Maria Bai

Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

BackgroundThe epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab.MethodsCRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH).ResultsEighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042).ConclusionPTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.

Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A Hellenic Cooperative Oncology Group phase II study.

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

B-cell differentiation immunophenotypes in classical Hodgkin lymphomas.

The bcl6/CD10/MUM1/CD138 B-cell differentiation immunophenotypes were analysed in 101 cases of classical Hodgkin lymphomas (cHL) aiming to elucidate their histogenesis. Three major bcl6/CD10/MUM1/CD138 immunophenotypes were distinguished on the basis of the immunohistochemical positivity of Hodgkin and Reed-Sternberg (H/RS) cells: (a) the late germinal center (GC)/early post-GC B-cell-like immunophenotype (bcl6−/CD10−/MUM1+/CD138−); 59/101 cases (59%), (b) the post-GC B-cell-like immunophenotype (bcl6−/CD10−/MUM1+/CD138+); 24/101 cases (24%) and (c) the indeterminate immunophenotype (bcl6+/CD10−/MUM1+/CD138−: 14 cases and bcl6+/CD10−/MUM1+/CD138+: four cases); 18/101 cases (18%). The above findings indicate that H/RS cells in most cHL display bcl6/CD10/MUM1/CD138 immunophenotypes consistent with late GC/early post-GC or post-GC B-cell differentiation. In addition, H/RS cells in a small fraction of cHL display indeterminate bcl6/CD10/MUM1/CD138 immunophenotypic profiles which are characterized by simultaneous expression of GC, late GC/early post-GC and post-GC B-cell differentiation proteins. These immunophenotypic profiles do not correspond to the differentiation immunophenotypes of normal B-cells and their identification in a part of cHL suggests that the differentiation process of H/RS cells is not complete in a fraction of these cells and/or is still ongoing at the time of observation.

Rectal Epstein-Barr virus-positive Hodgkin's lymphoma in a patient with Crohn's disease: case report and review of the literature.

We present the case of a 35-year-old man with Crohns disease diagnosed at the age of 27, several months after an operation for small-bowel adenocarcinoma. Seven years after the adenocarcinoma diagnosis, the patient presented with severe continuous anal pain and diarrhea. In parallel with antibiotic administration, the patient was given treatment with Infliximab, but without clinical symptom amelioration. Sigmoidoscopy and subsequent biopsies from an ulcerated rectal area supported the diagnosis of Epstein-Barr virus-positive (EBV(+)) primary Hodgkins lymphoma. Infliximab administration was immediately discontinued and the patient underwent oncological follow-up and began a course of chemotherapy. Only a few cases with primary gastrointestinal Hodgkins lymphoma in Crohns disease patients have so far been reported, including a variety of scenarios on the causal relationship including disease duration, presence of EBV, long-term immunosuppressive treatment and, recently, anti-TNFα administration.

Induction Chemotherapy with Cisplatin, Epirubicin, and Paclitaxel (CEP), Followed by Concomitant Radiotherapy and Weekly Paclitaxel for the Management of Locally Advanced Nasopharyngeal Carcinoma

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

Randomized phase II exploratory study of prophylactic amifostine in cancer patients who receive radical radiotherapy to the pelvis

BackgroundThis study aimed to investigate the efficacy of prophylactic amifostine in reducing the risk of severe radiation colitis in cancer patients receiving radical radiotherapy to the pelvis.MethodsPatients with pelvic tumours referred for radical radiotherapy who consented participation in this trial, were randomly assigned to receive daily amifostine (A) (subcutaneously, 500 mg flat dose) before radiotherapy or radiotherapy alone (R). Sigmoidoscopy and blinded biopsies were scheduled to conduct prior to initiation and following completion of radiotherapy and again 6 to 9 months later. Radiation colitis was assessed by clinical, endoscopic and histolopathological criteria.ResultsA total 44 patients were enrolled in this trial, the majority with rectal (20 patients) and cervical cancer (12 patients) and were assigned 23 in R arm and 21 in the A arm. In total 119 sigmoidoscopies were performed and 18 patients (18/44, 40.9%) were diagnosed with radiation colitis (15 grade 1 and 2, and 3 grade 3 and 4). Of them, 6 patients belonged to the A group (6/21, 28.6%) and 12 to the R group (12/23, 52.2%). Acute and grade IV radiation colitis was only developed in four patients (17.4%) in the R group. Amifostine side effects were mild. Amifostine treated patients were less likely to develop histologically detectable mucosal lesions, which indicate protection from acute mucosal injury.ConclusionsAmifostine given subcutaneously can lower the risk of acute severe radiation colitis in patients who receive radical radiotherapy to pelvic tumors.

Multiple brown tumors of the ribs simulating malignancy

Bone disease associated with primary hyperparathyroidism, known as osteitis fibrosa cystica, is now very rarely encountered, since the parathyroid disorder is most often diagnosed at the early stage of asymptomatic hypercalcemia. Here, we report the case of a patient with multiple pleural-based masses and hypercalcemia. which led to the presumptive diagnosis of malignancy. However, histological and laboratory data were consistent with the development of brown tumors of the ribs due to underlying severe hyperparathyroidism.

Cytokine Effects on Cell Viability and Death of Prostate Carcinoma Cells

We analyzed the effects of IL-13, IFN-γ, and IL-1β on cell viability and death of LNCaP and PC-3 cells and major signaling pathways involved in these effects. Significant increase of LNCaP cell death (apoptotic and necrotic) and increased levels of active caspase 3 were observed in cells treated with inhibitors of ERK 1/2 (UO126) and p38 (SB203580) prior to IL-1β treatment in comparison to cells treated with UO126, SB203580, or IL-1β alone. Significant increase of LNCaP but not PC-3 cell death was detected after treatment with LY-294002 (inhibitor of phosphatidylinositol 3-kinase). No significant increase of LNCaP and PC-3 cell death was observed after treatment with SP600125 (inhibitor of JNK), SB203580 (inhibitor of p38), UO126 (inhibitor of ERK 1/2), or BAY 11-7082 (inhibitor of NF-κB). Reduced c-FLIPL expression was observed in LNCaP cells treated with LY-294002. The significant potentiation of LNCaP cell death by inhibition of ERK 1/2, p38, and PI3-K pathways may provide a rationale for therapeutic approach in androgen-dependent prostate cancer.

DCC and TS protein expression in resected gastric cancer: A Hellenic Cooperative Oncology Group Study

There is a high risk of relapse after resection of gastric cancer. We studied the prognostic significance of the deleted colorectal cancer (DCC) gene and thymidylate synthase (TS) protein expression after resection of gastric cancer. Protein expression in the primary tumor of 146 patients with serosal and/or lymph node involvement was studied immunohistochemically by using anti-DCC and anti-TS monoclonal antibodies. DCC expression was found in 69.9%, while low TS staining intensity (0+,1+) and focal staining (<25% of tumor cells stained) were found in 44.6% and 33.8%, respectively. Overall survival (OS) was significantly longer in patients with DCC (p=0.014) negative tumors. TS expression was not an independent prognostic factor. Lack of DCC expression was associated with significantly longer cause-specific survival (CSS) (p=0.040) after curative resection. In conclusion, DCC expression is an independent prognostic factor in patients undergoing resection of gastric cancer while TS expression was not associated with the prognosis in our study.