Heterogeneity between Core Needle Biopsy and Synchronous Axillary Lymph Node Metastases in Early Breast Cancer Patients: A Comparison of HER2, Estrogen and Progesterone Receptor Expression Profiles during Primary Treatment Regime

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment

New Aspects in the Differential Diagnosis and Therapy of Bladder Pain Syndrome/Interstitial Cystitis

Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical “columns”: (i) clinical diagnostics, (ii) histopathology, and (iii) molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC

Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers: An Explorative Concept Study

Previously, we described prostate cancer (PCa) detection (83% sensitivity; 67% specificity) in seminal plasma by CE-MS/MS. Moreover, advanced disease was distinguished from organ-confined tumors with 80% sensitivity and 82% specificity. The discovered biomarkers were naturally occurring fragments of larger seminal proteins, predominantly semenogelin 1 and 2, representing endpoints of the ejaculate liquefaction. Here we identified proteases putatively involved in PCa specific protein cleavage, and examined gene expression and tissue protein levels, jointly with cell localization in normal prostate (nP), benign prostate hyperplasia (BPH), seminal vesicles and PCa using qPCR, Western blotting and confocal laser scanning microscopy. We found differential gene expression of chymase (CMA1), matrix metalloproteinases (MMP3, MMP7), and upregulation of MMP14 and tissue inhibitors (TIMP1 and TIMP2) in BPH. In contrast tissue protein levels of MMP14 were downregulated in PCa. MMP3/TIMP1 and MMP7/TIMP1 ratios were decreased in BPH. In seminal vesicles, we found low-level expression of most proteases and, interestingly, we also detected TIMP1 and low levels of TIMP2. We conclude that MMP3 and MMP7 activity is different in PCa compared to BPH due to fine regulation by their inhibitor TIMP1. Our findings support the concept of seminal plasma biomarkers as non-invasive tool for PCa detection and risk stratification

The Importance of Clinical Examination under General Anesthesia: Improving Parametrial Assessment in Cervical Cancer Patients

Background: Parametrial tumor involvement is an important prognostic factor in cervical cancer and is used to guide management. Here, we investigate the diagnostic value of clinical examination under general anesthesia (EUA) and magnetic resonance imaging (MRI) in determining parametrial tumor spread. Methods: Post-operative pathological findings of 400 patients with primary cervical cancer were compared to the respective MRI data and the results from EUA. The gynecological oncologist had access to the MR images during clinical assessment (augmented EUA, aEUA). Results: Pathologically proven parametrial tumor invasion was present in 165 (41%) patients. aEUA exhibited a higher accuracy than MRI alone (83% vs. 76%; McNemar’s odds ratio [OR] = 2.0, 95%CI 1.25–3.27, p = 0.003). Although accuracy was not affected by tumor size in aEUA, MRI was associated with a lower accuracy in tumors ≥2.5 cm (OR for a correct diagnosis compared to smaller tumors 0.22, p < 0.001). There was also a decrease in specificity when evaluating parametrial invasion by MRI in tumors ≥2.5 cm in diameter (p < 0.0001) compared to smaller tumors (< 2.5 cm). Body mass index had no influence on performance of either method. Conclusions: aEUA has the potential to increase the diagnostic accuracy of MRI in determining parametrial tumor involvement in cervical cancer patients

Performance of Layer-by-Layer-Modified Multibore® Ultrafiltration Capillary Membranes for Salt Retention and Removal of Antibiotic Resistance Genes

Polyether sulfone Multibore® ultrafiltration membranes were modified using polyelectrolyte multilayers via the layer-by-layer (LbL) technique in order to increase their rejection capabilities towards salts and antibiotic resistance genes. The modified capillary membranes were characterized to exhibit a molecular weight cut-off (at 90% rejection) of 384 Da. The zeta-potential at pH 7 was −40 mV. Laboratory tests using single-fiber modified membrane modules were performed to evaluate the removal of antibiotic resistance genes; the LbL-coated membranes were able to completely retain DNA fragments from 90 to 1500 nt in length. Furthermore, the pure water permeability and the retention of single inorganic salts, MgSO$_{4}$, CaCl$_{2}$ and NaCl, were measured using a mini-plant testing unit. The modified membranes had a retention of 80% toward MgSO$_{4}$ and CaCl$_{2}$ salts, and 23% in case of NaCl. The modified membranes were also found to be stable against mechanical backwashing (up to 80 LMH) and chemical regeneration (in acidic conditions and basic/oxidizing conditions)

Cell membrane softening in human breast and cervical cancer cells

Biomechanical properties are key to many cellular functions such as cell division and cell motility and thus are crucial in the development and understanding of several diseases, for instance cancer. The mechanics of the cellular cytoskeleton have been extensively characterized in cells and artificial systems. The rigidity of the plasma membrane, with the exception of red blood cells, is unknown and membrane rigidity measurements only exist for vesicles composed of a few synthetic lipids. In this study, thermal fluctuations of giant plasma membrane vesicles (GPMVs) directly derived from the plasma membranes of primary breast and cervical cells, as well as breast cell lines, are analyzed. Cell blebs or GPMVs were studied via thermal membrane fluctuations and mass spectrometry. It will be shown that cancer cell membranes are significantly softer than their non-malignant counterparts. This can be attributed to a loss of fluid raft forming lipids in malignant cells. These results indicate that the reduction of membrane rigidity promotes aggressive blebbing motion in invasive cancer cells

Endometrial carcinoma, grossing and processing issues: recommendations of the International Society of Gynecologic Pathologists.

Endometrial cancer is the most common gynecologic neoplasm in developed countries; however, updated universal guidelines are currently not available to handle specimens obtained during the surgical treatment of patients affected by this disease. This article presents recommendations on how to gross and submit sections for microscopic examination of hysterectomy specimens and other tissues removed during the surgical management of endometrial cancer such as salpingo-oophorectomy, omentectomy, and lymph node dissection-including sentinel lymph nodes. In addition, the intraoperative assessment of some of these specimens is addressed. These recommendations are based on a review of the literature, grossing manuals from various institutions, and a collaborative effort by a subgroup of the Endometrial Cancer Task Force of the International Society of Gynecological Pathologists. The aim of these recommendations is to standardize the processing of endometrial cancer specimens which is vital for adequate pathological reporting and will ultimately improve our understanding of this disease

Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease

Background:Extensive prostate specific antigen screening for prostate cancer generates a high number of unnecessary biopsies and over-treatment due to insufficient differentiation between indolent and aggressive tumours. We hypothesized that seminal plasma is a robust source of novel prostate cancer (PCa) biomarkers with the potential to improve primary diagnosis of and to distinguish advanced from indolent disease. &lt;br&gt;Methodology/Principal Findings: In an open-label case/control study 125 patients (70 PCa, 21 benign prostate hyperplasia, 25 chronic prostatitis, 9 healthy controls) were enrolled in 3 centres. Biomarker panels a) for PCa diagnosis (comparison of PCa patients versus benign controls) and b) for advanced disease (comparison of patients with post surgery Gleason score &#60;7 versus Gleason score &#62;&gt;7) were sought. Independent cohorts were used for proteomic biomarker discovery and testing the performance of the identified biomarker profiles. Seminal plasma was profiled using capillary electrophoresis mass spectrometry. Pre-analytical stability and analytical precision of the proteome analysis were determined. Support vector machine learning was used for classification. Stepwise application of two biomarker signatures with 21 and 5 biomarkers provided 83% sensitivity and 67% specificity for PCa detection in a test set of samples. A panel of 11 biomarkers for advanced disease discriminated between patients with Gleason score 7 and organ-confined (&#60;pT3a) or advanced (&#8805;pT3a) disease with 80% sensitivity and 82% specificity in a preliminary validation setting. Seminal profiles showed excellent pre-analytical stability. Eight biomarkers were identified as fragments of N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase​,prostatic acid phosphatase, stabilin-2, GTPase IMAP family member 6, semenogelin-1 and -2. Restricted sample size was the major limitation of the study.&lt;/br&gt; &lt;br&gt;Conclusions/Significance: Seminal plasma represents a robust source of potential peptide makers for primary PCa diagnosis. Our findings warrant further prospective validation to confirm the diagnostic potential of identified seminal biomarker candidates.&lt;/br&gt