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.

Identification of specific nuclear structural protein alterations in human breast cancer.

Breast cancer is the most commonly diagnosed type of cancer and a major cause of death in women. Reliable biomarkers are urgently needed to improve early detection or to provide evidence of the prognosis for each individual patient through expression levels in tumor tissue or body fluids. This proteomic analysis focused on the nuclear structure of human breast cancer tissue, which has been shown to be a promising tool for cancer biomarker development. The nuclear matrix composition of human breast cancer (n = 14), benign controls (n = 2), and healthy controls (n = 2) was analyzed by high-resolution two-dimensional gel electrophoresis and mass spectrometry. Validation studies were performed in an individual sample set consisting of additional breast cancer tissues (n = 3) and additional healthy control tissues (n = 2) by one-dimensional immunoblot. In this setting, we identified five proteins that were upregulated in human breast cancer tissue, but absent in the healthy and benign controls (P < 0.001). These spots were also present in the investigated human breast cancer cell lines, but absent in the MCF10a cell line, which represents normal human epithelial breast cells. Two of the breast cancer-specific proteins have been confirmed to be calponin h2 and calmodulin-like protein 5 by one-dimensional immunoblot. This is the first study demonstrating the expression of both proteins in human breast cancer tissue. Further studies are required to investigate the potential role of these proteins as biomarkers for early diagnosis or prognosis in human breast cancer.

Matched-pair analysis of patients with female and male breast cancer: a comparative analysis.

BACKGROUND: Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management. METHODS: MBC diagnosed between 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status). RESULTS: 108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC. CONCLUSION: Our comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer.

EVA-Scalp: Evaluation of Patient Satisfaction with a Scalp Cooling Device to Prevent Chemotherapy-Induced Alopecia in Breast Cancer Patients.

PURPOSE: Scalp cooling (SC) offers a chance to reduce hair loss (HL), but patient satisfaction, the effect on well-being, as well as patient selection criteria have not been sufficiently assessed yet. METHODS: In the EVAScalp trial, SC was offered to 70 breast cancer patients who received chemotherapy between November 2015 and September 2018. For SC, the Paxman-Orbis-II System was used. Satisfaction was measured by a questionnaire evaluating the level of depression with the WHO-5 well-being index (WHO-5) plus questions addressing the patient's experiences and side effects using the SC device. To evaluate efficacy, documentation by photo, by a physician, and by an HL-diary was conducted. RESULTS: Regarding efficacy, a significant difference between chemotherapy regimens is seen. Anthracycline-based therapies led to a stop of SC in 71% of the patients, whereas taxane-based therapies without anthracyclines were associated with a high acceptance of SC, and 88% of patients with paclitaxel-based therapies continued SC throughout their chemotherapy. Overall, only 7.69% of the patients stopped because of side effects. As an indicator for quality of life, WHO-5 was higher (65.8%) in patients with successful SC compared to in patients who stopped SC because of HL or side effects (only 53.0%). The majority of patients (82.22%) with successful SC would recommend SC to other patients. CONCLUSIONS: Patients tolerated SC as long as HL was successfully prevented. The well-being of patients with successful SC was significantly higher than that of patients who stopped SC prematurely. In general, SC is a promising approach and improves patient well-being, but there are still limitations to its utility depending on the chemotherapy regimen used.

Detection of lymphovascular invasion in vulvar cancer by D2-40 (podoplanin) as a predictor for inguinal lymph node metastases.

BACKGROUND: Lymphatic vessel invasion (LVI) plays a major role in the spread of vulvar cancer and predicts regional lymph node metastasis. D2-40, a monoclonal immunohistochemical marker might be able to increase the detection rate of LVI compared to conventional hematoxylin-eosin (HE) staining. The aim of the study was to evaluate the suitability of D2-40 for the prediction of regional lymph node metastases. PATIENTS AND METHODS: Immunohistochemical staining with D2-40 was performed on formalin-fixed, paraffin-embedded tissue sections of 32 patients with squamous cell carcinoma of the vulva. Slides were screened for the presence of LVI. Correlation with clinico-pathological features including LVI as retrieved by routine HE-stained sections was assessed. RESULTS: Immunostaining with D2-40 significantly (p = 0.019) increased the frequency of detection of lymphatic invasion compared to conventional HE staining. LVI was correctly identified by D2-40 (D2-40+ LVI) in 65.6% of tumor specimens as compared to 40.6% by routine HE staining (HE+ LVI). D2-40+ LVI significantly (p = 0.026) predicted inguinal lymph node metastases. CONCLUSIONS: Immunostaining with D2-40 significantly increased the frequency of detection of lymphatic invasion compared to conventional HE staining in squamous cell carcinomas of the vulva. D2-40+ LVI is a strong predictor for inguinal lymph node metastases.

Detection of lymphovascular invasion in early breast cancer by D2-40 (podoplanin): a clinically useful predictor for axillary lymph node metastases.

PURPOSE: The aim of this study was to investigate the use of D2-40 for the detection of lymphovascular invasion (LVI) in node positive and negative early breast cancer. LVI is associated with axillary lymph node metastases (ALNM) and a long-term prognostic factor. A precise identification of LVI would have a strong clinical impact for breast cancer patients. METHODS: Immunohistochemical staining with D2-40 and CD34 was performed on formalin-fixed, paraffin-embedded tissue sections of 254 invasive breast tumors of 247 patients with node negative and node positive early breast cancer. All slides were screened for the presence of LVI. Correlation with clinico-pathological factors including LVI as retrieved by routine haematoxylin and eosin (H.E.) stained sections and the eligibility for the prediction of ALNM was assessed. RESULTS: Using the D2-40 antibody for immunostaining, our results demonstrate a significant higher detection (P < 0.001) of LVI as compared with routine H.E.-staining in early breast cancer. LVI was correctly identified by D2-40 (D2-40+) in 70 out of 254 tumors (28%) as compared to 40 tumors (16%) by routine HE staining (HE+). There was a significant correlation between D2-40 + LVI and age, t-stage, nodal status, grading and hormonreceptor-status. Correlation between D2-40 + LVI and menopausal-status, HER2-status and histological type was not significant, while there was a significant correlation of D2-40 and so called "triple negative" tumors (ER/PR and HER2neu-negative). In a multivariate analysis D2-40+ was the strongest predictor for ALNM with an odds ratio of 3.489 and a P-value of P = 0.0003, followed only by T-stage and grading with odds ratios of 3.167 and 1.953 and P-values P = 0.0003 and P = 0.0352. CONCLUSION: Immunostaining with D2-40 significantly increased the frequency of detection of lymphatic invasion compared to conventional H.E.-staining in early breast cancer. As LVI is a strong predictive and prognostic marker, the monoclonal antibody D2-40 has the potential to play a significant role in pathological routine workup of breast tumors. Further prospective studies are needed to prove the clinical impact of D2-40.

Staging of primary breast cancer is not indicated in asymptomatic patients with early tumor stages.

BACKGROUND: The routinely practiced staging for distant metastasis in patients with primary breast cancer has been increasingly questioned. PATIENTS AND METHODS: Data from 742 patients with breast cancer who had completed staging (chest x-ray, liver ultrasound, and bone scan) were retrospectively analyzed. Present findings were transferred to a dataset of a voluntarily monitored benchmarking project by the West German Breast Center that included patient data of 179 breast cancer centers. RESULTS: Routine staging examinations revealed in 1.2% (n = 9) distant metastasis and in 38.8% (n = 288) suspicious results. In total, 15 patients (2%) had distant metastases confirmed by additional diagnostics. The existence of distant metastases correlated with tumor size, nodal state, and lymphatic vessel spread. Tumor size and nodal state were independent predictors for disseminated disease. The risk of exhibiting distant metastases was 0.77% for patients with tumor stage pT1 pN1. Based on these findings, in 159,310 patients 41,728 chest x-rays, 43,950 liver ultrasounds, and 39,037 bone scans could have been avoided. CONCLUSION: Asymptomatic patients with tumor stages ≤ pT1 pN1 do not benefit from staging of primary breast cancer. Suspending staging examinations for these patients could reduce cost without restricting oncologic safety.

Evaluation of E-cadherin, Ki-67 and lymphatic vessel invasion in abdominal metastases of human breast cancer.

BACKGROUND: Abdominal metastasis is a rare finding in human breast cancer and is associated with a poor prognosis. Previous data suggest that mainly invasive lobular carcinomas tend to metastasize to the abdomen. The aim of the present study was to offer deeper insight into the biology of this rare kind of tumor spread. MATERIALS AND METHODS: The expression of the cell adhesion protein E-cadherin, the cell proliferation marker Ki-67, as well as lymphatic vessel invasion (LVI), determined by staining with D2-40, were analyzed by immunohistochemistry in samples of primary breast cancer (n=12) and their associated abdominal metastases. RESULTS: In nine cases the tumors and their abdominal metastases were E-cadherin-positive and biologically belonged to the invasive ductal subtype. In three E-cadherin-positive cases, abdominal metastasis was an earlier event compared to E-cadherin-negative cases (90 months versus 37 months). None of the primary tumors showed LVI after immunostaining with D2-40. Higher Ki-67 levels were found in the E-cadherin-positive primaries and metastases. CONCLUSION: Most of the investigated tumors biologically belonged to the invasive ductal subtype. The findings of this analysis provided evidence that metastatic spread to the abdomen does not predominantly appear in lobular invasive carcinomas.

Targeting cancer with a bi-functional peptide: in vitro and in vivo results.

BACKGROUND: Current therapies to treat cancer, although successful for some patients, have significant side-effects and a high number of patients have disease that is either non-responsive or which develops resistance. Our goal was to design a small peptide that possesses similar functions to an antibody drug conjugate with regard to targeting and killing cancer cells, but that overcomes size restrictions. MATERIALS AND METHODS: We designed a novel cancer-specific killer peptide created by fusion of the toxic peptide (KLAKLAK)2 with the cancer recognition peptide LTVSPWY. RESULTS: This bi-functional peptide showed toxicity to breast cancer, prostate cancer, and neuroblastoma cell lines. Only low toxicity to non-cancer cells, colon cancer, lung cancer, and lymphoma cell lines was observed. In vivo injections of the bi-functional peptide caused tumor growth retardation compared to mice treated with control peptides. The bi-functional peptide caused retardation of MDA-MB-435S tumors in vivo and increased survival to 80% at day 100 after tumor implantation, whereas all control animals died at day 70. Previous reports showed that the recognition moiety LTVSPWY targets the tumor-associated antigen HER2. Here we found that our new peptide TP-Tox also excerts toxic effects on HER2-negative cell lines. Therefore, we searched for the molecular target of the bi-specific peptide using immunoprecipitation and mass spectrometry. Our data suggest a possible interaction with RAS GTPase-activating protein binding protein 1 (G3BP1). CONCLUSION: We designed a bi-functional peptide of 23 amino acids and demonstrated its ability to bind and kill several cancer cell lines in vitro and to strongly increase survival in breast cancer bearing mice in vivo. This novel toxin could be used in future cancer therapies and warrants further pre-clinical and clinical exploration.

Potential impact of preoperative magnetic resonance imaging of the breast on patient selection for accelerated partial breast irradiation.

PURPOSE: Accelerated partial breast irradiation (APBI) after breast-conserving therapy is currently under investigation in prospective randomized studies. Multifocality and multicentricity are exclusion criteria for APBI. Preoperative breast magnetic resonance imaging (MRI) can detect ipsilateral and contralateral invasive tumor foci or ductal carcinoma in situ in addition to conventional diagnostic methods (clinical examination, mammography, and ultrasonography). The objective of this retrospective study was to evaluate the impact of preoperative MRI on patient selection for APBI. METHODS AND MATERIALS: From 2002 to 2007, a total of 579 consecutive, nonselected patients with newly diagnosed early-stage breast cancer received preoperative breast MRI in addition to conventional imaging studies at the Bonn University Breast Cancer Center. In retrospect, 113 patients would have met the criteria for APBI using conventional imaging workup (clinical tumor size ≤3 cm; negative axillary lymph node status; unifocal disease; no evidence of distant metastases; no invasive lobular carcinoma, ductal and lobular carcinoma in situ, or Paget's disease). We analyzed the amount of additional ipsilateral and contralateral tumor foci detected by MRI. RESULTS: MRI detected additional tumor foci in 8.8% of patients eligible for APBI (11 tumor foci in 10 of 113 patients), either ipsilateral (n = 7, 6.2%) or contralateral (n = 4, 3.5%). In 1 patient, MRI helped detect additional tumor focus both ipsilaterally and contralaterally. CONCLUSIONS: Preoperative breast MRI is able to identify additional tumor foci in a clinically relevant number of cases in this highly selected group of patients with low-risk disease and may be useful in selecting patients for APBI.

Non-invasive proteomics-thinking about personalized breast cancer screening and treatment.

The early diagnosis of breast cancer in potentially curable stages improves prognosis and consecutively reduces mortality of breast cancer patients. Established screening programs have an unfavorable connotation due to significant rates of false negative as well as false positive results leading to overdiagnosis and overtherapy. The combination of a non-invasive breast-cancer-suspectability-biomarker with established clinical diagnostics could help to increase the acceptance of population based breast cancer screening programs by creating an individual risk profile, which is irrespective of mammography quality and interpretation. Recently, non-invasive proteomic biomarkers obtained from blood, saliva or nipple aspiration fluid have been extensively investigated and might play a future role in the personalized management of breast cancer screening. A simple, robust and inexpensive, non-invasive test for screening and diagnosis could easily be performed in every medical practice leading to an affordable, high-throughput instrument. This review describes recently investigated proteomic screening biomarkers that could improve the early diagnosis of breast cancer in the following years.

Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer.

PURPOSE: Sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways through inhibitory effects against MAP kinases and vascular endothelial growth factor receptor-2. The objectives of this neoadjuvant phase II-trial in patients with advanced epithelial ovarian cancer were to assess the activity and tolerability of the combination therapy of carboplatin/paclitaxel with multi-target tyrosine kinase inhibitor sorafenib. MATERIALS AND METHODS: Patients with histologically proven stage IIIC or IV disease and large volume ascites were eligible. Enrolled patients received 2 of 6 cycles carboplatin (area under the curve 5) and paclitaxel (175 mg/m(2)) preoperatively and concomitant sorafenib 400 mg twice daily. After four cycles of postoperative chemotherapy, a maintenance phase of single agent oral sorafenib through 1 year was planned. This phase II-study was planned with a sample size of 102 patients and progression-free survival as primary study endpoint. RESULTS: Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease. The study was terminated on the basis of the recommendation of an independent data safety monitoring board. CONCLUSION: The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted.

Prediction and prognosis: impact of gene expression profiling in personalized treatment of breast cancer patients.

Breast cancer is a complex disease, whose heterogeneity is increasingly recognized. Despite considerable improvement in breast cancer treatment and survival, a significant proportion of patients seems to be over- or undertreated. To date, single clinicopathological parameters show limited success in predicting the likelihood of survival or response to endocrine therapy and chemotherapy. Consequently, new gene expression based prognostic and predictive tests are emerging that promise an improvement in predicting survival and therapy response. Initial evidence has emerged that this leads to allocation of fewer patients into high-risk groups allowing a reduction of chemotherapy treatment. Moreover, pattern-based approaches have also been developed to predict response to endocrine therapy or particular chemotherapy regimens. Irrespective of current pitfalls such as lack of validation and standardization, these pattern-based biomarkers will prove useful for clinical decision making in the near future, especially if more patients get access to this form of personalized medicine.

Impact of the menstrual cycle on circulating cell-free DNA.

BACKGROUND: To determine serum levels of circulating cell-free DNA (cfDNA) throughout the stages of endometrial proliferation and apoptosis during the menstrual cycle. MATERIALS AND METHODS: cfDNA was measured in 176 blood samples from 17 healthy volunteers taken at three different time points (menstruation, follicular and secretory phase). Additionally, blood samples from 20 newly diagnosed breast cancer patients were analysed. Quantitative real-time PCR was performed in order to quantify cfDNA fragments of 106 bp. RESULTS: In healthy individuals, levels of cfDNA did not differ significantly during the menstrual cycle. In breast cancer patients, the median cfDNA level was significantly higher compared to healthy individuals, irrespective of the cycle phase (p<0.001). CONCLUSION: The female cycle does not influence cfDNA serum level measurements. Considering the diagnostic or prognostic value of cfDNA in cancer patients, different time points of blood sampling in premenopausal women seem to be negligible.

Increased detection of lymphatic vessel invasion by D2-40 (podoplanin) in early breast cancer: possible influence on patient selection for accelerated partial breast irradiation.

PURPOSE: Several international trials are currently investigating accelerated partial breast irradiation (APBI) for patients with early-stage breast cancer. According to existing guidelines, patients with lymphatic vessel invasion (LVI) do not qualify for APBI. D2-40 (podoplanin) significantly increases the frequency of LVI detection compared with conventional hematoxylin and eosin (HE) staining in early-stage breast cancer. Our purpose was to retrospectively assess the hypothetical change in management from APBI to whole breast radiotherapy with the application of D2-40. PATIENTS AND METHODS: Immunostaining with D2-40 was performed on 254 invasive breast tumors of 247 patients. The following criteria were used to determine the eligibility for APBI: invasive ductal adenocarcinoma of < or =3 cm, negative axillary node status (N0), and unifocal disease. Of the 247 patients, 74 with available information concerning LVI, as detected by D2-40 immunostaining and routine HE staining, formed our study population. RESULTS: Using D2-40, our results demonstrated a significantly greater detection rate (p = .031) of LVI compared with routine HE staining. LVI was correctly identified by D2-40 (D2-40-positive LVI) in 10 (13.5%) of 74 tumors. On routine HE staining, 4 tumors (5.4%) were classified as HE-positive LVI. Doublestaining of these specimens with D2-40 unmasked false-positive LVI status in 2 (50%) of the 4 tumors. According to the current recommendations for APBI, immunostaining with D2-40 would have changed the clinical management from APBI to whole breast radiotherapy in 8 (10.8%) of 74 patients and from whole breast radiotherapy to APBI in 2 patients (2.7%). CONCLUSION: These data support the implementation of D2-40 immunostaining in the routine workup to determine a patient's eligibility for APBI.