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Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

The authors regret that reference 5 (Milam et al., 2011) in the original article was included in the reference list incorrectly, and it should not have been included. The authors apologise for any inconvenience caused.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

OBJECTIVES: Hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, in particular hMLH1, hMSH2, and hMSH6. Dysfunction of MMR genes leads to loss of MMR protein expression and to microsatellite instability (MSI). MSI is also detected in 10-20% of sporadic colorectal cancers. Hyperplastic polyps (HP) may serve as precursor for these MSI+ sporadic colorectal cancers. The aim of this study was to examine whether hyperplastic polyps are also possible premalignant lesions in HNPCC. METHODS: All HPs resected from (suspected) mismatch repair gene mutation carriers were retrieved from a screening program database. Clinical information on patient age at colonoscopy and location of the HP was collected. MLH1, MSH2, and MLH6 protein expression was evaluated using immunohistochemistry. RESULTS: A total of 90 HPs were resected from 21 men and 19 women. The mean patient age at resection was 45.7 yr (44.7 yr in men and 46.6 yr in women). In all patients, 19 (21%) HPs were resected from the proximal colon, 23 (26%) from the distal colon, and 48 (53%) from the rectum. None of the HPs demonstrated loss of MMR protein expression. CONCLUSIONS: Mismatch repair dysfunction in HPs of HNPCC patients is apparently very rare. It seems unlikely that HPs in HNPCC patients are precursors for (MSI+) cancers in these patients.

Background: Colorectal adenoma patients are kept under surveillance because of the risk of developing metachronous neoplasia. The aim is to determine predictors of neoplasia development after polypectomy. Methods: It is an observational cohort study. 433 Patients who had >= 1 adenoma removed between 1988 and 2004 were included, with follow-up until 2010. Multivariate analysis of patient and adenoma characteristics was performed at initial colonoscopy and at consecutive positive examinations. The main outcome measured was the development of metachronous (advanced) adenomas during follow-up. Results: Median follow-up was 85 months. Multivariate analysis identified male sex, >= 3 adenomas, high-grade dysplasia and age >= 55 years as risk factors for metachronous lesions at first surveillance. Analysis using life expectancy as a timescale showed >= 3 adenomas to be the only predictive factor. The time to second or third metachronous adenoma did not depend on the number of adenomas. Patients with >= 3 adenomas were five years older at the time of their first polypectomy compared with those with fewer adenomas, but of the same age at the first recurrence. Prevalence of high-grade dysplasia was associated with age and high-grade dysplasia in the prior adenoma independent of time interval. Conclusions: Adenoma development after polypectomy occurs in a regular and repetitive way. Our data suggest that only the interval between the initial colonoscopy and the first follow-up colonoscopy should be based on initial findings, i.e. number of adenomas, and that subsequent colonoscopies can be planned at predetermined intervals.

Objective: P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are membrane efflux pumps that may have a role in the kinetics of Tc-99m-sestamibi (MIBI) in parathyroid tumors. P-gp and MRP1 expression in parathyroid tumors was studied and related to histology, weight and pre- and intraoperative MIBI imaging results.Design: Patient cohort studySetting: Tertiary referral centerPatients: Thirty-three patients underwent radioguided parathyroidectomy for primary or secondary hyperparathyroidism.Main outcome measures: P-gp and MRP1 expression.Methods: Dual-phase Tc-99m-MIBI scintigraphy and SPECT results were compared to the surgical findings. Radioactivity and weight of resected parathyroid tumors were measured. Intraoperative radioactivity measurements were decay corrected. After routine histology immunohistochemistry was performed using C494 monoclonal antibodies to P-gp and MRP1r1 to MRP1. P-gp and MRP1 expression were scored covering both distribution of positivity and degree of immunostaining semi quantitatively.Results: P-gp and MRP1 staining was observed in 97% and 43% of the glands respectively. P-gp staining was positive in 91% (21/23) of the adenomas and in all 36 hyperplastic glands. MRP1 staining was positive in 22% (5/23) of the adenomas and in 61% (22/36) of the hyperplastic glands. P-gp or MRP1 expression did not correlate with preoperative Tc-99m-MIBI imaging or intraoperative radioactivity. Parathyroid weight was associated with preoperative MIBI imaging results and MIBI uptake measured during surgery.Conclusion: P-gp and MRP1 expression did not correlate with Tc-99m-MIBI uptake in parathyroid tumors. Parathyroid weight remains the major known factor influencing Tc-99m-MIBI uptake.

Generally, estrogens are considered to be involved in the neoplastic transformation of endometrium. After the menopause these estrogens mainly originate from conversion of adrenal androgens by aromatization in body fat. However, in case of stromal hyperplasia of the ovaries, it cannot be excluded that production of aromatizable androgens by postmenopausal ovaries leads to increased availability of androgen precursors for intratumoral estrogen synthesis in the endometrial tissue as well. The local presence of androgens and the local expression and activity of aromatase is considered important for this steroidogenesis. In this review, we will discuss the available evidence that androgens, produced in hyperplastic ovarian stroma or body fat tissues, play a role in the development of endometrial cancer through conversion into estrogens, a reaction catalyzed in the endometrium by the enzyme aromatase cytochrome P450. As the presence of aromatase appeared to be a pathophysiological factor in the formation of breast cancer, the latter will be evaluated in relation to the development of endometrioid endometrial cancer as well, since both disorders appear partly estrogen dependent. As treatment with aromatase inhibitors appeared feasible in breast cancer, current knowledge of comparable treatment modalities in hormone dependent endometrial cancer will be reviewed

Prospectively, the relationship between androgen levels in the utero-ovarian circulation, aromatase activity in endometrial and body fat tissue, and the presence or absence of endometrioid endometrial cancer was studied in postmenopausal women. In 43 women with endometrioid endometrial cancer and 8 women with a benign gynecological condition, a hysterectomy with bilateral salpingo-oophorectomy was performed. Using tritium water-release assays, aromatase activities in endometrial and body fat tissue were determined and related to the steroid levels from the peripheral and the utero-ovarian venous circulation (estradiol, androstenedione, testosterone) and to the presence or absence of endometrial cancer. Significant aromatase activity was found in both benign and malignant endometrial tissue samples. Aromatase activity in samples of endometrial tissue and in samples of body fat did not correlate with steroid levels in peripheral or utero-ovarian venous blood. Aromatase activity in samples of benign or malignant endometrium did not differ. Remarkably, in four women with mainly poorly differentiated endometrial cancer, very high aromatase activity was found in endometrial tissue. It is likely that multiple pathogenetic pathways exist that eventually lead to the formation of endometrioid endometrial cancer. The local availability of androgens and the finding that aromatase activity is present in both endometrial cancer and benign endometrial tissue support the hypothesis that aromatase activity in the endometrium may play a role in malignant transformation by converting androgens into mitogenic estrogens in the endometrial tissue.

Current morphology-based cervical cancer screening is associated with significant false-positive and false-negative results. Tumor suppressor gene hypermethylation is frequently present in cervical cancer. It is unknown whether a cervical scraping reflects the methylation status of the underlying epithelium, and it is therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on cervical scrapings could be used as a future screening method augmenting the current approach. Cervical scrapings and paired fresh frozen cervical tissue samples were obtained from 53 cervical cancer patients and 45 controls. All scrapings were morphologically scored and analyzed with QMSP for the genes APC, DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were calculated against DNA levels of a reference gene. Hypermethylation ratios of paired fresh frozen tissue samples and scrapings of cervical cancer patients and controls were strongly related (Spearman correlation coefficient, 0.80 for APC, 0.98 for DAPK, and 0.83 for MGMT; P

Background: Cell cycle regulating proteins (p53/p21) and proliferation index Ki-67 have been associated with prognosis and response to chemotherapy. The aim of this study was to determine the significance of these molecular markers on tumor response and prognostic effect in a group of esophageal cancer patients treated with neoadjuvant chemotherapy. Patients and Methods: Immunohistochemical expression of p53/p21 and Ki-67 was examined in pretreatment biopsy specimen of 30 patients, in phase II neoadjuvant studies for locally advanced adenocarcinoma of the esophagus, who underwent surgery. Seven patients (23%) had progressive disease. Resection was achieved in all responders (n=23; 77%) and histochemical expression of the above-mentioned proliferating markers was examined in pre-treatment and resection specimens after chemotherapy. Results: Responders had a significantly better survival compared to non-responders (p=0.001). Expression of p53, p21 and high Ki-67 in pre-treatment specimens was 73% (22/30), 63% (19/30) and 30% (10/30), respectively and was not related to response to chemotherapy. However, alteration in expression of p53-positivity in the pre-treatment specimens to p53-negativity in the resection specimens and p21-negativity to p21-positivity in 6 of the 23 (26%) resected tumors was correlated with better response and survival (p=0.011). Conclusion: Data from this study showed that alteration of p53 and p21 expression rather than the initial expression seems to be related to chemotherapy response and overall survival in patients with esophageal adenocarcinoma.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis intumour cell lines. Four membrane-bound receptors for TRAIL have been identified, two apoptosis-mediating receptors, DR4 and DR5, and two apoptosis-inhibiting receptors, DcR1 and DcR2. The aim of this study was to examine the role of TRAIL and its receptors in colorectal cancer development. The immunohistochemical expression and localization of TRAIL and its receptors were investigated in normal mucosa (n = 10), adenomas (n = 19), and carcinomas (n = 21). Correlations between the expression of TRAIL and its receptors and the degree of apoptosis (assessed by M30 expression) and histopathological characteristics were explored. TRAIL and its receptors were expressed in normal mucosal epithelium. Expression of the receptors was seen in adenomas and carcinomas. TRAIL expression was lost in a subset of colorectal tumours, more frequently in carcinomas than in adenomas (p

BACKGROUND. The objective of this study was to evaluate the author's recent, preliminary experience with the sentinel lymph node procedure in patient with vulvar melanoma and to compare this experience with treatment and follow-up of patients with vulvar melanomas who were treated previously at their institution. METHODS. From 1997, sentinel lymph node procedure with the combined technique ((99m)Technetium-labeled nanocolloid and Patente Blue-V was performed as a standard staging procedure for patients with vulvar melanoma with a thickness > 1 mm and no clinically suspicious inguinofemoral lymph nodes. For the current study, clinicopathologic data from all 33 patients with vulvar melanoma who were treated between 1978 and 2000 at the University Hospital Groningen were reviewed and analyzed. RESULTS. From January 1997 until December 2000, identification of sentinel lymph nodes was successful in all nine patients who were referred for treatment of vulvar melanoma. Three patients underwent subsequent complete inguinofemoral oral lymphadenectomy because of metastatic sentinel lymph nodes. In follow-up, groin recurrences (in-transit metastases) occurred in two of nine patients, both 12 months after primary treatment. Both patients had melanomas with a thickness > 4 mm and previously had negative sentinel lymph nodes. There was a trend toward more frequent groin recurrences in patients after undergoing the sentinel lymph node procedure (2 of 9 patients) compared with 24 historic control patients (0 of 24 patients; P = 0.06). Five of 33 patients developed local recurrences: Two patients had groin recurrences, and 11 patients developed distant metastases. Twelve patients died of vulvar melanoma. Seventeen patients with a median follow-up of 66 months (range, 9-123 months) are currently alive (overall survival rate, 52%). CONCLUSIONS. Although the numbers were small, this study showed that the sentinel lymph node procedure is capable of identifying patients who have occult lymph node metastases and who may benefit from lymphadenectomy for locoregional control and prevention of distant metastases. However, the data also suggest that the sentinel lymph node procedure may increase the risk of locoregional recurrences (in-transit metastases), especially in patients with thick melanomas. The potential role of the sentinel lymph node procedure as an alternative method of lymph node staging in patients with vulvar melanoma needs further investigation only within the protection of clinical trials and probably should be restricted to patients with melanomas with intermediate thickness (1-4 min). (C) 2002 American Cancer Society.

This study investigates whether and to what extent cyclooxygenase type-2 (COX-2) and inducible nitric oxide-synthase (iNOS), both known to have an immunosuppressive effect, are expressed in human ovarian tumors. Because COX-2 and iNOS can be expressed by activated macrophages, the presence of tumor-associated macrophages and the expression of COX-2 and iNOS by these tumor-associated macrophages were determined. The results obtained may provide insight into the function of COX-2 and iNOS expression by tumors. The expression of COX-2 and iNOS in tumor cells and macrophages was assessed in 18 malignant, 15 borderline, and 14 benign human ovarian tumors by immunohistochemical staining of frozen tissue sections. The intra- and peritumoral macrophages were stained using an anti-CD68 monoclonal antibody. Most of the malignant tumors (15 of 18), 10 of 15 borderline, and 9 of 14 benign tumors showed COX-2 expression in the epithelial cells, a result which indicates that COX-2 expression is not exclusive to malignancy. In addition, COX-2 staining was more intense in the epithelial cells of benign and borderline tumors than in malignant tumors. Weak iNOS staining was observed in 5 of 18 malignant, 4 of 15 borderline, and 5 of 14 benign tumors. The number of tumor-associated macrophages varied widely between the different tumors. The highest number of tumor-associated macrophages ( greater than or equal to 20/0.125 mm(2)) was observed in malignant tumors, whereas low to moderate intra- and peritumoral macrophage infiltration (5-20/0.125 mm(2)) was observed in the borderline and benign tumors. COX-2-positive tumor-associated macrophages were found in 3 of 18 malignant tumors, 7 of 15 borderline tumors, and 1 of 14 benign tumors. The number of COX-2-positive tumor-associated macrophages ranged from 3 to 30% of the total macrophage population. Some malignant (4 of 18), borderline (5 of 15), and benign (2 of 14) tumors contained iNOS-positive macrophages. Notable was that COX-2- and iNOS-positive macrophages were predominantly located in the tumor stroma, the regions between tumor and stroma, and in the lumina of the tumor when located in the tumor tissue. These data indicate that not only malignant but also borderline and benign ovarian tumors can exhibit increased levels of COX-2 and iNOS expression. In addition, a small proportion of the tumor-associated macrophages found in malignant, borderline, and benign tumors seems to be in an activated state, judged by their iNOS and COX-2 expression. This subpopulation of tumor-associated macrophages was invariably located in the tumor stroma or in the lumina of the tumor, specifically suggesting that macrophages outside the tumor can be tumor cytotoxic.