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Catalano V, Mellone P, d’Avino A, Shridhar V, Staccioli M P, Graziano F, Giordani P, Rossi D, Baldelli A M, Alessandroni P, Santini D, Lorenzon L, Testa E, D’Emidio S, De Nictolis M, Muretto P, Fedeli S L & Baldi A (2011) Histopathology58, 669–678 HtrA1, a potential predictor of response to cisplatin-based combination chemotherapy in gastric cancer Aims: HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer. Methods and results: HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32–82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7–88.2], 66.7% (95% CI 47.8–85.5) and 28.6% (95 CI 11.8–45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037). Conclusions: Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.

Vascular endothelial growth factor (VEGF) seems to be essential for angiogenesis and for the growth of colorectal cancer; thus its inhibition can arrest tumor growth and decrease metastatic potential. Octreotide has been shown to inhibit growth of colorectal tumors in vitro and in vivo. Part of the antiproliferative activity of octreotide could be related to its antiangiogenic properties. Effects of octreotide on VEGF expression were evaluated in 35 patients with operable colorectal cancer receiving octreotide for 2 weeks before surgery. Tissue VEGF expression and serum VEGF concentrations were determined before and after treatment with octreotide. There was a statistically significant reduction in the tissue VEGF expression both considering the percentage of VEGF positive cells (P = 0.006) and the intensity of VEGF staining (P = 0.003). A similar significant reduction was observed in serum values of VEGF (P = 0.03). The present study indicates that octreotide inhibits expression of VEGF in colorectal cancer patients, and, furthermore, that serum VEGF expression correlates with tissue VEGF, representing a safe method to monitor the activity of antiangiogenic agents.

Calcium and antioxidant vitamins, such as A, C, and E, have been shown to reduce colorectal epithelial proliferation and thereby to act as possible chemoprotective agents in colorectal cancer. We investigated the effects of an intervention with calcium and vitamins on cell proliferation in the colonic mucosa of patients operated on for colorectal cancer. Patients with resected colorectal cancer Dukes' stage B-C were randomized to receive daily 30,000 IU of axerophthol palmitate (vitamin A) plus 1 g ascorbic acid (vitamin C) plus 70 mg of dl-alpha-tocopherol acetate (vitamin E) and 2 g natural calcium daily or indistinguishable placebo for 6 months. At the time of surgery and after 6 and 12 months of treatment, cell kinetics of normal colonic mucosa were assessed by using proliferating cell nuclear antigen (PCNA). Ninety patients were enrolled and 77 were assessable: 34 in the treatment group and 43 in the placebo group. A significant reduction of mean total PCNA labeling index (PCNALI) was evident in both groups after 6 months (vitamins/calcium, from 16.11 +/- 2.43 to 10.71 +/- 2.81; placebo, from 17.30 +/- 2.63 to 12.53 +/- 3.40). The difference in the percentage of reduction of mean PCNALI between baseline and after 6 months was not statistically significant in the treatment and placebo groups: 34% and 28%, respectively. A second control, 6 months after discontinuation of vitamin and calcium supplementation, showed a further decrease of mean total PCNALI in both groups, but this was not statistically significant. Our randomized trial showed that calcium and vitamin supplementation does not reduce cell kinetics of colon epithelium. Furthermore, this study suggests the need for extreme caution in the interpretation and publication of studies on chemoprotectants in colon cancer without a control group.

The vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis, and it is the target of innovative anti-cancer therapies. In colorectal carcinomas, differences in the VEGF expression have been found between the primary tumor and its metastases. We postulated that differences in the VEGF expression may also exist between liver and abdominal metastases from colon cancer. Consecutive colon cancer patients with liver or abdominal metastases were considered eligible for the study. Biopsies had to be performed before chemotherapy and the VEGF analysis were conducted through immunohistochemistry. The staining results were correlated to the metastatic pattern. The study population consisted of 41 patients with a metastatic site in the liver in 19 patients and the abdomen in 22 patients. A positive VEGF staining was found in 19 of the 41 metastatic samples (46%). Cases with positive VEGF expression were found more frequently in abdominal (15 out of 22 patients; 68%) than in liver metastases (4 out of 19 patients; 21%). Also, the degree of VEGF immunoreactivity was significantly higher in abdominal than in liver metastases. Evidence is supported that the VEGF expression may be different between colon cancer metastatic sites. The efficacy of anti-VEGF treatments may depend on the VEGF expression status, and this finding deserves further investigation.

HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer.HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32-82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7-88.2], 66.7% (95% CI 47.8-85.5) and 28.6% (95 CI 11.8-45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037).Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies.

To determine the relationship between p53 overexpression and vascular endothelial growth factor (VEGF) upregulation in liver and abdominal metastases from colon cancer. The analysis in the two metastatic sites was carried out to evaluate the potential role of microenvironment in the molecular regulation of VEGF.Bioptic specimens of liver and abdominal metastases from colon carcinomas were examined by immunohistochemistry for p53 and VEGF expressions. Consecutive cases with assessable tumor tissue were selected.The study population consisted of 24 cases having liver metastases and 34 cases having abdominal metastases. Abdominal metastases showed a higher number of VEGF-positive cases and a higher intensity of VEGF immunoreactivity than liver metastases did (p = 0.01). The combined analysis of p53 and VEGF showed a strong association between the two markers in the 24 liver metastases; 9 cases were VEGF positive/p53 positive and 15 cases were VEGF negative/p53 negative. This relationship was not found in the 34 abdominal metastases, which showed concordance between the two markers in 9 VEGF-positive/p53-positive cases only.Microenvironment factors like hypoxia may have a predominant role in inducing VEGF expression and they can override the molecular control of p53 on VEGF.

Background In gastric juice, high levels of the carcinoembryonic antigen (CEA) and the carbohydrate antigen 19-9 (CA 19-9) have been found to correlate with precancerous lesions and gastric cancer. So far, sampling of gastric juice has required upper endoscopy. In place of this invasive procedure, we investigated a new tool for the quantitation of tumor markers in gastric juice. Materials and methods The study population consisted of healthy controls and consecutive subjects with suspected gastric cancer or dyspepsia/epigastric distress. Patients were asked to swallow a small gelatine capsule (14 mm in length and 5 mm in diameter) containing a pierced plastic cover and surrounding a piece of absorbent paper. The capsule was left in the gastric cavity for 60 min to allow saturation of the absorbent paper with gastric juice. A 45–50 cm length of nylon thread connected to the inner capsule was used to remove the device from the gastric cavity. After processing the absorbent paper for radioimmunoassay, CEA and CA 19-9 levels were correlated to the findings of upper endoscopy and biopsies of gastric mucosa or suspected lesions. Results The endogastric capsule did not cause any side-effects and 62 participants were fully compliant to the procedure. Assessable gastric juice samples were taken from 23 patients with gastric cancer, 15 patients with intestinal metaplasia or dysplasia, 12 patients with gastritis and 12 controls without gastric diseases. In the 12 samples of gastric juice from control patients, mean values of CEA and CA 19-9 were 1.1 ± 0.9 ng/ml and 16 ± 7.5 ng/ml, respectively. The mean levels of both markers were found to increase according to the severity of gastric lesions and in patients with cancer, mean CEA and CA 19-9 levels were 513 ± 627 ng/ml and 545 ± 510 ng/ml, respectively. Patients with precancerous lesions and cancer showed higher levels of CEAand CA 19-9 than patients with normal findings or gastritis (P Conclusions The endogastric capsule is a simple, non-invasive tool for the measurement of CEA and CA 19-9 levels in gastric juice. These values may discriminate between normal or minor pathologic changes and precancerous lesions or carcinomas. Further investigations are warranted, since this may represent a new method for gastric cancer screening.

Background Loss of activity of tumor suppressor genes is considered a fundamental step in a genetic model of carcinogenesis. Altered expression of the p53 and the Deleted in Colon Cancer (DCC) proteins has been described in gastric cancer and this event may have a role in the development of the disease. According to this hypothesis, we investigated the p53 and the DCC proteins expression in different stages of gastric carcinomas. Methods An immunohistochemical analysis for detection of p53 and DCC proteins expression was performed in tumor tissue samples of patients with UICC stage I and II gastric cancer. For the purpose of the analysis, the staining results were related to the pathologic data and compared between stage categories. Results Ninety-four cases of gastric cancer were analyzed. Disease stage categories were pT1N0 in 23 cases, pT2N0 in 20 cases, pT3N0 in 20 cases and pT1-3 with nodal involvment in 31 cases. Stage pT1-2N0 tumors maintained a positive DCC expression while it was abolished in pT3N0 tumors (p Conclusions Altered expression of both DCC and p53 proteins is detectable in gastric carcinomas. It seems that loss of wild-type p53 gene function and consequent p53 overexpression may be involved in early stages of tumor progression while DCC abnormalities are a late event.

Summary Background: The behaviour of colorectal carcinomas may depend on molecular properties of tumors. In node-positive colon cancer, we assessed the S-phase fraction (SPF) index, the vascular endothelial growth factor (VEGF) expression and the TS levels. The combined analysis of SPF/VEGF was studied for predictivity of recurrent disease, the TS quantitation was related to the efficacy of fluorouracil- based adjuvant chemotherapy. Patients and methods: Consecutive patients with surgicallyresected, node-positive colon cancer were studied. Flow cytometry for the SPF and immunohistochemistries for the TS and the VEGF expression were carried out on the primary tumor. Recurrences had to be proven by biopsy or surgery, and they were categorized as early, if occurred within 12 months after surgery, or late if occured 13 months or more. Results: Of 150 evaluable patients, 100 had received fluorouracil-based adjuvant chemotherapy and 50 control patients were untreated. The combined analysis of the VEGF and the SPF showed a strong association between the two markers; 48 patients (32%) had high SPF/VEGF positive tumors and 69 patients (46%) had low SPF/VEGF negative tumors (P < 0.0001). The majority of disease-free patients (73.4%) showed VEGF negative/low SPF tumors (P < 0.0001). Early recurrences occurred more frequently in patients with VEGF positive/high SPF tumors (P < 0.001). In the 100 patients treated with adjuvant chemotherapy, 86% of relapsed patients had TS overexpressin g tumors and 69% of disease-free patients had TS negative tumors (P < 0.001). Also, early recurrences occurred more frequently in TS overexpressing tumors (P < 0.0001). Conclusions: Evidence is supported that node-positive colon cancer constitutes a heterogenous disease. Patients with VEGF positive/high SPF tumors showed an unfavourable outcome compared to patients with VEGF negative/low SPF tumors. The efficacy of fluorouracil-based adjuvant chemotherapy may depend on theTS status.

Tumours of patients with node-positive rectal cancer were studied by immunohistochemistry for p53, BAX and vascular endothelial growth factor expressions. Results were correlated to the relapse rate, the pattern of relapse and the event-free survival after radical surgery and adjuvant chemoradiation. After a median follow-up of 60 months, 39 patients remained disease-free and 40 patients relapsed (18 local relapses and 22 distant metastases). The majority of disease-free patients showed p53 negative and vascular endothelial growth factor negative tumours. Local relapses occurred more frequently in patients with p53 overexpressing tumours (P

Summary Background We assessed the hypothesis that a compromised p53 function could account for the non response of colon cancer patients with low thymidylate synthase (TS) expression receiving a bolus 5-fluorouracil (5-FU)-leucovorin (LV) combination. Patients and methods The study population consisted of 41 patients with unresectable metastatic colon cancer, homogeneosuly, treated with bolus 5-FU and LV. Results Twenty-seven patients (66%) showed high levels of TS expression. The difference in the proportion of objective responses between patients with low (CR + PR: 7 of 14, 50%) and high (CR + PR: 0 of 27) TS levels was statistically significant (P = 0.0001, chi-square test). p53 nuclear over-expression was found in 27 of 41 patients (66%). No differences were observed in p53 overexpression in patients with high (66%) or low (66%) TS expression. p53 status was not found to be associated with response even in patients with low TS expression. Conclusions p53 status measured by immunohistochemistry does not seem to be useful to identify unresponsive patients with low TS expression.

Recently, we have demonstrated that thymidylate synthase (TS) protein expression predicts for the clinical response to a regimen of infusional 5-fluorouracil (5FU) in advanced colorectal cancer patients. Previous studies by other groups that showed a correlation between TS gene expression and response to the fluoropyrimidine also involved infusional regimens. Considering the putatively different mechanism of action of bolus compared with continuous infusion of 5FU, the aim of the present study was to test whether the correlation between TS expression and the clinical response to 5FU is valid for bolus regimens. A secondary aim was to compare TS levels between liver metastases and abdominal recurrences from colon cancer, because these sites have a distinctly different responsiveness to 5FU chemotherapy. The study population consisted of 41 patients (25 males and 16 females; median age, 60 years) with unresectable metastatic or recurrent colon cancer, homogeneously treated with 5FU (420 mg/m 2 i.v., days 1–5) and leucovorin (20 mg/m 2 i.v., days 1–5); cycles were repeated every 28 days. Twenty-seven patients (66%) showed high levels of TS expression as defined by TS scores equal to 3 and 4. The proportion of cases with high levels of TS expression was significantly higher in abdominal recurrences (18 of 22, 82%) compared with liver metastases (9 of 19, 47%; P = 0.02). Intratumoral TS protein expression was inversely correlated with response to chemotherapy (response rate: 7 of 14, 50%, versus 0 of 27 in patients with low and high levels of TS expression, respectively; P = 0.0001). These results confirm that the level of TS protein expression predicts for response to 5FU, even with a bolus schedule. The higher TS levels observed in abdominal compared with liver metastases may account for their different responsiveness to 5FU chemotherapy. Immunohistochemical quantitation of TS protein levels may thus allow us to change the therapeutic approach to advanced colorectal cancer from a general to an individual treatment strategy at a time when new non TS-targeted drugs have become available for this disease.

A primary inflammatory malignant fibrous histiocytoma of the kidney is reported. The differential diagnosis from other sarcomas and pseudosarcomatous lesions is discussed on the grounds of the histologic, immunohistochemical and ultrastructural results. The neoplasm was made up of histiocytes, fibroblasts, myofibroblasts, foam cells and undifferentiated mesenchymal cells with admixed granulocytes, lymphocytes and plasma cells. The immunohistochemical study showed a positivity for alpha-1-antichymotrypsin and a weak positivity for alpha-1-antitrypsin in mononuclear and pleomorphic multinucleated tumor cells. PASpositive, diastase-resistant intracytoplasmic hyaline globules in necrotic cells, examined by electron microscopy, most likely represent lysosomal structures, in accordance with the theories of De Duve, Vattiaux and Von Ardenne.

A case of Paget's disease and gynecomastia in a 70-year-old man is reported. Paget's disease was connected to an intraductal carcinoma, and the immunohistochemical study revealed similar positivity for cytokeratin A, carcinoembryonic antigen and epithelial membrane antigen in Paget cells and intraductal neoplastic cells whereas Paget cells resulted negative for cytokeratin B and C. The study using monoclonal anti-cytokeratin A (35 βH11), B (34 βE12) and C (34 βB4) could represent a good tool, supporting the theory of a ductal origin of Paget cells. A review of the literature has shown the rarity of Paget's disease in the male breast and revealed only two previous reports with an associated gynecomastia, in 2 patients with Klinefelter's syndrome and infiltrating breast carcinoma.