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Abstract Background It is widely accepted that vulvar carcinoma with a depth of invasion of less than one millimeter is sufficiently treated by vulvectomy or wide local excision without inguinal lymphadenectomy. Case presentation However, a patient with inguinal lymph node recurrence 21 months after radical vulvectomy for stage IA squamous cell carcinoma was observed. Conclusion According to a review of the literature, there are five additional cases of metastasizing vulvar cancer with a depth of invasion of less than one millimeter. Therefore, the definition of microinvasive carcinoma of the vulva based on depth of invasion alone may not be as reliable as previously thought and does not rule out inguinal lymph node involvement or recurrence. Consequently, the necessity of inguinal node dissection for microinvasive carcinoma needs to be discussed on an individual basis taking into account the age of the patient as well as the potential morbidity of extended surgery.

Rationale and Objectives: Common computed tomography (CT) investigation plays a limited role in characterizing and assessing the response of rectal cancer (RC) to neoadjuvant radiochemotherapy (NARC). Photon counting computed tomography (PCCT) improves the imaging quality and can provide multiparametric spectral image information including iodine concentration (IC). Our purpose was to analyze associations between IC and histopathology in RC and to evaluate the role of IC in response prediction to NARC., Materials and Methods: Overall, 41 patients were included into the study, 14 women and 27 men, mean age, 65.5 years. PCCT in a portal venous phase of the abdomen was performed. In every case, a polygonal region of interest (ROI) was manually drawn on iodine maps. Normalized IC (NIC) was also calculated. Tumor stage, grade, lymphovascular invasion, circumferential resection margin, and tumor markers were analyzed. Tumor regression grade (absence/presence of tumor cells) after NARC was analyzed. NIC values in groups were compared to Mann-Whitney-U tests. Sensitivity, specificity, and area under the curve values were calculated. Intraclass correlation coefficient (ICC) was calculated., Results: ICC was 0.93, 95%CI= (0.88; 0.96). Tumors with lymphovascular invasion showed higher NIC values in comparison to those without (p = 0.04). Tumors with response grade 2-4 showed higher pretreatment NIC values in comparison to lesions with response grade 0-1 (p = 0.01). A NIC value of 0.36 and higher can predict response grade 2-4 (sensitivity, 73.9%; specificity, 91.7%; area under the curve, 0.85)., Conclusion: NIC values showed an excellent interreader agreement in RC. NIC can predict treatment response to NARC., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The history of the autopsy is naturally also a part of the history of anatomy and pathology and spans over about 2300 years. The first documented autopsies were conducted in about 300 B.C. Thereafter, due to the prohibition of dissections due to religious, social, or hygienic reasons, a long period of stagnation took place. With the onset of the Renaissance in the 15th and 16th century, interest in the ancient sciences such as anatomy began to rise and consequently an increasing number of dissections for anatomical studies were conducted. Nevertheless, it took nearly 200 years until clinical symptoms and/or causes of disease and death were correlated with anatomical findings. In the second half of the 19th century, the clinical autopsy based on the combination of macroscopic and microscopic findings became more and more important as a precondition for the systematic description of diseases. Based on autopsy findings and together with several new techniques, modern pathology could be established at the beginning of the 20th century as a source of scientific knowledge for the clinical medicine and as a theoretical discipline of its own.

BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide., (© 2016 UICC.)

The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring anti-angiogenic treatment options in the patients with such highly angiogenic tumor subtypes.

Purpose: To investigate the potential of Y-box-binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens., Patients and Methods: YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (> or = 10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions., Results: At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2x] epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 14 days, followed by 2x epirubicin 90 mg/m(2), cyclophosphamide 3,000 mg/m(2), and thiotepa 400 mg/m(2) every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4x epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), followed by 3x cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS., Conclusion: In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.

Intensive lymph node involvement indicates poor prognosis in breast cancer patients. The significance of other molecular prognostic factors in this subgroup is unclear. Karyopherin alpha2 (KPNA2) has been reported as an important factor of tumorgenesis and progression of breast cancer. The aim of present study was to evaluate the impact of KPNA2 expression on prognosis of patients with high risk breast cancer (HRBC) and response intensive chemotherapy within the randomized WSG-AM-01 trial. KPNA2 nuclear expression (>10% vs. <10% of nuclei) was measured by immunohistochemistry on tissue arrays of 191 patients randomized to tandem high dose vs. conventional dose-dense chemotherapy in HRBC with >9 positive lymph nodes and correlated with clinical outcome (median follow-up of 63.3 months) by Kaplan-Meier and multivariate Cox hazard model analysis, including, molecular subtypes determined by k-clustering (k = 5). KPNA2 overexpression (n = 74, 39%) significantly correlated with shorter event-free and overall survival (OS) in both therapy arms by univariate analysis. Multivariate analysis showed that the overexpression of KPNA2 was an independent prognostic factor of decreased OS HR = 1.86 [95% CI: 1.07-3.23, p = 0.03]. This predictive value was independent of basal-like/Her-2/neu subtypes, significantly associated with KPNA2 and was addressed particularly to G2 tumors. Our data suggest the use of KPNA2 nuclear expression as novel prognostic marker in node-positive patients, especially in determination of G2 tumors in 2 subgroups of different prognosis. KPNA2 expression may be also considered as a marker for global chemoresistance, which can not be overcome by conventional dose-modification of chemotherapy in advanced breast cancer., (Copyright 2008 Wiley-Liss, Inc.)

In Ewing's sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer.

Renal cell carcinoma (RCC) occurring in renal allografts after cadaveric kidney transplantation has rarely been observed. RCC accounts for 2.3% of all malignancies in the general population, but up to 4.8% of malignancies in renal transplant recipients. Most have been reported in the patient's own diseased kidneys, whereas RCC in the renal allograft occur in only 10%. Here, we describe an organ-preserving surgical technique of a malignant renal tumor in a kidney allograft using a harmonic scalpel (Ultracision) for tumor enucleation. Furthermore we demonstrate by DNA microsatellite analysis the tumor's genetic origin as donor related. Collectively, we suggest that patients with a well defined low grade RCC in the kidney allograft and altogether low malignancy and good allograft function should only undergo an organ-preserving procedure and short-term postoperative screening.

Purpose: A common characteristic of mammary carcinomas is an inverse relationship between the estrogen receptor (ER) status and the proliferative activity of the tumor. Yet, a subset of ER-positive breast cancers is characterized by a high proliferation, suggesting malfunctions in ER responsiveness that influence the biological and therapeutic behavior of tumor cells. The expression of several ER-dependent genes seems to be dysregulated among those "uncoupled" tumors. One of those genes is plexin B1, a cell-surface receptor for the semaphorin Sema4D (CD 100). However, the biological role of plexin B1 in breast cancer is largely unknown., Experimental Design: Expression data of plexin B1 were obtained from Affymetrix microarray analysis of n = 119 breast cancer specimens. Validation was done by quantitative real-time PCR and protein expression was evaluated by immunohistochemistry. Expression data were compared with clinical characteristics as well as follow-up data of the disease., Results: Low plexin B1 expression levels characterize a more aggressive tumor phenotype. The expression of plexin B1 is strongly correlated with the ER status. However, even among ER-positive tumors, loss of plexin B1 is associated with an impaired prognosis of breast cancer patients in both univariate (all patients, P = 0.0062; ER positive, P = 0.0107) and multivariate analyses (all patients, P = 0.032; ER positive, P = 0.022). Immunohistochemistry reveals that the tumor cells themselves and not the endothelial cells are the major source of plexin B1 expression in the tumor., Conclusion: Plexin B1 acts not only as a new important prognostic but should also represent a predictive marker indicating an endocrine resistance. These data give a new insight in markers that could be involved in endocrine dysregulation of breast cancer.

Despite tremendous effort and progress in the diagnostics of pancreatic cancer with respect to imaging techniques and molecular genetics, only very few patients can be cured by surgery leading to a 5-year survival rate of only 3%. Especially the lack of chemotherapeutical options in this entity requires a better understanding of the molecular mechanisms leading to pancreatic carcinoma growth and progression in order to develop novel treatment regimens. To identify signaling pathways that are critical for this tumor entity, we compared six well-established pancreatic cancer cell lines (Capan-1, Capan-2, HUP-T3, HUP-T4, KCL-MOH, PaTu-8903) with colon cancer cell lines and tumor cell lines of non-epithelial origin by expression profiling. For this purpose we employed Human Genome Focus Arrays representing about 8500 well annotated human genes. We identified 353 genes with significantly high expression in the group of pancreatic carcinomas. Based on Gene Ontology annotations these genes are especially involved in Rho protein signal transduction, proteasome activator activity, cell motility, apoptotic program, and cell-cell adhesion processes indicating these pathways to be interesting candidates for the design of targeted therapies. Most pancreatic carcinomas are characterized by mutations in the TP53 and the KRAS genes and the absence of microsatellite instability, which could also be confirmed for our panel of pancreatic carcinoma cell lines. Looking for individual differences within this group that may be responsible for more or less aggressive behavior, we identified genomic amplifications at the 8q22.1 and the 8q24.22 loci to be associated with enhanced gene transcription. Because we have previously shown that gains of genomic material from the long arm of chromosome 8 have an adverse effect on the outcome of pancreatic carcinoma patients, we conclude that functional analysis of amplified genes at 8q22 and/or 8q24 may lead to an improved understanding of pancreatic carcinoma progression.

Purpose: To characterize the prognostic and predictive impact of protein expression profiles in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT)., Experimental Design: The expression of 34 protein markers was evaluated using tissue microarrays containing paraffin-embedded breast cancer samples from 236 patients who were randomized to the West German Study Group AM01 trial., Results: (a) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters (subtypes) by K-means clustering: luminal-A (27%), luminal-B (12%), HER-2 (21%), basal-like (13%) cluster, and a so-called "multiple marker negative" (MMN) cluster (27%) characterized by the absence of specifying markers. (b) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival [EFS; hazard ratio (HR), 3.6 [95% confidence interval (95% CI), 1.65-8.18; P = 0.001] and HR, 3.7 (95% CI, 1.68-8.48; P < 0.0001), respectively] when compared with both luminal groups. (c) After HDCT, the HR was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroup and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroup, which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. The MMN cluster showed a trend to a better EFS after HDCT compared with DDCT., Conclusions: Protein expression profiling in high-risk breast cancers identified five subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal-A and luminal-B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit, and the MMN cluster had a trend to a predictive benefit, both from HDCT when compared with DDCT.

The prognostic and predictive impact of protein expression profiles was analyzed in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT). Using tissue microarrays, the expression of 34 protein markers was evaluated in 236 patients who had received either HDCT or DDCT (in the WSG AM01 trial). 1) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters by K-means clustering: luminal A (27%), luminal B (12%), HER-2 (21%), basal-like (13%) cluster and a so called 'multiple marker negative'=MMN cluster (27%) characterized by the absence of specifying markers. 2) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival (EFS) (HR 3.6 (95% CI, 1.65-8.18; p = 0.001) and HR 3.7 (95% CI, 1.68-8.48); p < 0.0001), respectively) when compared to both luminal groups. 3) After HDCT, the hazard ratio was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroups and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroups which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. Protein expression profiling in high-risk breast cancers identified 5 subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal A and B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit from HDCT when compared to DDCT.

Background: It is widely accepted that vulvar carcinoma with a depth of invasion of less than one millimeter is sufficiently treated by vulvectomy or wide local excision without inguinal lymphadenectomy., Case Presentation: However, a patient with inguinal lymph node recurrence 21 months after radical vulvectomy for stage IA squamous cell carcinoma was observed., Conclusion: According to a review of the literature, there are five additional cases of metastasizing vulvar cancer with a depth of invasion of less than one millimeter. Therefore, the definition of microinvasive carcinoma of the vulva based on depth of invasion alone may not be as reliable as previously thought and does not rule out inguinal lymph node involvement or recurrence. Consequently, the necessity of inguinal node dissection for microinvasive carcinoma needs to be discussed on an individual basis taking into account the age of the patient as well as the potential morbidity of extended surgery.