone receptor-positive tumors (23/24), while detection of AE-positive DTC was more frequent among hormone receptor negative patients (P=0.006). Survival analyses of all patients revealed shorter distant disease-free survival (P=0.039) for patients with A45-positive DTC, whereas the prognostic relevance of AE-positive DTC was restricted to node-positive patients. The clinical utility of immunocytochemical (ICC) DTC detection depends on the anti-CK antibody used, which may reflect the complex CK composition of DTC.

The effect of family history on screening procedures and prognosis in breast cancer patients - Results of a large population-based case-control study.

BACKGROUND: The potential benefit of additional breast cancer screening examinations in moderate risk patients (patients with a history of breast cancer in one or two family members) remains unclear. METHODS: A large population-based case-control study on breast cancer in postmenopausal women in Germany recruited 2002-2005 (3813 cases and 7341 age-matched controls) was used to assess the association of family history with breast cancer risk. Analysis of family history, participation in screening procedures, and tumor size regarding prognosis in patients was based on follow-up data until 2015. RESULTS: A first degree family history of breast cancer was associated with higher breast cancer risk (OR 1.39, p < 0.001). Patients with a first degree family history of breast cancer were more likely to have had >10 mammograms (MG) (42.7% vs. 24.9%, p < 0.001) and showed a higher rate of imaging-detected tumors (MG or ultrasound) (45.8% vs. 31.9%, p < 0.001). A smaller tumor size at initial diagnosis (below 2 cm) was more likely in patients with a positive family history (OR 1.45, p < 0.001) and a higher number of MG (≥10 MG: OR 2.29). After accounting for tumor characteristics, mammogram regularity (HR 0.72, p < 0.001) and imaging-assisted tumor detection (HR 0.66, p < 0.001) were associated with better overall survival but not with a positive family history. DISCUSSION: Patients with a positive family history had a higher rate of imaging detected tumors with smaller size at initial diagnosis compared to patients without affected family members. Screening was associated with improved survival after a breast cancer diagnosis, irrespective of a positive family history.

Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial.

In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001-10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT.

Clinicopathological prognostic factors and patterns of recurrence in vulvar cancer.

BACKGROUND: Vulvar cancer is a rare disease and knowledge on prognostic factors is therefore limited and inconsistent. The aim of this study was to determine prognostic variables for recurrence and survival and to identify patterns of recurrence in patients with vulvar cancer. PATIENTS AND METHODS: All patients (n = 103) with primary vulvar cancer treated at the University Medical Center Hamburg-Eppendorf between 1996 and 2003 were retrospectively analysed regarding the prognostic relevance of different clinicopathological variables. Recurrences were evaluated with regard to their characteristics and localisation. RESULTS: Age, lymph node metastasis, tumor size, depth of invasion and involvement of resection margins predicted poor disease-free and overall survival in univariate analysis. In multivariate analysis, lymph node status was the most important independent prognostic factor (p = 0.002). No correlation was observed between lymph node metastasis and localization of recurrent disease. Regardless of initial nodal involvement, recurrences occurred primarily in the vulvar region. CONCLUSION: Inguinofemoral lymph node status at initial diagnosis is of critical prognostic importance for patients with vulvar cancer. Further tumour biological characteristics need to be identified to stratify patients with nodal involvement for adjuvant radiotherapy of the vulva to prevent local recurrences.

Prognostic significance of CA-125 in the management of patients with recurrent epithelial ovarian carcinoma selected for secondary cytoreduction.

BACKGROUND: Despite radical surgical and chemotherapeutic treatment of ovarian cancer, the majority of patients develop recurrence and die due to progressive disease. Routine measurement of the tumor marker CA-125 is often used in the follow-up management. However, the role of preoperative CA-125 as a prognostic factor before secondary cytoreduction of relapsed ovarian cancer has not been determined. PATIENTS AND METHODS: CA-125 serum concentration and relevant clinico-pathological variables were analyzed regarding their potential prognostic impact in patients selected for secondary cytoreduction of recurrent epithelial ovarian cancer. RESULTS: In total, 48 patients underwent secondary cytoreduction at the University Medical Center Hamburg-Eppendorf between 1996 and 2004 and 36 patients were evaluable for serum CA-125 concentration. Median age was 60 years (range 30-78 years) and median relapse-free survival before secondary cytoreduction was 18 months. The median time to progression after secondary surgery was 22 months (range 1-100 months), and median overall survival was 26 months (range 1-100 months). Serum CA-125 at the time of secondary cytoreduction was elevated (>35 kU/L) in 30 of 36 patients (81%) with a median of 212 kU/L (range 6-3866 kU/L). Multivariate analysis did not reveal a prognostic significance for preoperative CA-125. The only independent prognostic factors of improved survival were progression-free interval before secondary cytoreduction (p=0.047) and minimal residual disease after secondary cytoreduction (p=0.024). CONCLUSION: Although most patients had elevated serum CA-125 at the time of secondary cytoreductive surgery, CA-125 had no prognostic relevance.