HER2 Low Expression in Primary Male Breast Cancer.

Purpose: The introduction of HER2-targeting antibody drug conjugates (ADCs) offers new treatment options for female breast cancer patients (FBC) expressing low levels of HER2 (HER2 low). No evidence was found that HER2 low describes a new FBC subtype. There is a lack of studies determining the impact of HER2 low in male breast cancer (MBC). In this study, we evaluate the prevalence of HER2 low in primary MBC and correlate the results with patient characteristics. Patients and Methods: In this study, histological specimens were obtained from 120 male patients diagnosed and treated for primary invasive breast cancer from 1995 to 2022 at Breast Cancer Units in Bergisch Gladbach, Chemnitz, and Zwickau, Germany. HER2 immunostaining and in situ hybridization were performed by central pathology and evaluated based on the ASCO/CAP guidelines. The correlation of expression of HER2 low with tumor biological characteristics and patient outcomes was investigated. Results: Out of all cases, four patients (3.3%) showed HER2 positivity (3+), 39 (32.5%) patients were classified as HER2 low, 7 (5.8%) were HER2 2+ (no amplification), 32 (26.7%) were HER2 1+, and 77 (64.2%) were classified as HER2 zero. Out of 77 HER2 zero cases, 47 tumors (61.0%) showed incomplete staining, with <10% of tumor cells classified as HER2 ultralow. No statistical correlation between HER2 low and tumor biological characteristics and patients' survival was found. Conclusion: Our findings show a notable, albeit lower, prevalence of HER2 low expression in primary MBC. However, tumors expressing HER2 low do not show specific tumor biological features to define a new breast cancer subtype in MBC. Our results suggest that a significant number of MBC patients could benefit from ADCs, as shown in FBC. Further studies are required to better understand HER2 low breast cancer, both generally and in MBC.

Immune Profiling of Vulvar Squamous Cell Cancer Discovers a Macrophage-rich Subtype Associated with Poor Prognosis.

The incidence rates of vulvar squamous cell cancer (VSCC) have increased over the past decades, requiring personalized oncologic approaches. Currently, lymph node involvement is a key factor in determining prognosis and treatment options. However, there is a need for additional immune-related biomarkers to provide more precise treatment and prognostic information. Here, we used IHC and expression data to characterize immune cells and their spatial distribution in VSCC. Hierarchical clustering analysis identified distinct immune subtypes, of which the macrophage-rich subtype was associated with adverse outcome. This is consistent with our findings of increased lymphogenesis, lymphatic invasion, and lymph node involvement associated with high macrophage infiltration. Further in vitro studies showed that VSCC-associated macrophages expressed VEGF-A and subsequently induced VEGF-A in the VSCC cell line A-431, providing experimental support for a pro-lymphangiogenic role of macrophages in VSCC. Taken together, immune profiling in VSCC revealed tumor processes, identified a subset of patients with adverse outcome, and provided a valuable biomarker for risk stratification and therapeutic decision making for anti-VEGF treatment, ultimately contributing to the advancement of precision medicine in VSCC. SIGNIFICANCE: Immunoprofiling in VSCC reveals subtypes with distinct clinical and biological behavior. Of these, the macrophage-rich VSCC subtype is characterized by poor clinical outcome and increased VEGF-A expression, providing a biomarker for risk stratification and therapeutic sensitivity.

Prognostic relevance of Ki67 expression in primary male breast cancer: determination of cut-off points by different evaluation methods and statistical examinations.

PURPOSE: 1% of all breast cancer cases occur in men. There are significant differences regarding clinical behaviour and genetic profiles between female (FBC) and male breast cancer (MBC). Parameters for decision-making on treatment and prognosis are derived from FBC. Ki67 has a high value as a prognostic and predictive factor in FBC, but accurate Ki67 cut-off points for MBC are missing. In this study, we aimed to evaluate adequate examination methods and reliable cut-off points for Ki67 to assess the highest prognostic value for patient's overall survival (OS). METHODS: In this multicentric retrospective study, histological specimens were obtained from 104 male patients who were diagnosed and treated for primary invasive breast cancer. We applied three methods of Ki67 analysis: Tumor average scoring (TA), tumor border scoring (TB) and hot-spot scoring (HS). Calculated Ki67 cut-off points for each method were assessed as a threshold for patients' overall survival (OS). RESULTS: Ki67 cut-off points were 13.5 for the TA group, 22.5 for the HS group and 17.5 for the TB group. Only Ki67 TA cut-off calculations demonstrated statistical significance (p = 0.04). Ki67 expression analysis of TA showed that more than 90% of patients with low Ki67 levels (< 13.5) were alive after 5-year follow-up. CONCLUSION: Our findings demonstrate that determination of Ki67 expression in TA is the most reliable to define a cut-off point with high prognostic value. A Ki67 cut-off point of 13.5 shows highest statistical power to define luminal A subgroup and OS.

Digital Technical and Informal Resources of Breast Cancer Patients From 2012 to 2020: Questionnaire-Based Longitudinal Trend Study.

BACKGROUND: Digitalization offers enormous potential in medicine. In the era of digitalization, the development of the use of digital, technical, and informal resources of breast cancer patients and factors influencing the degree of digitization of patients has been insufficiently researched. OBJECTIVE: The aim of this study was to assess the development of the use of digital technical and informal resources in a well-defined patient cohort. METHODS: A longitudinal study on 513 breast cancer patients from 2012 to 2020 was conducted using a questionnaire that included the main aspects of the degree of digitalization, including digital device availability and use, stationary and mobile internet access and use, and communication and information seeking regarding breast cancer diagnosis and treatment. RESULTS: The majority of patients (421/513, 82.1%) owned the technical resources to benefit from eHealth, used the internet to obtain information (292/509, 57.4%), and were willing to use new eHealth solutions (379/426, 89%). Two-thirds of the patients discussed information about their cancer on the internet with their doctor, one-third found additional treatment options on the internet, and 15.3% (44/287) of the patients stated that this had changed their cancer therapy. The degree of digitization is increasing yet still significantly depends on 3 factors: (1) age (whereas 100% [39/39] of the <59-year-old group used the internet in 2020, 92% of the 60 to 69-year-old group [11/12] and only 47% [6/13] of the >70-year-old group used the internet), (2) education (internet use significantly depended on education, as only 51.8% [59/114] of patients with primary school education used the internet, but 82.4% [126/153] with middle school education and 90.3% [213/236] with high school education used the internet; P<.001), and (3) household size (67.7% [111/164] of patients living alone used the internet, whereas 84.7% [287/339] of patients living in a house with ≥2 people used the internet; P<.001). CONCLUSIONS: To implement digital solutions in health care, knowledge of the composition and degree of the use of digital technical and informal resources of the patient group for which the respective solution is developed is crucial for success. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00012364; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012364.

Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men: Results from the MALE Phase 2 Randomized Clinical Trial.

IMPORTANCE: The extent of changes in estradiol levels in male patients with hormone receptor-positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated. OBJECTIVE: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor-positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018. INTERVENTIONS: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months. MAIN OUTCOMES AND MEASURES: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months. RESULTS: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients' median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (-23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (-18.5 ng/L) with AI plus GnRHa (P < .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (-19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (-17.0 ng/L) with AI plus GnRHa (P < .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01638247.

Complete Clinical Response in Locally Advanced Metastatic de novo Breast Cancer after Front-Line Treatment with Ribociclib/Letrozole within the RIBANNA Study.

INTRODUCTION: Ribociclib is an orally bioavailable cyclin-dependent kinase 4/6 inhibitor. In combination with aromatase inhibitor letrozole, it has approval for treatment of hormone receptor positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. First-line therapy with ribociclib + letrozole significantly improves progression-free survival compared to placebo + letrozole in patients with HR+/HER2- advanced breast cancer. In patients with de novo advanced or metastatic breast cancer, ribociclib was able to provide substantial clinical benefit according to data from the MONALEESA-2 study. CASE PRESENTATION: Here, we report the complete clinical response in a postmenopausal patient with de novo, locally advanced, pulmonary metastatic breast cancer treated with ribociclib + letrozole. Our patient presented an ulcerated breast-consuming tumor with multiple pulmonary metastases. HR+/HER2- breast cancer was confirmed by tumor biopsy. Ki67 expression was 90%. After three months of initial treatment, the tumor-associated ulcerations disappeared, and no measurable pulmonary disease was detectable on CT scan. Treatment was well tolerated, and after dosage reduction due to neutropenia, no further side effects have been documented. At present, complete clinical response remains after 15 months of ongoing treatment. CONCLUSION: This case report documents an exceptional tumor response of a fast growing, locally advanced, pulmonary metastatic HR+/HER2- de novo breast cancer treated by ribociclib/letrozole combination therapy. Treatment success was long lasting with few side effects. The patient was very satisfied with the treatment and had no specific restrictions in her daily life.

Early metabolic response assessment of breast cancer liver metastases: 4-week posttreatment FDG PET predicts survival after 90Y microsphere radioembolization.

AIM: To evaluate the feasibility of early metabolic response assessment with 18F-FDG PET/CT in patients with breast cancer liver metastases 4 weeks after radioembolization with Yttrium-90 labeled microspheres. METHODS: 25 patients (mean age 58y, range 40-74) with advanced stage liver metastases of breast cancer were treated with 1.9 ± 0.4 GBq of 90Y-microspheres in the salvage setting and underwent 18F-FDG PET/CT at baseline and 4 weeks post-radioembolization. 14 patients (56 %) had an excessive hepatic tumor burden (> 50 % of total liver volume), 21 patients (84 %) had extrahepatic disease. Liver lesions with the highest SUVmax were selected as target lesions and a cut-off was set at 50 % reduction to separate responders from non-responders. The predictive impact of metabolic response on overall survival (OS) was investigated along with other prognostic factors. RESULTS: The median OS in this highly advanced metastatic cohort was 7 months (95 % CI, 5-9). All patients had a reduction in SUVmax (mean ΔSUVmax: -49 ± 26 %) at 4 weeks post-treatment. Patients with > 50 % SUVmax reduction survived longer (median OS 13 mo, 95 % CI 8-18) than the remaining patients (median OS 4 mo, 95 % CI 2-6; p = 0.001). From all investigated baseline factors including age, performance status, and presence of extra-hepatic disease, only the hepatic tumor burden had a significant impact on OS (p = 0.02). CONCLUSIONS: This is the first preliminary evidence in breast cancer that early post-radioembolization molecular response assessment of treated liver metastases - as early as 4 weeks posttreatment - may predict survival. If confirmed by larger series, FDG PET/CT could be considered for early response-adapted treatment modifications.

Impact of Open Laparoscopy in Patients Under Suspicion of Ovarian Cancer.

BACKGROUND/AIM: Feasibility and value of diagnostic open laparoscopy (DOL) was assessed in patients presenting under suspicion of advanced ovarian cancer (AOC) mostly with large-volume ascites. PATIENTS AND METHODS: This retrospective study analyzed 143 consecutive patients who underwent DOL for histopathological verification of AOC performed from 2002 to 2012. RESULTS: Out of the 143 patients presenting at our Center with an ovarian mass and mostly with ascites under suspicion of ovarian cancer, we diagnosed 125 AOCs, three AOCs with three concomitant tumors of other origin, and 15 other diseases causing an ovarian mass and ascites mimicking AOC (e.g. gastrointestinal malignancies, tuberculosis, mesothelioma, endometrial cancer and benign conditions). CONCLUSION: DOL can be considered a valid and safe diagnostic tool for histopathologically verifying epithetlial ovarian cancer and preventing patients with other diagnoses undergoing the wrong course of therapy.

Color Doppler examination for the diagnosis of subacute puerperal uterine inversion.

PURPOSE: Obstetric uterine inversion is a rare and life-threatening complication. Diagnosis is often difficult to establish, particularly in recurrent or chronic cases. METHOD: We performed color Doppler examination in addition to B-mode sonography in a case of subacute recurrent uterine inversion. RESULTS: Identification of the vessels providing uterine blood supply helped to clarify the distorted anatomy; furthermore, information about tissue viability was gained. CONCLUSION: We propose to perform color Doppler examination in all cases with suspected uterine inversion or vaginal masses of unknown origin.

Surgical Strategies in the Treatment of Gynecomastia Grade I-II: The Combination of Liposuction and Subcutaneous Mastectomy Provides Excellent Patient Outcome and Satisfaction.

BACKGROUND: Gynecomastia (GM) is a benign condition with glandular tissue enlargement of the male breast. GM is classified into 4 grades of increasing severity. We describe a series of GM grade I-II, diagnosed, treated surgically and analyzed regarding feasibility, complication rate, and satisfaction. METHODS: From 2005 to 2012, a chart review was performed for 53 patients. Preoperative examination included endocrine and urological examination and exclusion of other pathological conditions. The surgical technique consisted of liposuction through an inframammarian-fold incision and excision of the glandular tissue by a minimal periareolar approach. RESULTS: A total number of 53 male patients with 104 breasts were available for analysis. By liposuction, a median of 300 ml (range: 10-1000 ml) was aspirated from each breast and 25.1 g (range: 3-233 g) gland tissue was resected. Surgery lasted between 25 and 164 min per patient (median: 72 min). 2 postoperative hemorrhages occurred (n = 2, 3.8%). 2 patients underwent re-operation due to cosmetic reasons (n = 2, 3.8%). CONCLUSIONS: This analysis demonstrates that treatment of GM grade I-II can easily be performed by liposuction combined with subcutaneous resection of the glandular tissue as a minimally invasive and low-impact surgical treatment with a low rate of complications and excellent patient satisfaction. Preoperative workup is important to rule out specific diseases or malignancy causing the GM.

c-myc copy number gain is a powerful prognosticator of disease outcome in cervical dysplasia.

Cervical carcinoma develops from preneoplasia by a multistep process. Although most low-grade dysplastic lesions will regress without intervention and even high-grade changes exhibit a substantial rate of regression, a small percentage of dysplasia will progress over time. Thus, indicators are needed to estimate the biological risk and to help avoid overtreatment in women who desire to preserve fertility. In addition to the classical biomarkers, PCR-ELISA-determined HPV genotype and immunohistochemically assessed p16INK4a and Ki-67 expression, cells with integrated HPV and copy number gain of TERC and c-myc were quantified in a panel of 104 benign, intraepithelial neoplastic (CIN I, II, III) and cancerous lesions using fluorescence in situ hybridization. Optimal cut-off values were calculated; Kaplan-Meier curves and a Cox proportional hazard regression model were used to evaluate prognostic signatures. The assay reliably identified HPV integration, TERC and c-myc copy number gain as determined by comparisons with established biomarkers. All biomarker levels increased with the progression of the disease. However, only c-myc copy number gain independently prognosticated a low probability of dysplastic regression. Our results suggest that c-myc plays a key role in the process of dysplastic transformation and might thus be exploited for treatment and follow-up decision-making of cervical dysplasia.

Long-term Outcome of Peripherally Implanted Venous Access Ports in the Forearm in Female Cancer Patients.

PURPOSE: The aim of this retrospective study was to analyze the long-term outcome of peripherally implanted venous access ports in the forearm at our institution in a female patient collective. METHODS: Between June 2002 and May 2011, a total of 293 female patients with an underlying malignancy had 299 forearm ports implanted in our interventional radiology suite. The mean age of the cohort was 55 ± 12 years (range 26-81 years). The majority of women suffered from breast (59.5 %) or ovarian cancer (28.1 %). Complications were classified as infectious complications, thrombotic and nonthrombotic catheter dysfunction (dislocation of the catheter or port chamber, fracture with/without embolization or kinking of the catheter, port occlusion), and others. RESULTS: We analyzed a total of 90,276 catheter days in 248 port systems (47 patients were lost to follow-up). The mean device service interval was 364 days per catheter (range 8-2,132, median 223 days, CI 311-415, SD 404). Sixty-seven early (≤ 30 days from implantation) or late complications (>30 days) occurred during the observation period (0.74/1,000 catheter days). Common complications were port infection (0.18/1,000 days), thrombotic dysfunction (0.12/1,000 days), and skin dehiscence (0.12/1,000 days). Nonthrombotic dysfunction occurred in a total of 21 cases (0.23/1,000 days) and seemed to cumulate on the venous catheter entry site on the distal upper arm. CONCLUSION: Peripherally implanted venous access ports in the forearm are a safe alternative to chest or upper-arm ports in female oncology patients. Special attention should be paid to signs of skin dehiscence and nonthrombotic dysfunction, especially when used for long-term treatment.

HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Metastatic male breast cancer: a retrospective cohort analysis.

BACKGROUND: Metastasized male breast cancer (MMBC) is a rare disease. Given its low incidence, data regarding tumor biology, current treatment options, and survival rates are scarce. PATIENTS AND METHODS: A chart review was performed of MMBC patients consecutively registered in regional cancer registries in Germany between 1995 and 2011. Tumor characteristics, treatment, and survival rates were documented and statistically evaluated. RESULTS: 41 men with MMBC represented 25.6% of a total of 160 patients with MBC. 16 (39%) patients showed primary metastases, and 25 (61%) had recurrent metastases. Median survival from occurrence of metastasis was 32 months. Median overall survival (OS) was 68 months. 68.3% (n = 28) of the cohort received systemic therapy favoring endocrine therapy (n = 25, 61.9%). Prolonged metastatic OS (p = 0.02) was observed in patients having had a systemic treatment. Metastatic patients having received endocrine treatment showed significantly prolonged survival rates. Furthermore, patients receiving palliative chemotherapy had a significant survival benefit compared to those in whom chemotherapy was omitted. CONCLUSION: Our results suggest that systemic treatment in the form of both palliative chemotherapy and endocrine therapy improves outcome of R. Foerster and L. Schroeder contributed equally to this article and are listed in alphabetical order. MMBC. Therefore, it seems reasonable that treatment of MMBC should be based on the guidelines for female breast cancer.

Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma.

OBJECTIVE: Endometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed. METHODS: To provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163(+) tumor-associated macrophages and Foxp3(+) regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan-Meier curves were generated; multivariate analysis was undertaken as appropriate. RESULTS: A substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival. CONCLUSIONS: Our results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma.

Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study.

INTRODUCTION: The increased thrombotic risk of oral contraceptives (OC) has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC). To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use. PATIENTS AND METHODS: Blood samples were collected prospectively from healthy women (n = 21) before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA) technology. Thrombin generation markers and other hemostasis parameters were measured additionally. RESULTS: All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003). Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur. CONCLUSIONS: In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk.

Tamoxifen induces resistance to activated protein C.

INTRODUCTION: The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet. MATERIALS AND METHODS: Blood samples were collected prospectively from women with breast cancer before (n=25) and monthly after start of adjuvant TAM treatment (n=75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally. RESULTS: APC sensitivity decreased by 41% (p=0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p=0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed. CONCLUSIONS: This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.

Therapeutic strategies in male breast cancer: clinical implications of chromosome 17 gene alterations and molecular subtypes.

Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens. In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings. HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival. Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype.

Interval debulking surgery in patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV ovarian cancer.

BACKGROUND: The feasibility of neoadjuvant chemotherapy (NAC) and the outcome in patients with Federation of Gynecology and Obstetrics (FIGO) IIIC and IV ovarian cancer were assessed. PATIENTS AND METHODS: 67 patients undergoing interval debulking surgery (IDS) and ≥ 4 courses of platinum-based NAC were analyzed for survival, perioperative morbidity and mortality. RESULTS: The median follow-up was 30 months. The median progression-free survival (PFS) was 17 months, the overall survival (OS) 34 months. The PFS of patients without residual disease (n = 23; 34.3%) was 31 months (p = 0.003), the OS 65 months (p = 0.001). PFS and OS were significantly longer in patients with no residual disease than in patients with 1-10 mm (n = 34; 47.9%) (p = 0.005 and p = 0.0001, respectively) residual disease. No survival benefit was seen for patients with 1-10 mm compared to > 1 cm (n = 12; 16.9%) residual disease (PFS p = 0.518; OS p = 0.077). 1 patient (1.4%) died; 12 patients needed interventional treatment or operation (16.9%) within the first 30 days postoperatively. Out of these, 5 patients (7.0%) had residual or lasting disability. CONCLUSIONS: NAC and IDS are safe and feasible in this series of patients with unfavorable prognosis. IDS does not change the goal of complete cytoreduction and therefore does not compensate for a less radical surgical approach.

Detection of lymphovascular invasion by D2-40 (podoplanin) immunoexpression in endometrial cancer.

BACKGROUND: Lymph node involvement is a major feature in tumor spread of endometrial cancer and predicts prognosis. Therefore, evaluation of lymph vessel invasion (LVI) in tumor tissue as a predictor for lymph node metastasis is of great importance. Immunostaining of D2-40 (podoplanin), a specific marker for lymphatic endothelial cells, might be able to increase the detection rate of LVI compared with conventional hematoxylin-eosin (H-E) staining. The aim of this retrospective study was to analyze the eligibility of D2-40-based LVI evaluation for the prediction of lymph node metastases and patients' outcome. PATIENTS AND METHODS: Immunohistochemical staining with D2-40 monoclonal antibodies was performed on paraffin-embedded tissue sections of 182 patients with primary endometrioid adenocarcinoma treated in 1 gynecologic cancer center. Tumors were screened for the presence of LVI. Correlations with clinicopathological features and clinical outcome were assessed. RESULTS: Immunostaining of D2-40 significantly increased the frequency LVI detection compared with conventional H-E staining. Lymph vessel invasion was identified by D2-40 in 53 (29.1%) of 182 tumors compared with 34 (18.3%) of 182 carcinomas by routine H-E staining (P = 0.001). D2-40 LVI was detectable in 81.0% (17/21) of nodal-positive tumors and significantly predicted lymph node metastasis (P = 0.001). Furthermore, D2-40 LVI was an independent prognostic factor for patients overall survival considering tumor stage, lymph node involvement, and tumor differentiation (P < 0.01). D2-40-negative tumors confined to the inner half of the myometrium showed an excellent outcome (5-year overall survival, 97.8%). CONCLUSIONS: D2-40-based LVI assessment improves the histopathological detection of lymphovascular invasion in endometrial cancer. Furthermore, LVI is of prognostic value and predicts lymph node metastasis. D2-40 LVI detection might help to select endometrial cancer patients who will benefit from a lymphadenectomy.