Domenico Borzomati

Fever After Zoledronic Acid Administration Is Due to Increase in TNF-α and IL-6

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-α, interferon-γ (IFN-γ), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-α circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to ...

Apoptotic index or a combination of Bax/Bcl‐2 expression correlate with survival after resection of pancreatic adenocarcinoma

In the present study, the prognostic impact of factors involved in the apoptosis pathway were tested on 67 consecutive patients treated with surgical resection. Included in the study were all patients resected for pancreatic adenocarcinoma from 1988 to 2003. Expression analysis for p53, Bax, and Bcl‐2 were performed by immunohistochemical staining. Apoptotic cells were identified by the TUNEL method. These data were correlated with survival. Sixty‐seven tumor specimens were included in the study. A strong positive correlation was recorded between p53 overexpression and Bax expression levels (P < 0.001). By univariate analysis, overall survival seemed to be improved with Bcl‐2 and Bax expression (respectively, P = 0.0379 and 0.0311). The median survival time in patients with low apoptotic index was better versus those with a high index (P = 0.0127). Lymph node involvement was the only clinico‐pathologic parameter that significantly correlated with overall survival (P = 0.0202). By a multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was the apoptotic index (P = 0.040). Tumors overexpression of both Bax and Bcl‐2 resulted the strongest independent prognostic factor (P = 0.013). This is the first study to report a statistically significant association of apoptosis to overall survival for pancreatic cancer patients treated with surgical resection. The contemporary overexpression of Bax and Bcl‐2 represents the strongest prognostic factor. J. Cell. Biochem.

Carcinoma of the ampulla of Vater: morphological and immunophenotypical classification predicts overall survival.

Objectives The objective of the study was to verify if histopathological differentiation of ampullary carcinoma after surgical resection may be related to survival. Methods The prognostic role of an accurate histological and immunohistochemical classification has been investigated in a multicentric series of carcinoma of the ampulla of Vater. Immunohistochemical expression of cytokeratin 7 (CK7) and CK20 were analyzed in the different morphological histotypes of ampullary cancers, and results were compared with overall survival. Results Of 72 ampullary cancers, 48.6% were classified as pancreaticobiliary-type carcinomas, 43.1% were classified as intestinal-type carcinomas, and 8.3% were classified as “unusual”-type carcinomas. Cytokeratin 20 was expressed in 28 (90.3%) of the 31 intestinal-type carcinomas, whereas it was always negative in the pancreaticobiliary histotype; CK7 was expressed in 32 (91.4%) of the 35 pancreaticobiliary-type carcinomas and in 18 (58.1%) of the 31 intestinal-type carcinomas. By univariate analysis, overall survival was influenced significantly by pathological T factor, lymph node involvement, and histological/immunohistochemical subtyping. Furthermore, using a multivariate Cox regression model, lymph node metastasis and CK20 were identified as significant independent factors related to prognosis. Conclusion Our results prove the clinical use of ampullary cancer subclassification based on different histotypes and indicate the useful role of the CK7/CK20 expression profile for consistent histopathological classification and prognostic relevance.

Prognostic value of Bax, Bcl-2, p53, and TUNEL staining in patients with radically resected ampullary carcinoma

Background: There is a lack of data in the literature concerning the identification of potential prognostic factors in ampullary adenocarcinoma. Aims: To examine the prognostic significance of Bax, Bcl-2, and p53 protein expression and the apoptotic index in a large cohort of uniformly treated patients with radically resected ampullary cancer. Methods: All patients with a pathological diagnosis of ampullary cancer and radical resection were evaluated. Expression analysis for p53, Bax, and Bcl-2 was performed by immunohistochemistry. Apoptotic cells were identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). Results: Thirty nine tumour specimens from patients with radically resected ampullary adenocarcinoma were studied. A positive significant correlation between Bax and p53 expression was found by rank correlation matrix (p < 0.001). A trend towards a positive correlation was found between the apoptotic index and p53 expression (p  =  0.059). By univariate analysis, overall survival was influenced by Bax expression, p53 expression, and TUNEL staining (p  =  0.001, p  =  0.01, and p  =  0.03, respectively). Bcl-2 expression did not influence overall survival in these patients (p  =  0.55). By multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was Bax expression (p  =  0.020). Conclusions: These results provide evidence that apoptosis may be an important prognostic factor in patients with radically resected ampullary cancer. This study is the first to assess the clinical usefulness of Bax expression in radically resected ampullary cancer.

COX-2 expression of ampullary carcinoma : correlation with different histotypes and clinicopathological parameters

Epidemiological studies suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced incidence of gastrointestinal cancer. Several lines of evidence indicate that the antineoplastic effect of NSAIDs is attributable to COX-2 inhibition. The aim of our study was to assess COX-2 expression in a series of primary untreated ampullary carcinomas and its possible correlation with clinicopathological parameters. In the present study, 45 surgical specimens of invasive ampullary carcinomas were histologically classified into pancreaticobiliary, intestinal, and unusual types. COX-2 expression by immunohistochemical method was analyzed. High COX-2 expression was detected in 35 (77.8%) ampullary carcinomas. Among these, 20/21 (95.2%) were classified as intestinal, 9/18 (50%) pancreaticobiliary, and 6/6 (100%) unusual type. A significant statistical difference in terms of COX-2 expression was found between pancreaticobiliary vs intestinal type (P=0.002). Furthermore, a negative significant statistical correlation was found between T factor and COX-2 expression (P=0.047). The different COX-2 expression among histopathological types supports the concept of histogenetical difference of ampullary carcinomas. Furthermore, the high rate of COX-2 expression in the intestinal subtype of ampullary carcinoma may represent the rational for a histotype-tailored therapy targeting COX-2.

COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables.

Background: There is evidence that the anti-neoplastic effect of non-steroidal anti-inflammatory drugs is attributable to cyclooxygenase-2 (COX-2) inhibition, but the exact mechanisms whereby COX-2 can promote tumour cell growth remain unclear. One hypothesis is the stimulation of tumour angiogenesis by the products of COX-2 activity. To data, there have been few clinicopathological studies on COX-2 expression in human ampullary carcinoma and no data have been reported about its relation with tumour angiogenesis. Objective: To investigate by immunohistochemistry the expression of COX-2 and the angiogenesis process in a series of primary untreated ampullary carcinomas. Methods: Tissue samples from 40 archival ampullary carcinomas were analysed for COX-2, vascular endothelial growth factor (VEGF), and an endothelial cell marker von Willebrand factor (vWF) by immunohistochemistry, using specific antibodies. Results: COX-2 expression was detected in 39 tissue samples (97.5%), of which two (5%) were graded as weak, 26 (65%) as moderate, and 11 (27.5%) as strong. Only one lesion (2.5%) was negative for COX-2 expression. VEGF expression was detected in 36 tissue samples (90%). A significant positive correlation was found between COX-2 and VEGF expression. No statistic correlation was found between COX-2 expression and microvessel density. Conclusions: COX-2 is highly expressed in ampullary carcinomas. This suggests an involvement of the COX-2 pathway in ampullary tumour associated angiogenesis, providing a rationale for targeting COX-2 in the treatment of ampullary cancer.

Cerebellar Metastasis from Pancreatic Adenocarcinoma

The first discovery of a cerebellar metastasis of pancreatic carcinoma in a living patient is described. Two years earlier the patient had undergone a pancreaticoduodenectomy for an adenocarcinoma of the head of the pancreas with a lymph node metastasis. After complete surgical removal of the tumor, he underwent adjuvant chemoradiation. Two years later the patient presented with intractable vomiting, which was attributed to peritoneal carcinomatosis. Clinical evaluation revealed an intracranial tumor without signs of pancreatic recurrence. The tumor was surgically removed. One year later the patient developed multiple brain metastases and he is currently undergoing gemcitabine-based chemotherapy.

Thymidylate Synthase Expression in Normal Colonic Mucosa: A Predictive Marker of Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-Based Adjuvant Chemotherapy

Objectives: We retrospectively evaluated the relevance of thymidylate synthase (TS) expression in normal colonic mucosa as a predictive factor of toxicity in colorectal cancer patients receiving adjuvant fluorouracil (5-FU)-based chemotherapy. Methods: TS expression was immunohistochemically assessed on normal colonic mucosa from 50 patients with colorectal cancer Dukes’ stages B (15 patients) and C (35 patients) treated with 5-FU-based adjuvant chemotherapy. Results: The incidence of grade 2–3 diarrhea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (p < 0.0001). Moreover, patients with low TS expression in normal colonic mucosa developed weight loss and worsening of the performance status (according to ECOG score) more commonly than patients with high TS expression (p = 0.005 and p = 0.02, respectively). Furthermore, low TS expression in normal colonic mucosa significantly correlated with a higher rate of a delay of chemotherapy courses, dose reduction and treatment discontinuation. Conclusions: Immunohistochemical TS expression in normal colonic mucosa may represent an important predictive parameter for identifying a subset of patients with a high risk of developing severe 5-FU-related toxicities.

MUC2 but not MUC5 expression correlates with prognosis in radically resected pancreatic cancer patients

Introduction: Pancreatic cancer is one of the most aggressive gastrointestinal cancer with less than 10% long-term survivors. The apoptotic pathway deregulation is a postulated mechanism of carcinogenesis of this tumour. The present study investigated the prognostic role of MUC2 and MUC5 apomucin expression in a series of surgically resected pancreatic cancer patients. Material and Methods: All patients affected by pancreatic ductal adenocarcinoma and treated with surgical resection from 1988 to 2003 were considered for the study. MUC2 and MUC5 expression were evaluated by immunohistochemical staining. Tumour specimens of 59 resected patients were included in the study. Results: By univariate analysis, survival was influenced by MUC2 expression but not by MUC5 expression. The MUC2 overexpression was associated with better prognosis (P=0.003). By a multivariate Cox regression analysis, MUC2 overexpression maintained the prognostic statistical value. In particular, patients with high MUC2 staining showed a longer survival. Moreover the present study does report the absence of a prognostic role of MUC5 expression in this type of cancer. Conclusions: the study demoinstrated the prognostic relevance of MUC2 expression in pancreatic cancer and underlined its potential role as target gene in the field of therapy research.

Percutaneous ultrasound-guided ablation of BW7756-hepatoma using ethanol or acetic acid in a rat model

BackgroundTo compare tumor necrosis in hepatoma induced in rats by a single percutaneous injection of ethanol (PEI) or acetic acid (PAI).MethodsBW7756 hepatomas of 1 mm3 were implanted in the liver of 40 male healthy rats. After 14 days, the 36 surviving rats were treated, in a single session, by ultrasound-guided injection of 300 μl of 95% ethanol (n = 17) or 100 μl of 50% acetic acid (n = 19). They were sacrificed 14 days after treatment and explanted tumoral livers were examined. The same PAI procedure was repeated on 13 additional rats to exclude a suspected occurrence of technical failures during the experiment, due to a surprisingly high rate of deaths within 30 minutes after PAI.ResultsFour rats died within four days after tumor implantation; after PEI, 1/17 (6%) died, whereas after PAI 9/19 (47%) died. The remaining 26 rats, after 14 days post-percutaneous ablation, were sacrificed. Gross and microscopic examinations showed that the hepatomas nodules treated with PEI had 45.3 ± 19.4% tumor necrosis compared to 49 ± 23.3% (P = NS) for those treated with PAI. Complete tumor necrosis was not found in any animal. Peritoneal invasion was present in 4/16 (25%) and 2/10 (20%) rats treated with PEI or PAI, respectively (P = NS). Autopsy was performed in the 5 additional rats that died within 30 minutes after PAI.ConclusionOur results show that there is no significant difference in the percentage of tumor necrosis between two local ablation methods in spite of the different dosages used. However, mortality in the PAI-treated group was greater than in PEI-treated group, presumably due to greater acetic acid systemic diffusion and its metabolic side effects. In human subjects, HCC occurs in the setting of cirrhosis, where the non-tumoral tissue is firmer than the tumor structure, with consequent reduction of drug diffusion. This could be the reason why some human studies have concluded similar or even better safety and efficacy with PAI compared to PEI.