Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer.

BACKGROUND: It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer. METHODS: A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed. RESULTS: The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1-2 vs. G3 (Pinteraction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy. CONCLUSIONS: This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.

Trophoblast expression dynamics of the tumor suppressor gene gastrokine 2.

Gastrokines (GKNs) were originally described as stomach-specific tumor suppressor genes. Recently, we identified GKN1 in extravillous trophoblasts (EVT) of human placenta. GKN1 treatment reduced the migration of the trophoblast cell line JEG-3. GKN2 is known to inhibit the proliferation, migration and invasion of gastric cancer cells and may interact with GKN1. Recently, GKN2 was detected in the placental yolk sac of mice. We therefore aimed to further characterize placental GKN2 expression. By immunohistochemistry, healthy first-trimester placenta showed ubiquitous staining for GKN2 at its early gestational stage. At later gestational stages, a more differentiated expression pattern in EVT and villous cytotrophoblasts became evident. In healthy third-trimester placenta, only EVT retained strong GKN2 immunoreactivity. In contrast, HELLP placentas showed a tendency of increased levels of GKN2 expression with a more prominent GKN2 staining in their syncytiotrophoblast. Choriocarcinoma cell lines did not express GKN2. Besides its trophoblastic expression, we found human GKN2 in fibrotic villi, in amniotic membrane and umbilical cord. GKN2 co-localized with smooth muscle actin in villous myofibroblasts and with HLA-G and GKN1 in EVT. In the rodent placenta, GKN2 was specifically located in the spongiotrophoblast layer. Thus, the gestational age-dependent and compartment-specific expression pattern of GKN2 points to a role for placental development. The syncytial expression of GKN2 in HELLP placentas might represent a reduced state of functional differentiation of the syncytiotrophoblast. Moreover, the specific GKN2 expression in the rodent spongiotrophoblast layer (equivalent to human EVT) might suggest an important role in EVT physiology.

Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study.

BACKGROUND: No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer. METHODS: In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use. RESULTS: Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41). CONCLUSION: This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.

Fine needle aspiration cytology of lymph nodes in breast cancer follow-up is a feasible alternative to watchful waiting and to histology.

BACKGROUND: Early detection of loco-regional breast cancer recurrence improves patients' overall survival, as treatment can be initiated or active treatment can be changed. If a suspicious lymph node is diagnosed during a follow-up exam, surgical excision is often performed. The aim of this study was to evaluate the diagnostic performance of the minor invasive ultrasound-guided fine-needle aspiration cytology (FNAC) in sonomorphologically suspicious lymph nodes in breast cancer follow-up. METHODS: Between April 2010 and November 2012, we performed ultrasound-guided FNAC in 38 sonographically suspicious lymph nodes of 37 breast cancer follow-up patients. Cytological specimens were evaluated if the sample material was sufficient for diagnosis and if they contained cancer cells. Patients with negative cytology were followed up clinically and sonographically. To evaluate the diagnostic performance we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for physical examination, the different sonomorphological malignancy criteria and FNAC. RESULTS: In 36/38 (94.7 %) lymph nodes, the pathologist had enough material to establish a final diagnosis; in 2/38 (5.3 %) lymph nodes, the probe material was non-evaluable during cytology, these 2 were excluded from further statistical evaluation. Cytology revealed malignancy in 21 lymph nodes and showed no evidence for malignancy in 15 lymph nodes. There was no evidence for malignant disease in follow-up exams in the 15 cytologically benign lymph nodes with an average follow-up time of 3 years. The diagnostic performances of physical examination and FNAC were: Sensitivity 52/100 %, specificity 88/100 %, PPV 85/100 %, NPV 60/100 %, respectively. CONCLUSIONS: Our preliminary results show that FNAC is a safe and fast diagnostic approach for the evaluation of suspicious lymph nodes in the follow-up of patients with breast cancer and, thus, together with follow-up represents a feasible alternative to surgery.

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant.

The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway.

HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics.

Gene amplification is an important factor for altered gene expression in breast cancers. TOP2A-amplification often occurs concomitantly with HER2 amplification, and it has been suggested to be predictive for the response to anthracycline chemotherapy. This study assessed the correlation between HER2 status and TOP2A co-amplification, the possible association of TOP2A single-nucleotide polymorphisms with the frequency of this co-amplification as well as confirmation of association with outcome. HER2 and TOP2A amplification were analyzed in a tissue microarray from a clinical cohort study. Additionally, a common genetic variant (rs13695) in the TOP2A gene was genotyped in germline DNA. HER2 gene amplification was compared with HER2-IHC findings assessed during clinical routine work, and the association between all the biomarkers analyzed and the clinical outcome was determined. As an exploratory aim, rs13695 genotypes were compared with TOP2A amplification status. HER2 amplification was seen in 101 of 628 (16.1 %) and TOP2A amplification in 32 (5.1 %) cancers. No TOP2A amplification occurred without HER2 co-amplification. HER2 amplification was found in 8, 13.6, and 55.1 % of patients with HER2-IHC 0/1+, 2+, and 3+ tumors, respectively. HER2-IHC was not associated with an effect on the prognosis, but HER2-FISH was. There was an association between the rs13695 genotype and TOP2A amplification status (P = 0.03). Although there was a significant correlation between HER2 status determined by IHC and HER2 by FISH, only HER2 gene amplification status by FISH was correlated with outcome indicating greater utility for FISH in routine clinical settings.

An inexpensive device to treat postpartum hemorrhage: a preliminary proof of concept study of health provider opinion and training in Nepal.

BACKGROUND: Obstetric hemorrhage remains the leading cause of maternal mortality in resource limited areas. An inexpensive pneumatic anti-shock garment was devised of bicycle tubes and tailored cloth which can be prepared from local materials in resource-limited settings. The main purposes of this study were: 1) to determine acceptability of the device by nurses and midwives and obtain suggestions for making the device more suitable for use in their particular work environments, 2) to determine whether a three hour training course provided adequate instruction in the use of this device for the application of circumferential abdominal pelvic pressure, and 3) determine production capability and cost in a resource-limited country. METHODS: Fifty-eight nurse and midwife participants took part in three sessions over eight months in Nepal. Correct device placement was assessed on non-pregnant participants using ultrasound measurement of distal aortic flow before and after device inflation, and analyzed using confidence intervals. Participants were surveyed to determine acceptability of the device, obtain suggestions for improvement, and to collect data on clinical use. RESULTS: Device placement achieved flow decreases with a mean of 39% (95% CI 25%-53%, p < 0.001) in the first session, 28% (95% CI 21%-33%, P < 0.001) after four months and 29% (95% CI 24%-34%, p < 0.001) at 8 months. All nurses and midwives thought the device would be acceptable for use in obstetric hemorrhage and that they could make, clean, and apply it. They quickly learned to apply the device, remembered how to apply it, and were willing and able to use the device clinically. Ten providers used the device, each on one patient, to treat obstetric hemorrhage after routine measures had failed; bleeding stopped promptly in all ten, two of whom were transported to the hospital. Production of devices in Kathmandu using local tailors and supplies cost approximately $40 per device, in a limited production setting. CONCLUSIONS: Preliminary data suggest that an inexpensive, easily-made device is potentially an appropriate addition to current obstetric hemorrhage treatment in resource-limited areas and that further study is warranted.

Tumor-microenvironment interactions studied by zonal transcriptional profiling of squamous cell lung carcinoma.

Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumor-microenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch-aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa-miR-196a in the inner tumor; moderate expression of hsa-miR-224 in the inner tumor and tumor front, and strong expression of hsa-miR-650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling.

Prognostic relevance of Ki-67 in the primary tumor for survival after a diagnosis of distant metastasis.

Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer.

Oncofertility: combination of ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval.

BACKGROUND: New anticancer treatments have increased survival rates for cancer patients, but often at the cost of sterility. Several strategies are currently available for preserving fertility. However, the chances of achieving a pregnancy with one technique are still limited. A combination of methods is therefore recommended in order to maximize women's chances of future fertility. In this retrospective study, ovarian stimulation with subsequent ovarian tissue extraction on the day of oocyte retrieval were combined and the quality of the ovarian tissue, the numbers and quality of oocytes, time requirements, and the safety of the strategy were examined. METHODS: Fourteen female patients suffering from malignant diseases underwent one in vitro fertilization cycle. Different stimulation protocols were used, depending on the menstrual cycle. Transvaginal oocyte retrieval was scheduled 34-36 h after human chorionic gonadotropin administration. Immediately afterwards, ovarian tissue was extracted laparoscopically. RESULTS: A mean of 10 oocytes were retrieved per patient, and 67% of the oocytes were successfully fertilized using intracytoplasmic sperm injection. No periprocedural complications and no complications leading to postponement of the start of chemotherapy occurred. The ovarian tissues were of good quality, with a normal age-related follicular distribution and without carcinoma cell invasion. CONCLUSIONS: An approach using ovarian stimulation first, followed by laparoscopic collection of ovarian tissue, is a useful strategy for increasing the efficacy of fertility preservation techniques. The ovarian tissue is not affected by prior ovarian stimulation.

ARFI cut-off values and significance of standard deviation for liver fibrosis staging in patients with chronic liver disease.

BACKGROUND: Acoustic radiation force impulse (ARFI) elastometry quantifies hepatic stiffness, and thus degree of fibrosis, non-invasively. Our aim was to analyse the diagnostic accuracy of ARFI cut-off values, and the significance of a defined limit of standard deviation (SD) as a potential quality parameter for liver fibrosis staging in patients with chronic liver diseases (CLD). MATERIAL AND METHODS: 153 patients with CLD (various aetiologies) undergoing liver biopsy, and an additional 25 patients with known liver cirrhosis, were investigated. ARFI measurements were performed in the right hepatic lobe, and correlated with the histopathological Ludwig fibrosis score (inclusion criteria: at least 6 portal tracts). The diagnostic accuracy of cut-off values was analysed with respect to an SD limit of 30% of the mean ARFI value. RESULTS: The mean ARFI elastometry showed 1.95 ± 0.87 m/s (range 0.79-4.40) in 178 patients (80 female, 98 male, mean age: 52 years). The cut-offs were 1.25 m/s for F ≥ 2, 1.72 m/s for F ≥ 3 and 1.75 m/s for F = 4, and the corresponding AUROC 80.7%, 86.2% and 88.7%, respectively. Exclusion of 31 patients (17.4%) with an SD higher than 30% of the mean ARFI improved the diagnostic accuracy: The AUROC for F ≥ 2, F ≥ 3 and F = 4 were 86.1%, 91.2% and 91.5%, respectively. CONCLUSION: The diagnostic accuracy of ARFI can be improved by applying a maximum SD of 30% of the mean ARFI as a quality parameter--which however leads to an exclusion of a relevant number of patients. ARFI results with a high SD should be interpreted with caution.

Prognostic molecular markers and neoadjuvant therapy response in anthracycline-treated breast cancer patients.

BACKGROUND: Identifying biomarkers that can predict the prognosis and treatment response is helpful for individualizing breast cancer (BC) therapy. A neoadjuvant treatment setting is ideal for testing biomarkers capable of predicting the treatment response. This study analyzed the value of immunohistochemical biomarkers for predicting pathological complete response (pCR) and prognosis in a group of BC patients receiving standardized treatment. PATIENTS AND METHODS: A total of 100 BC patients were treated with neoadjuvant chemotherapy (four cycles of epirubicin and cyclophosphamide) between 2000 and 2005. Formalin-fixed and paraffin-embedded core biopsies were taken before chemotherapy for immunohistochemical staining of ER, PgR, HER2, Bcl-2, p53, cyclin D1, CK5/6, CK8, CK18, and TOP2A. Patient and tumor characteristics and biomarker scores were used to predict pCR and prognosis, using logistic regression and Cox proportional hazard models. RESULTS: pCR was achieved in 11 patients and was predicted by the established marker Ki-67. In addition, CK5/6 and CK18 improved the prediction model and were associated with lower pCR rates. For the prognosis, only the established markers nodal status, Ki-67, and PgR predicted overall survival and nodal status; Ki-67 and PgR predicted distant disease-free survival. CONCLUSIONS: In this small retrospective study, CK5/6 and CK18 appeared to improve prediction of pCR in addition to the established markers. CK5/6 may indicate a tumor type resembling a basal phenotype that is more resistant to anthracycline-based therapy, and CK18 may indicate a luminal subtype that is more resistant to chemotherapy. However, these results need to be replicated in larger studies.

Paratesticular cystadenomas with ovarian stroma, metaplastic serous Müllerian epithelium, and male adnexal tumor of probable wolffian origin: A series of 5 hitherto poorly recognized testicular tumors.

We present 5 paratesticular tumors, which manifested ovarian-type stroma and various serous müllerian epithelial structures including serous fallopian-like epithelium and proliferations closely mimicking cystic serous borderline tumors of the ovary. In addition, 3 of the tumors in our series revealed a solid epithelial component, which was morphologically and immunohistochemically similar to so called "female adnexal tumor of probable wolffian origin," which is a rare neoplasm described so far only in the female genital tract, retroperitoneum, and the pelvic cavity. In analogy with mixed epithelial and stromal tumors of the kidney, which are renal neoplasms producing ovarian-type stroma, we suggest to designate the above paratesticular tumors containing ovarian-type stroma as "mixed epithelial and stromal tumors of the paratestis with features of cystic serous borderline tumor" (cases 1 and 2) and "mixed epithelial and stromal tumors of the paratestis with male adnexal tumor of probable wolffian origin" (cases 3-5).

Expression of the Immunohistochemical Markers CK5, CD117, and EGFR in Molecular Subtypes of Breast Cancer Correlated with Prognosis.

Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort-case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS.

Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer.

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression in hepatocellular carcinoma. A clinicopathological analysis with emphasis on diagnostic value.

AIMS: Patients with hepatocellular carcinoma (HCC) usually present with advanced disease and rarely qualify for curative therapy. Immunohistochemical markers that help to discriminate benign from malignant processes early, and that have prognostic significance, would be useful. Expression of the oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3) in malignant cells of different tumour types correlates with reduced overall survival. METHODS AND RESULTS: Tissue microarrays (TMAs) containing 55 normal liver samples, 365 HCCs (122 with corresponding non-tumorous liver), 10 hepatocellular adenomas, 13 focal nodular hyperplasias and nine dysplastic nodules from western European patients were stained for IMP3. IMP3 was analysed in 61 core needle biopsies and findings were compared to glypican-3 and CD34. HCCs in TMAs were strongly positive for IMP3 in 18.4% of cases compared to absent expression in normal and non-tumorous liver tissue and benign liver tumours. Patients with IMP3 expression in HCCs showed significantly poorer overall survival in multivariate analysis (P = 0.044). Of the 61 core needle biopsies analysed, 32 (52.5%) of the HCCs were IMP3-positive. CONCLUSIONS: In core needle biopsies, IMP3 expression seems to be of limited use as a single marker for the diagnosis of HCC, given a sensitivity of 52%, but it may be helpful in combination with other markers.

Dynamic contrast-enhanced micro-CT on mice with mammary carcinoma for the assessment of antiangiogenic therapy response.

OBJECTIVE: To evaluate the potential of in vivo dynamic contrast-enhanced micro-computed tomography (DCE micro-CT) for the assessment of antiangiogenic drug therapy response of mice with mammary carcinoma. METHODS: 20 female mice with implanted MCF7 tumours were split into control group and therapy group treated with a known effective antiangiogenic drug. All mice underwent DCE micro-CT for the 3D analysis of functional parameters (relative blood volume [rBV], vascular permeability [K], area under the time-enhancement curve [AUC]) and morphology. All parameters were determined for total, peripheral and central tumour volumes of interest (VOIs). Immunohistochemistry was performed to characterise tumour vascularisation. 3D dose distributions were determined. RESULTS: The mean AUCs were significantly lower in therapy with P values of 0.012, 0.007 and 0.023 for total, peripheral and central tumour VOIs. K and rBV showed significant differences for the peripheral (P(per)(K) = 0.032, P(per) (rBV) = 0.029), but not for the total and central tumour VOIs (P(total)(K) = 0.108, P(central)(K) = 0.246, P(total) (rBV) = 0.093, P(central) (rBV) = 0.136). Mean tumour volume was significantly smaller in therapy (P (in vivo) = 0.001, P (ex vivo) = 0.005). Histology revealed greater vascularisation in the controls and central tumour necrosis. Doses ranged from 150 to 300 mGy. CONCLUSIONS: This study indicates the great potential of DCE micro-CT for early in vivo assessment of antiangiogenic drug therapy response. KEY POINTS: Dynamic contrast enhanced micro-CT (computed tomography) is a new experimental laboratory technique. DCE micro-CT allows early in vivo assessment of antiangiogenic drug therapy response. Pharmaceutical drugs can be tested before translation to clinical practice. Both morphological and functional parameters can be obtained using DCE micro-CT. Antiangiogenic effects can be visualised with DCE micro-CT.

A cutaneous vascular neoplasm with hobnail microscopic morphology and unusual gross features.

Vascular tumors are categorized into benign hemangiomas, frankly malignant angiosarcomas and tumors with intermediate biological behavior (hemangioendotheliomas). The latter group includes hemangioendotheliomas of the epithelioid, kaposiform, retiform and composite subtypes. Furthermore, a heterogeneous group of both benign and intermediate vascular tumors exhibits a peculiar hobnail cell morphology. This heterogeneous group encompasses hobnail hemangioma, retiform hemangioendothelioma, papillary intralymphatic angioendothelioma and a subset of angiosarcoma. We herein present a case of a cutaneous vascular neoplasm with hobnail morphology and unusual gross features.

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment.

BACKGROUND: The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. METHODS: Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. RESULTS: Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. CONCLUSIONS: Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.