Prognostic Value of En-Block Radical Bowel Resection in Advanced Ovarian Cancer Surgery With HIPEC.

PURPOSE: To identify prognostic factors of survival and recurrence in advanced ovarian cancer patients undergoing radical surgery and HIPEC. METHODS: In a single Department of Surgical Oncology, Peritoneal Surface Malignancy Program, and over a 16-year period, from a total of 274 epithelial ovarian cancer patients, retrospectively, we identified 152 patients undergoing complete (CC-0) or near-complete (CC-1) cytoreduction, including at least one colonic resection, and HIPEC. RESULTS: Mean age of patients was 58.8 years and CC-0 was possible in 72.4%. Rates of in-hospital mortality and major morbidity were 2.6% and 15.7%. Only 122 (80.3%) patients completed Adjuvant Systemic Chemotherapy (ASCH). Rates of metastatic Total Lymph Nodes (TLN), Para-Aortic and Pelvic Lymph Nodes (PAPLN) and Large Bowel Lymph Nodes (LBLN) were 58.7%, 58.5%, and 51.3%, respectively. Median, 5- and 10-year survival rates were 39 months, 43%, and 36.2%, respectively. The recurrence rate was 35.5%. On univariate analysis, CC-1, high Peritoneal Cancer Index (PCI), in-hospital morbidity, and no adjuvant chemotherapy were adverse factors for survival and recurrence. On multivariate analysis, negative survival indicators were the advanced age of patients, extensive peritoneal dissemination, low total number of TLN and no systemic PAPLN. Metastatic LBLN and segmental resection of the small bowel (SIR) were associated with a high risk for recurrence. CONCLUSION: CC-O is feasible in most advanced ovarian cancer patients and HIPEC may confer a survival benefit. Radical bowel resection, with its entire mesocolon, may be necessary, as its lymph nodes often harbor metastases influencing disease recurrence and survival. The role of metastatic bowel lymph nodes has to be taken into account when assessing the impact of systemic lymphadenectomy in this group of patients.

A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

Long-Term (≥25 Years) Kidney Allograft Survivors: Retrospective Analysis at a Single Center.

INTRODUCTION: Despite great improvements in the short-term patient and kidney graft survival, the long-term morbidity and mortality in kidney transplant recipients still remains a significant problem. The aim of the study was to evaluate the impact of both donor and transplant recipient factors, as well as renal function indices on the very long-term (>25 years) kidney allograft survival. MATERIAL AND METHODS: Retrospective analysis was performed on the data of 41 kidney transplant recipients (KTR), group A: follow-up = 25 years, 20 KTR, 10 male, mean age (mean [M] ± standard deviation [SD]): 34.6 ± 12.6 years, 14 living donors (LD), 6 cadaveric donors (CD); group B: follow-up > 25 years, 21 KTR, 16 male, mean age (M ± SD): 30.86 ± 12.37 years, 14 LD, 7 CD). Kidney graft origin, post-kidney transplantation diabetes mellitus, HLA compatibility, delayed graft function, and acute rejection episodes were also analyzed retrospectively. Statistical analysis with Mann-Whitney test and Kaplan-Meier survival analysis was performed (SPSS 20.0 for Windows). RESULTS: The mean age of CDs was lower than that of LDs: CD mean age (M ± SD): 23.84 ± 16.26 years vs LD mean age: 52.75 ± 12.42 years (P < .001). Cadaveric kidney graft was associated with better renal allograft function 10, 15, and 25 years post kidney transplant. None of the other factors analyzed reached statistical significance between the 2 groups. CONCLUSION: The age of the donor and the kidney graft origin are important co-factors of the very long-term kidney allograft survival.

ABREAST: a prospective, real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and quality of life of patients with metastatic breast cancer.

PURPOSE: The efficacy of nab-paclitaxel in patients with metastatic breast cancer (MBC) has been demonstrated in randomized clinical trials. However, real-world evidence on effectiveness remains limited. PATIENTS AND METHODS: The primary objective of this multicenter prospective study was to assess the overall response rate (ORR) of patients with MBC treated with nab-paclitaxel. Secondary objectives included progression-free survival (PFS), overall survival (OS) and quality of life, assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. RESULTS: Eligible patients (N = 150; 36% with de novo MBC presentation) with a median age of 64.5 years were enrolled (86% were ER+, 33.3% (50/150) were ≥ 70 years of age and 53% were treated in the third or later line of treatment). A median of 6 cycles were administered but 26% of patients required dose reduction due to toxicity. The ORR was 26.7% [95% confidence interval (CI) 19.6-33.7], the median PFS was 6.2 months (95% CI 5.2-7.3), and the median OS 21.1 months (95% CI 17.2-not estimable). There was no statistical significant difference in the median PFS of patients < and ≥ 70 years of age. The patients' baseline FACT-B total score remained unchanged. The serious and non-serious adverse event incidence rates were 13% and 48%, respectively. CONCLUSIONS: This prospective study provides further evidence on quality of life, efficacy, and safety of nab-paclitaxel in patients with MBC and sheds more light in special subpopulations such as the elderly and those treated beyond the second line.

Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy.

Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.

Ionospheric response to solar and interplanetary disturbances: a Swarm perspective.

The ionospheric response to solar and interplanetary disturbances has been the subject of intense study for several decades. For 5 years now, the European Space Agency's Swarm fleet of satellites surveys the Earth's topside ionosphere, measuring magnetic and electric fields at low-Earth orbit with unprecedented detail. Herein, we study in situ the ionospheric response in terms of the occurrence of plasma instabilities based on 2 years of Swarm observations. Plasma instabilities are an important element of space weather because they include irregularities like the equatorial spread F events, which are responsible for the disruption of radio communications. Moreover, we focus on three out of the four most intense geospace magnetic storms of solar cycle 24 that occurred in 2015, including the St Patrick's Day event, which is the strongest magnetic storm of the present solar cycle. We examine the associated ionospheric response at Swarm altitudes through the estimation of a Swarm Dst-like index. The newly proposed Swarm derived Dst index may be suitable for space weather applications. This article is part of the theme issue 'Solar eruptions and their space weather impact'.

Low circulating mannan-binding lectin levels correlate with increased frequency and severity of febrile episodes in myeloma patients who undergo ASCT and do not receive antibiotic prophylaxis.

Patients with multiple myeloma (MM) who undergo autologous stem cell transplantation (ASCT) are susceptible to severe infections. Low levels of circulating mannan-binding lectin (MBL) are associated with increased risk of infection. In this prospective study, we evaluated 100 patients who underwent ASCT regarding the effect of MBL on the incidence and severity of febrile episodes. Seventeen patients had MBL levels <500 ng/mL (11 received antibiotic prophylaxis and 6 did not). Although there was no statistical difference regarding the development of febrile episodes between patients with low and normal MBL, among 17 patients with low MBL levels, six out of eleven patients who received antibiotic prophylaxis developed a febrile episode compared with six out of six patients who did not receive antibiotic prophylaxis and developed a febrile episode. Patients with low MBL levels who responded less frequently to first line antibiotic therapy required more frequent administration of a second more advanced line of antibiotics, independently of receiving or not prophylaxis, and required prolonged hospitalization. In the univariate analysis low MBL associated with shorter OS. Our results suggest that patient with low MBL levels should receive antibiotic prophylaxis to reduce the number of febrile episodes and raise the issue of MBL replacement for these patients.

Haplotype analysis reveals that the recurrent BRCA1 deletion of exons 23 and 24 is a Greek founder mutation.

A recurrent large genomic rearrangement (LGR) encompassing exons 23 and 24 of the BRCA1 gene has been identified in breast-ovarian cancer families of Greek origin. Its breakpoints have been determined as c.5406 + 664_*8273del11052 (RefSeq: NM_007294.3) and a diagnostic polymerase chain reaction (PCR) has been set up for rapid screening. In a series of 2,092 high-risk families completely screened for BRCA1 and BRCA2 germline mutations, we have found the deletion in 35 families (1.68%), representing 7.83% of the mutations identified in both genes and 10.3% of the total BRCA1 mutations. In order to characterize this deletion as a founder mutation, haplotype analysis was conducted in 60 carriers from 35 families, using three BRCA1 intragenic microsatellite markers and four markers surrounding the BRCA1 locus. Our results demonstrate a common shared core disease-associated haplotype of 2.89Mb. Our calculations estimate that the deletion has originated from a common ancestor 1450 years ago, which most probably inhabited the Asia Minor area. The particular (LGR) is the third mutation of such type that is proven to have a Greek founder effect in the Greek population, illustrating the necessity for LGRs testing in individuals of Greek descent.

A hierarchical Bayesian framework for force field selection in molecular dynamics simulations.

We present a hierarchical Bayesian framework for the selection of force fields in molecular dynamics (MD) simulations. The framework associates the variability of the optimal parameters of the MD potentials under different environmental conditions with the corresponding variability in experimental data. The high computational cost associated with the hierarchical Bayesian framework is reduced by orders of magnitude through a parallelized Transitional Markov Chain Monte Carlo method combined with the Laplace Asymptotic Approximation. The suitability of the hierarchical approach is demonstrated by performing MD simulations with prescribed parameters to obtain data for transport coefficients under different conditions, which are then used to infer and evaluate the parameters of the MD model. We demonstrate the selection of MD models based on experimental data and verify that the hierarchical model can accurately quantify the uncertainty across experiments; improve the posterior probability density function estimation of the parameters, thus, improve predictions on future experiments; identify the most plausible force field to describe the underlying structure of a given dataset. The framework and associated software are applicable to a wide range of nanoscale simulations associated with experimental data with a hierarchical structure.

VTD consolidation, without bisphosphonates, reduces bone resorption and is associated with a very low incidence of skeletal-related events in myeloma patients post ASCT.

We prospectively evaluated the effect of bortezomib, thalidomide and dexamethasone (VTD) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation (ASCT). VTD started on day 100 post ASCT; patients received four cycles of VTD (first block), were followed without treatment for 100 days and then received another four VTD cycles (second block). During this 12-month period, bisphosphonates were not administered. Best response included stringent complete remission (sCR) in 15 (35.7%) patients, complete response (CR) in 13 (30.9%), vgPR in 7 (16.6%), PR in 4 (9.5%), while 3 (7.1%) patients developed a progressive disease (PD). Importantly, 33.3% and 47.6% of patients improved their status of response after the first and second VTD block, respectively. VTD consolidation resulted in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I (CTX), soluble receptor activator of the nuclear factor-kappa B ligand (sRANKL) and osteocalcin (OC), whereas bone-specific alkaline phosphatase (bALP) remained stable compared with pre-VTD values. During the study period, only one patient with a PD developed a skeletal-related event (that is, radiation to bone). The median time to progression (TTP) after ASCT was 34 months and the median time of next treatment was 40 months. We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events (SREs) despite the absence of bisphosphonates; the later do not appear to be necessary in this context.

Y-box-binding protein 1 (YB1) in breast carcinomas: relation to aggressive tumor phenotype and identification of patients at high risk for relapse.

AIMS: To investigate the expression pattern of Y-box-binding protein 1 (YB1) in breast carcinomas, its clinicopathological and prognostic value, and its association with the breast cancer stem cell phenotype [CD44(+)/CD24(-/low)]. METHODS AND RESULTS: Immunohistochemistry was performed on 225 paraffin embedded specimens of invasive breast carcinomas to detect the expression of the proteins YB1, ER, PR, HER2, p53, Ki67, bcl-2, CD44 and CD24. YB1 protein was detected in the nuclei, the cytoplasm and the stroma of the tumor cells. Cytoplasmic YB1 was detected more often in carcinomas of ductal type (p = 0.002), of higher nuclear grade (p < 0.001), with lack of ER expression (p = 0.002), positive expression of p53 and Ki67 (p = 0.002 and p = 022, respectively), and with present CD44(+)/CD24(-/low) breast cancer stem cells (p = 0.001), while its association with bcl-2 was found to be inverse (p = 0.042). Nuclear YB1 was found to exert unfavorable impact on the disease-free survival of the unselected patients (p = 0.05) and the patients having been subjected to adjuvant chemotherapy and radiotherapy (p = 0.036 and p = 0.05, respectively). CONCLUSIONS: Cytoplasmic YB1 is associated with an aggressive and "stem cell-like" tumor phenotype, while nuclear localization discriminates patients at high risk for recurrence, especially those who are subjected to chemo- and radiotherapy.

Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

Protozoans as indicators of sequential batch processes for phenol treatment; an autoecological approach.

The objective of this study was the investigation of the potential use of protistan species as quality indicators of the activated sludge performance in sequential batch processes receiving toxic compounds. Two laboratory scale sequential batch reactors (SBR) were used, a conventional one and a system with plastic biofilm carriers (SBBR), treating wastewater containing phenol at concentrations ranging from 1 up to 40 mg/L. Physicochemical analyses of the samples included the determination of MLSS, effluent suspended solids, BOD5, nitrogen-ammonia, nitrogen-nitrate and phenol. The activated sludge protistan community was identified and enumerated in each reactor. Statistical analyses included Canonical Correspondence Analysis and Indicator Species Analysis of the collected experimental data. Canonical Correspondence Analysis showed inversely proportional relationships between the protozoa and the physicochemical parameters of the effluent as well as protozoan species competition. Indicator species analysis revealed the presence and the prevalence of different species under various phenol influent concentrations. No indicator species were observed for the period of operation under 5 mg/L influent phenol in both reactors, while no indicator species were observed for 20 mg/L influent phenol in the SBR reactor. Carchesium and Epistylis sp. showed the higher values for 1 mg/L phenol in the SBR, while Holophrya sp. showed lower indicator values for the same period in the SBBR. Although several species showed a good correlation to the treatment efficiency of the reactors, Blepharisma sp., could be used as the primary indicator species in both reactors for the operation period under 40 mg/L phenol, as deduced by statistical analysis.

Structure and function of the oncologic boards in Greece. Description of the institutional and scientific frame; objective problems and difficulties.

PURPOSE: Oncology boards should constitute a routine in all hospitals that are dealing with the care of cancer patients. Unfortunately the procedure which should be followed to deal with this health problem has some deficiencies. METHODS: A literature review has recently been attempted, searching Internet databases by using key words such as oncologic board, medical legislation and medical ethics. RESULTS: Current mentality suggests that hiding the truth from the patient is wrong and unethical. However, in the Greek society, this is not the case as it seems not right to adopt foreign practices, i.e. to disclose directly to the patient all information relevant to his health status, the intended therapy and possible outcome. Instead, ambiguous information pass onto relatives who in turn bear the burden of informing the patient. CONCLUSIONS: The best solution would be the integration of the positive elements of the patient's awareness and the beneficial effects of the involvement of the Greek family in the general care of the cancer patient.

High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer.

BACKGROUND: The mesenchymal-epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors. METHODS: We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors. RESULTS: Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65-7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65-8.46; P=0.002). CONCLUSION: These results provide further evidence that the MET pathway could be exploited as a target for TNBC.

A test for adequate wastewater treatment based on glutathione S transferase isoenzyme profile.

Discharge to the environment of treated or non-treated municipal wastewater imposes several threats to coastal and estuarine ecosystems which are difficult to assess. In our study we evaluate the use of the isoenzyme profile of glutathione S transferase (GST) in combination with the kinetic characteristics of the whole enzyme and of heme peroxidase, as a test of adequate treatment of municipal wastewater. For this reason, Artemia nauplii were incubated in artificial seawater prepared by wastewater samples, such as secondary municipal effluents produced by a conventional activated sludge unit and advanced treated effluents produced by the employment of coagulation, activated carbon adsorption and chlorination as single processes or as combined ones. Characteristic changes of the isoenzyme pattern and the enzymes' kinetic properties were caused by chlorinated secondary municipal effluent or by secondary non-chlorinated effluent. Advanced treatment by combination of coagulation and/or carbon adsorption resulted to less prominent changes, suggesting more adequate treatment. Our results suggest that GST isoenzyme profile in combination with the kinetic properties of the total enzyme family is a sensitive test for the evaluation of the adequateness of the treatment of reclaimed wastewater and the reduction of potentially harmful compounds. Potentially, it may offer a 'fingerprint' characteristic of a particular effluent and probably of the treatment level it has been subjected.

Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies.

BACKGROUND: Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. METHODS: We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. RESULTS: Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance. CONCLUSIONS: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.

Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial.

PURPOSE: It is well recognized that breast cancer is a heterogeneous disease. The purpose of the current study was to classify patients according to the immunohistochemical phenotype of their tumors in an effort to evaluate the outcome of the respective groups of patients and specifically of those with triple-negative breast cancer (TNBC) following dose-dense sequential adjuvant chemotherapy. METHODS: A total of 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel in the context of a randomized study. ER, PgR, HER2, Ki67, EGFR, and CK5 protein expression were evaluated in 298 formalin-fixed paraffin-embedded tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH). HER2 status and Ki67 protein expression differentiated luminal IHC subtypes (luminal B tumors being HER2 and/or Ki67-positive). RESULTS: Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2 enriched, and 36 (12%) as TNBC. The median follow-up time was 97 months. Patients with luminal A tumors had the best prognosis, with improved disease-free survival (log-rank, P = 0.033) and overall survival (P = 0.006) compared with the other three tumor subtypes. The three subtypes had an increased risk for relapse and death compared with luminal A in multivariate analysis, as well. No benefit from paclitaxel treatment was detected in any of the four subtypes or the total cohort. Hierarchical clustering based on mRNA expression of ER, PgR, and HER2 by quantitative RT-PCR identified patient groups that were comparable to the subtypes identified by IHC. CONCLUSIONS: The results of this study confirm that triple negative, luminal B and HER2-enriched phenotypes identified by IHC are of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy.

The prognostic and predictive value of ERCC-1, p53, bcl-2 and bax in epithelial ovarian cancer.

AIM: To evaluate the expression of ERCC-1 in patients with epithelial ovarian cancer (EOC) and to correlate it with the expression of p53, bcl-2 and bax. MATERIALS AND METHODS: Tumor samples from 60 patients with EOC were immunohistochemically investigated for the expression of ERCC1, p53, bcl-2 and bax. RESULTS: ERCC-1 expression was significantly decreased in serous and endometrioid compared to clear cell carcinomas. P53 expression was significantly increased in serous compared to clear cell carcinomas. Bax expression was significantly increased in serous carcinomas as compared to MMTs. High disease stage was correlated with low ERCC-1 and high bcl-2 expression. ERCC-1 expression was associated with increased disease-free interval. CONCLUSION: ERCC-1 status seems to be correlated with disease-free interval, stage and tumor histologic subtype in patients with EOC. Nevertheless, our results indicate that single-gene expressions may be unreliable and thus caution is needed when used as potential prognostic or predictive markers.