Dimitrios Pectasides

Germ cell tumors of the ovary

PURPOSE Malignant ovarian germ cell tumors (MOGCTS) are rare but curable at all stages of disease. This review gives an outline of the management of this disease. METHODS We performed a literature search in the PubMed of almost all relevant articles concerning MOGCTs on pathology, prognostic factors, surgery, post-operative therapy and late effects of therapy. The available literature is mainly composed of retrospective reviews and articles. RESULTS Prognostic factors include stage, amount of residual tumor, histologic type and raised tumor markers. For patients with early stage disease, cure rates approach 100%, while for those with advanced-stage disease are at least 75%. Appropriate surgical treatment for patients where fertility needs to be preserved consists in laparotomy with unilateral salpingo-oophorectomy (USO) and resection of all visible disease. For patients with advanced-stage disease, the role and the extent of debulking surgery remain controversial despite its routine use. However, it is suggested a benefit from minimal residual disease at completion of primary surgical cytoreduction with both non-platinum and platinum-based chemotherapy regimens. Second-look surgery clearly is not indicated in patients with early stage non-dysgerminoma or in all patients with dysgerminoma. However, teratoma patients may benefit from secondary cytoreduction. Three courses of bleomycin, etoposide and cisplatin (BEP) is the current standard adjuvant chemotherapy and four courses of BEP are recommended in case of bulky residual tumor after surgery. More evidence is required to show that surveillance is a safe option. There is a hint that high-dose chemotherapy may play a role in relapsed patients. The majority of MOGCTs patients who undergo fertility-sparing surgery and chemotherapy retain their gonadal and reproductive function. There is an increasing concern about life-threatening long-term effects of treatment. CONCLUSION MOGCTs are rare neoplasms that affect girls and young women and have excellent prognosis at all stages of disease with optimal therapy. The majority of MOGCTs patients retain their reproductive function.

Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma

PURPOSE A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively. PATIENTS AND METHODS We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m2 IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B). RESULTS Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. CONCLUSION There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment.

Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.

Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

BackgroundMore than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.MethodsPreviously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.ResultsOnly PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).ConclusionsBRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.

Chemotherapy for recurrent cervical cancer

PURPOSE Cervical cancer is the second most common cancer of women worldwide and one of the leading cause of death in relative young women. This review gives an outline of chemotherapy of advanced, persistent or recurrent cervical cancer. METHODS We performed a literature search in the PubMed of almost all relevant articles concerning chemotherapy of advanced, persistent or recurrent cervical cancer. RESULTS The available data from the literature is mainly composed of most recent reviews, phase II and randomized phase III clinical trials. CONCLUSION Single-agent cisplatin remains the current standard therapy for advanced, persistent or recurrent cervical cancer. Several single-agents have been tested, but none has been found to be superior compared to cisplatin. Both topotecan and paclitaxel in combination with cisplatin, have yielded superior response rates and progression-free survival without diminishing patient quality of life. However, only the combination of cisplatin and topotecan has improved overall survival. It is important to identify clinical and tumor-related factors predictive of response to cisplatin-based chemotherapy. Future trials are necessary, not only to compare combinations of existing agents, but to incorporate biological agents (monoclonal antibodies or small molecules) to chemotherapy in order to improve the treatment results of advanced, persistent or recurrent cervix cancer.

Phosphatidylinositol 3′-Kinase Catalytic Subunit α Gene Amplification Contributes to the Pathogenesis of Mantle Cell Lymphoma

Purpose: Activation of phosphatidylinositol 3′-kinase pathway is implicated in the pathogenesis of mantle cell lymphoma (MCL). The genetic change in phosphatidylinositol 3′-kinase catalytic subunit α (PIK3CA) in MCL has not been identified. Experimental Design: Thirty-five primary MCL cases and 2 MCL cell lines (GRANTA-519 and Rec-1) were used to investigate somatic mutation and gene copy number of PIK3CA. Gene copy number was determined using quantitative real-time PCR and fluorescence in situ hybridization. We used quantitative real-time reverse transcription-PCR to measure PIK3CA transcription levels. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and phoshorylated AKT protein levels were analyzed using Western blotting and immunohistochemistry. Flow cytometry was used to assess apoptosis after treatment of MCL cell lines and one control cell line with LY294002, a specific inhibitor of PI3KCA. Results: Fifteen of 22 (68%) MCL cases and the MCL cell lines harbored a gain (≥3) of PIK3CA gene copy number. In addition, cases with increased PIK3CA gene copy number had elevated PIK3CA mRNA levels. Furthermore, amplification of PIK3CA correlated with the status of AKT phosphorylation in 7 of 12 (58%) primary MCL cases. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by Western blotting, whereas 5 of 33 (15%) cases tested by immunohistochemistry had loss of PTEN expression. Conclusions: We conclude that a gain of gene copy number of PIK3CA is frequent genetic alteration that contributes to MCL progression. PIK3CA is a promising therapeutic target in MCL. (Clin Cancer Res 2009;15(18):5724–32)

Tpa, Tati, Cea, Afp, β-hcg, Psa, Scc, and Ca 19-9 for Monitoring Transitional Cell Carcinoma of the Bladder

A total of 76 patients with transitional cell carcinoma of the bladder were prospectively monitored with simultaneous serum value estimations of tumor polypeptide antigen (TPA), tumor-associated trypsin inhibitor (TATI), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-HCG), prostatic specific antigen (PSA), squamous cell carcinoma antigen (SCC), and CA 19-9 in different stages and phases of their disease. In locally advanced disease positive values were noted for TATI in 22/28 patients (78.5%), for TPA in 17/28 (60.7%), for CA 19-9 in 10/28 (35.7%), for CEA 11/28 (39.2%), for beta-HCG in 3/28 (10.7%), for PSA in 6/28 (21.4%), for SCC in 6/28 (21.4%), and for AFP in 0/28. In metastatic disease elevated levels were observed for TATI in 43/48 patients (89.5%), for TPA in 41/48 (85.4%), for CA 19-9 in 19/48 (39.5%), for CEA in 20/48 (41.6%), for beta-HCG in 6/48 (12.5%), for PSA in 7/48 (14.5%), for SCC in 8/48 (16.6%), and for AFP in 1/48 (2.1%). In metastatic disease TATI and TPA values were significantly modified in patients with complete remission and TATI, TPA, and CA 19-9 in patients with partial remission and nonresponders. In T2-T4-N0M0 tumors, TPA, TATI, CA 19-9, and CEA were significantly increased in nonresponders. In patients with complete remission, a change in serum TATI, TPA, and CA 19-9 levels cannot be evidenced with the available numbers. The concurrent determination of TATI and TPA in T2-T4N0M0 tumors and TATI, TPA, and CA 19-9 in generalized disease could predict the response to chemotherapy. This study indicates that only the determination of TATI and TPA and in some degree the CA 19-9 is a potential tool for monitoring the efficacy of treatment.

Carboplatin and paclitaxel in advanced or metastatic endometrial cancer

OBJECTIVES The purpose of this study was to evaluate the activity and toxicity of carboplatin and paclitaxel combination in advanced or recurrent endometrial carcinoma. METHODS Forty-seven eligible patients with measurable advanced or recurrent endometrial carcinoma were treated with carboplatin [area under the curve (AUC) 5] and paclitaxel 175 mg/m(2) every 3 weeks for 6-9 cycles or until disease progression or unacceptable toxicity. RESULTS There were 10 complete responses (CRs) (21%) and 19 partial responses (PRs) (41%) for an overall response rate (RR) of 62% (29 patients) (95% confidence interval [CI], 47-76%). The median progression-free survival (PFS) was 15 months (95% CI, 7.3-22.7 months) and the median overall survival (OS) was 25 months (95% CI, 19.0-31.0 months). No difference was found in RR and OS in patients with primary advanced disease and those with recurrent tumors. Similarly, no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 36% of patients and 6% experienced febrile neutropenia. One patient each developed grade 4 thrombocytopenia and anemia. Grade 3 sensory neuropathy was recorded in 6% of patients. CONCLUSION The combination of carboplatin and paclitaxel appears to have activity in advanced or recurrent endometrial carcinoma with an acceptable toxicity profile.

Increasing frequency of gram‐positive cocci and gram‐negative multidrug‐resistant bacteria in spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is historically caused by Gram‐negative bacteria (GNB) almost exclusively Enterobacteriaceae. Recently, an increasing rate of infections with Gram‐positive cocci (GPC) and multidrug‐resistant (MDR) microorganisms was demonstrated.

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis

BackgroundThe aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer.MethodsPatients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-β1 and VEGF-A were measured at baseline and during treatment.ResultsAmong 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3–4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS.ConclusionsThis trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. (Registration number: ACTRN12610000270011)