Overexpression of ETV4 is oncogenic in prostate cells through promotion of both cell proliferation and epithelial to mesenchymal transition.

The discovery of translocations that involve one of the genes of the ETS family (ERG, ETV1, ETV4 and ETV5) has been a major advance in understanding the molecular basis of prostate cancer (PC). Each one of these translocations results in deregulated expression of one of the ETS proteins. Here, we focus on the mechanism whereby overexpression of the ETV4 gene mediates oncogenesis in the prostate. By siRNA technology, we show that ETV4 inhibition in the PC3 cancer cell line reduces not only cell mobility and anchorage-independent growth, but also cell proliferation, cell cycle progression and tumor growth in a xenograft model. Conversely, ETV4 overexpression in the nonmalignant human prostate cell line (RWPE) increases anchorage-independent growth, cell mobility and cell proliferation, which is probably mediated by downregulation of p21, producing accelerated progression through the cell cycle. ETV4 overexpression is associated with changes in the pattern of E-cadherin and N-cadherin expression; the cells also become spindle-shaped, and these changes are characteristic of the so-called epithelial to mesenchymal transition (EMT). In RWPE cells overexpressing ETV4 EMT results from a marked increase in EMT-specific transcription factors such as TWIST1, SLUG1, ZEB1 and ZEB2. Thus, whereas ETV4 shares with the other ETS proteins (ERG, ETV5 and ETV1) a major role in invasiveness and cell migration, it emerges as unique in that it increases at the same time also the rate of proliferation of PC cells. Considering the wide spectrum in the clinical course of patients with PC, it may be highly relevant that ETV4 is capable of inducing most and perhaps all of the features that make a tumor aggressive.

Thymidine phosphorylase profiles in nonmalignant and malignant pancreatic tissue. Potential therapeutic role of capecitabine on tumoral and endothelial cells and tumor-infiltrating macrophages.

The drug capecitabine (CAP) is a thymidine Pi-deoxyribosyltransferase (TP) activated oral fluorpyrimidine that generates 5-fluorouracil (5-FU), preferentially, within tumors. Here, in 38 patients with pancreatic cancer we analyzed immunohistochemical TP expression in pancreatic cancer tissue (PCT) and adjacent nonmalignant pancreatic tissue (ANMPT). In addition, a correlation with the main clinical pathological features was made. Furthermore, TP-positive macrophages (MO) isolated from neoplastic tissue were determined. The mean of TP-positive epithelial cells and endothelial cells in terms of microvessel density was significantly higher in PCT than in ANMPT. Because pancreatic cancer is sensitive to 5-FU, TP-activated oral CAP in tumoral and endothelial cells and tumor infiltrating MO could increase the concentration of 5-FU at tumor site, thus resulting in an enhanced antitumor activity.

[Colorectal cancer screening: comparison among strategies]. / Screening del cancro del colon-retto. Metodiche a confronto.

Colorectal cancer (CCR) screening is justified since CCR is 2nd leading cause of death for malignancy: most colorectal cancers arise from preexisting adenomatous polyps that remain clinically silent until presentation, often with advanced and incurable malignant disease. The merits and cost-effectiveness of screening for colorectal cancer are evident because the detection and removal of early carcinomas and adenomatous polyps reduces colorectal cancer mortality. Several screening methods are available, each of them presenting advantages and limits. Conventional colonoscopy is considered as the gold standard for the study of colon and, at present, it is the method of screening with the highest effectiveness in reducing CCR morbidity and mortality. However, the use of colonoscopy as the most important screening strategy is limited, because it causes major complications, it has a low compliance, and there are few specialized structures and few specialists to carry out a high number of colonoscopies as screening methods. The screening strategies used at present are described and their advantages and limits are compared.

Endoscopic surveillance of Barrett's Esophagus. Personal experience.

BACKGROUND: The possible progression of Barrett's Esophagus (BE) to carcinoma is well established: the incidence of cancer in BE is about 1.9-10% or 1/52-1/441 patients/year with a risk up to 30-125 times the normal population. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable. The purpose of endoscopic and histologic surveillance in patients with BE is to follow its evolution in order to characterize possible affiliation to a neoplastic risk group. METHODS: From 1998 to 2000 we have endoscopically identified 12 patients with EB, histologically confirmed: 9 males and 3 females, with a M/F ratio of 3:1 and an average of 45.25 years. RESULTS: During the endoscopic and histologic follow-up have observed the sequence from intestinal metaplasia with a low-grade dysplasia in one patient, confirmed after 2 months of treatment with double-dose pump inhibitor (PPI), to intestinal metaplasia with a high-grade dysplasia on biopsy samples done after vital staining with Lugol. So the patient had an endoscopic mucosal ablation, because he rejected esophagectomy. In the other patients without dysplasia, we used prokinetic drugs and PPI and we involved them in a follow-up every 2/3 years. CONCLUSIONS: Histological grading of dysplasia is currently the most important parameter used to follow-up patients with EB: the guidelines suggest a periodic endoscopic surveillance, from six months to 2 or 5 years, according to higher or lower risk of carcinoma arising, because there is no medical or surgical therapy able to decrease cancer risk.

DNA flow cytometry, p53 levels and proliferative cell nuclear antigen in human colon dysplastic, precancerous and cancerous tissues.

BACKGROUND: The cancerogenic process of colorectal cancer depends on a series of events involving oncogenes and inactivation of suppressor genes. This study concerns changes in DNA content, p53 and PCNA expression in human colon in dysplastic, precancerous and cancerous tissues. MATERIALS AND METHODS: These characteristics were analyzed in a series of hyperplastic polyps (HP), adenomas (AD), adenocarcinomas evolved within adenomas (AC-AD) and adenocarcinomas (AC) of the large bowel. DNA ploidy was analyzed by flow cytometry and PCNA and p53 expression was evaluated by immunohistochemistry using monoclonal antibodies PC10 and PAb 1801. RESULTS: Aneuploidy was found in 43/67 (64%) of AC and only occasionally in other subgroups (AC vs all other groups: 64% vs 99%; p = 0.00002). PCNA positivity gradually increased in the sequence from HP to AC and were significantly higher in AC compared to HP (90% vs 44%; p = 0.00007). p53 positive cells were found in 67% of AC while only occasionally in other groups (HP vs AC: p = 0.0002, AD (low dysplasia) vs AC: p = 0.001; AD (moderate dysplasia) vs AC: p = 0.001). CONCLUSIONS: These results demonstrated a progressive immunoreactivity for PCNA in the HP to AC sequence, while p53 positivity and aneuploidy seemed specific for colon carcinoma.

Role of prognostic factors in the therapeutic strategy of primary gastric non Hodgkin's lymphomas.

PURPOSE: To evaluate retrospectively in 64 gastric non-Hodgkin lymphoma (G-NHL) patients the role of some prognostic factors in the therapeutic strategy of this disease. PATIENTS AND METHODS: Sixty-four primary G-NHL patients (39 males and 25 females; median age: 57 years) were retrospectively evaluated. Treatment consisted of surgery alone (S) in 7 patients, chemotherapy alone (CT) in 15, CT + radiotherapy (RT) in 2, S + RT in 2, S + CT in 19, S + CT + RT in 16. Three patients had no treatment. Forty-four patients received sub-total gastrectomy (21) or total gastrectomy (23), and 20 were not submitted to surgery. RESULTS: After a median follow-up of 106 months (range 48-201), the four-year disease free survival (DFS) was 56% and overall survival (OS) was 59%. In the univariate analysis, tumor invasion depth (p = 0.007), stage (IIE1 vs IIE2: p = 0.007; I-IIE1 vs IIE2-IV: p = 0.0000009) and treatment (in stage IE-IIE1: p = n.s.; in stage IIE2-IV: p = 0.002) were significantly different. In the multivariate Cox regression model, stage was the only significant variable negatively influencing survival. CONCLUSIONS: Our study confirms the prognostic value of both the depth of invasion and the disease stage. In patients with early disease stages and disease localized to the gastric wall, a conservative approach can be recommended. No difference was found between the sub-total and total gastrectomy but surgery retains its fundamental role for G-NHL, even in advanced disease. Prospective trials are needed to confirm these results.

Three cycles of ABDV plus extended field radiotherapy in patients with poor prognosis early-intermediate stage Hodgkin's disease.

The aim of the study was to verify the possibility of treating patients with poor prognosis early-intermediate Hodgkin's disease with a combined modality therapy consisting of three cycles of ABVD followed by extended field irradiation (EFRT). No patient had bulky mediastinum or had previously been administered chemo- or radiotherapy. At pathological restaging, 40/44 (91%) evaluable patients achieved complete responses (CR). After a ten-year followup, freedom from progression (FFP), relapse-free survival (RFS) and overall survival (OS) were 80%, 83% and 81%, respectively. Of the prognostic factors, univariate analysis showed that only stage III negatively influenced RFS, but not OS. Toxicity was mild except for subclinical mediastinal fibrosis in 32.5% of CR patients. No patient reported reduced fertility. Two cases of second neoplasms were recorded: one ameboid glioma and one thymoma, both occurring within five years after discontinuing chemo-radiotherapy. Our data suggest that three cycles of ABVD preceeding EFRT is an effective treatment for poor prognosis early-intermediate stage Hodgkin's disease; nevertheless, stage III patients and some stage II patients with unfavorable prognostic factors should be treated with a more aggressive approach.

CEOP-B alternated with VIMB in intermediate-grade and high-grade non-Hodgkin's lymphoma: a pilot study.

PURPOSE: To improve response and toxicity in treatment of non-Hodgkin's lymphomas (NHLs), a prospective single-arm trial was initiated using cyclophosphamide, epirubicin, vincristine, prednisone, and bleomycin (CEOP-B) alternated with etoposide (VP-16), ifosfamide, mitoxantrone, and bleomycin (VIMB). PATIENTS AND METHODS: From December 1988 to April 1992, 60 consecutive previously untreated patients with intermediate- or high-grade NHL were admitted to the study and were assessable. Patient characteristics were as follows: 32% greater than 60 years of age, 63% with stage III to IV disease, 42% with a performance status (PS) of 2 or 3, 23% with high lactate dehydrogenase (LDH) levels, and 22% with two or more extranodal disease sites. Stage I and II patients received three cycles of CEOP-B/VIMB plus radiotherapy (RT) to involved fields; stage III and IV patients received four cycles of chemotherapy alone. RESULTS: The complete remission (CR) rate was 77%; actuarial 48-month overall survival (OS) and time to treatment failure (TTF) rates were 70% and 59%, respectively. With univariate analysis, CR, OS, and TTF rates were significantly influenced by serum LDH levels (P = .0485, P = .0017, and P = .0064, respectively) and performance status (P = .0005, P < .00005, and P = .0001, respectively). The actuarial 48-month disease-free survival (DFS) rate was 83% and was negatively influenced only by high-grade histology (P < .004). Toxicity was mild. A lower epirubicin dose-intensity (DI) was found in patients older than 60 years of age, with a borderline P value. Patients were divided into four groups according to the International Prognostic Factor Project; low-risk and low-intermediate-risk groups had similar OS and TTF rates; when considered together, they showed superior, but not statistically significant, OS and TTF rates as compared with the high-intermediate-risk group, which in turn had significantly superior OS and TTF rates when compared with the high-risk group. CONCLUSION: CEOP-B/VIMB compares favorably with third-generation regimens and results in lower toxicity.

Flow cytometry DNA content and morphobiological characteristics in chronic and neoplastic human liver disease.

In the search for parameters that can indicate changes in the behaviour of liver tissue from normal to chronic to neoplastic disease, DNA content by FCM (ploidy and percent of 4N cells) and morphobiological characteristics were investigated in fresh liver specimens of 16 patients with normal liver, 21 with persistent hepatitis (CPH), 23 with chronic active hepatitis (CAH), 17 with cirrhosis, and 13 with hepatocellular carcinoma (HCC). Aneuploidy was mostly found in HCC specimens (54%), whereas the percentage of 4N peak decreased in chronic hepatitis and cirrhosis patients but increased to 11.09% in HCC samples (r = -0.02; p = 0.05). Finally, the binuclearity rate decreased gradually from normal to flogistic to HCC specimens. The 4N peak and the binuclearity rate were closely correlated in non-HCC (p = 0.0006, by T-test) but not in HCC samples. Only DNA ploidy and the binuclearity rate have been confirmed as being significantly and independently related to the histology of liver tissue by multivariate regression analysis.

Bulky mediastinal Hodgkin's disease: results of a combined modality approach (ABVD/MOPP alternating chemotherapy plus radiation therapy).

BACKGROUND: Bulky mediastinal involvement is a challenging presentation of Hodgkin's disease (HD). Radiotherapy alone has provided a good response rate but also a high percentage of recurrences, and therefore many studies have been initiated to evaluate combined modality treatment. METHOD: In a prospective study 23 stage IIA/IIIB HD patients treated with ABVD/MOPP alternating chemotherapy and radiotherapy were evaluated with regard to overall (OS) and disease-free survival (DFS), acute and long-term toxicity. RESULTS: A 95% CR rate was obtained. Ten-year actuarial OS and DFS were 83 and 91%, respectively. Two patients (8.8%) relapsed 8 and 9 months after achieving CR. One patient (4.4%) died following severe bone marrow failure 25 months after diagnosis. No clinically evident acute or chronic cardiac or pulmonary toxicity was evident, and no second malignancies were observed. At the end of therapy 7/14 evaluable women became amenorrheal and remained so at their last follow-up. Two male patients were considered azoospermic on the basis of laboratory evaluation at the end of therapy, and after 68 and 122 months, respectively; 4 of 5 male patients had sexual intercourse freely but did not fertilize their partners. CONCLUSIONS: In our opinion and in agreement with available literature, chemotherapy has a fundamental place alongside radiotherapy in the treatment of bulky mediastinal HD. Combined modality treatment improves the disease-free survival obtained with radiotherapy or chemotherapy alone. In our experience a high percentage of patients (83%) can be considered cured without the need for second-line therapy. However, long-term and especially gonadal toxicity greatly influence the quality of life of these patients. Therefore treatment must be personalized according to age, sex, cardiopulmonary status and desire to preserve reproductive function.

Metastatic involvement of the stomach secondary to breast carcinoma. A case report.

The Authors describe a case of gastric metastases from breast cancer. The staging procedures in breast cancer do not usually include the endoscopic examination of the gastroenteric tract; nevertheless the complaint of persistent gastric disorders in patients affected by metastatic breast cancers must not be underestimated. In this case the finding of gastric neoplastic involvement led to effective treatment of the above mentioned disorders and consequently to an improvement in the patient's quality of life. Moreover, the evaluation of this clinical case shows that chemotherapeutic treatment of this metastatic localisation does not differ from that of metastases in other sites.

The Krukenberg tumor. A case report.

Krukenberg tumor, a malignant ovarian neoplasm with well defined histological characteristics, is often bilateral and secondary to a tumor of the gastrointestinal tract. We describe the case of a 44 year old woman affected by gastric cancer, who only 10 months after such diagnosis and subsequent total gastrectomy, came to our observation with ascites and bulky peritoneal involvement. During this period the patient achieved only haematochemical dosages of tumoral markers, particularly of TAG-72 which after 180 days rose to pathological values. We remark the importance of a careful clinical control and monitoring of TAG-72 for the follow-up of gastric cancer.