Federico Aragona

PED mediates AKT-dependent chemoresistance in human breast cancer cells

Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs-induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.

PSA reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients.

Microscopic foci of prostatitis may induce prostate-specific antigen (PSA) increase. PSA reduction after antibiotics might identify those patients in whom biopsy can be avoided. Ninety-nine patients received ciprofloxacin for 3 weeks, of whom 59 showed PSA reduction. Histology detected small foci of prostatitis in 65% of cases. Carcinoma was found in 40 and 20.3% of patients with unchanged or decreased PSA, respectively (P=0.03). No cancer was detected if PSA decreased below 4 ng/ml or more than 70%. Biopsy can be postponed, with a low risk of missing a cancer, if PSA decreases more than 70% or below 4 ng/ml.

Ultrasound detection of abdominal lymphadenomegaly in subjects with hepatitis C virus infection and persistently normal transaminases: a predictive index of liver histology severity

BACKGROUND/AIMS The indications for liver biopsy in anti-HCV-positive patients with persistently normal alanine aminotransferase levels are not clearly established. Recent studies have correlated the presence of abdominal lymphoadenomegaly with disease severity in patients with chronic hepatitis C. Our study aimed to evaluate the frequency of abdominal lymphoadenomegaly in an anti-HCV positive blood donor population with persistently normal alanine aminotransferase and the relationship of abdominal lymphoadenomegaly with the severity of liver changes. METHODS Eighty-six anti-HCV positive blood donors (58 M, 28 F) with normal alanine aminotransferase were followed up for a median of 31 months (range 12-50). To evaluate the frequency of abdominal lymphoadenomegaly, all patients underwent ultrasound scan. The common parameters of liver function as well as serum HCV RNA levels were determined. Histological changes were evaluated both in a conventional manner and using the numerical scoring systems of Knodell and Desmet. RESULTS Of the 86 donors, 68 (79%) maintained persistently normal alanine aminotransferase levels during follow-up, and abdominal lymphoadenomegaly was present in 15 of them (22.0%). The remaining 18 donors (21%) showed rises in alanine aminotransferase above normal levels during the follow-up and seven of them (38%) had abdominal lymphoadenomegaly (p=n.s.). In the subjects with normal alanine aminotransferase, there were no significant differences in the common parameters of liver function and the serum presence of HCV RNA between those with or without abdominal lymphoadenomegaly. Normal liver was found in five patients without abdominal lymphoadenomegaly, but never in patients with abdominal lymphoadenomegaly. Analysis with the Mantel-Haenszel test showed a trend toward more serious changes in patients with abdominal lymphoadenomegaly (chi-square MH=9.5, p<0.003). Histological changes did not differ when Knodells score was used; in contrast, staging, evaluated by Desmets score, and periportal necrosis were significantly higher in subjects with abdominal lymphoadenomegaly (p<0.01 and p<0.004, respectively). Multiple logistic regression showed a significant relation between histological changes and the presence in serum of HCV RNA (p<0.004) and gamma-globulin (p<0.002), and abdominal lymphoadenomegaly p<0.003). CONCLUSION Our study shows a prevalence of 22.0% of abdominal lymphoadenomegaly in anti-HCV positive subjects with normal alanine aminotransferase values and a relationship with the degree of liver histology change. Therefore, we suggest that the evidence of abdominal lymphoadenomegaly in these patients could be an indication to perform liver biopsy.

Percutaneous liver biopsy: A safe outpatient procedure?

Following the discovery of hepatitis C virus, more liver biopsies (LB) than before are being performed to assess the severity of liver disease. In this study, following the recommendations for outpatient LB made by the Patient Care Committee of the American Gastroenterological Association, we assessed the feasibility and benefits of LB performed as an outpatient versus inpatient procedure over the last 7 years in our centre. The study included 1,581 patients consecutively examined in our institute; all LBs were performed by a single operator with a 16-gauge needle using the Menghini technique, and in all cases the puncture site was determined using prebiopsy ultrasound. Liver lesions were classified using grading and staging scores. Ultrasound-guided LB of focal lesions were excluded from this study. LB was performed on 1,318 outpatients and 263 hospitalized patients. The mean age of the hospitalized patients was higher than that of the outpatients (p < 0.0001). As major side effects, one death and one haemoperitoneum requiring blood transfusion were recorded in the hospitalized patients. As minor side effects, one haemorrhage occurred in the hospitalized patients, whereas a case of haemobilia and 2 cases of subcapsular haematoma were recorded in the outpatients. In both groups pain at the puncture site was the most frequent minor complication which easily resolved after non-steroid drug administration. Severe histological diagnoses, both in terms of grading and staging, were significantly associated with hospitalized patients. In conclusion, by carefully selecting patients and using prebiopsy ultrasound to assess the puncture site, outpatient LB can be safely performed in most cases; this procedure should be more widely used, because it has met with the favour of patients who are able to return home the same day and reduces public health care service costs.

Expression of cytokeratin 7 and 20 in pathological conditions of the bile tract

Expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) helps to establish the origin of biliary and metastatic carcinomas. We investigated the expression of CK7 and CK20 in inflammatory, metaplastic and neoplastic conditions of the bile ducts, and evaluated possible relationships between the CK expression pattern and extrahepatic bile duct/gallbladder carcinomas (EBDCs) or intrahepatic bile duct carcinomas (IBDCs). We used immunohistochemistry for the investigation of 48 formalin-fixed, paraffin-embedded specimens grouped as: A) lithiasic or inflamed surgically resected extrahepatic bile ducts/gallbladders: all were CK7+/CK20+; B) percutaneous liver biopsies from patients with chronic hepatitis C primary biliary cirrhosis and primary sclerosing cholangitis: all were CK7+/CK20-; C) EBDCs: all were CK7+/CK20+, except for two cases which were CK7-/CK20-; D) IBDCs: all were CK7+/CK20-, except for one case showing CK20 positivity. Metaplastic changes were seen only among specimens in groups A and C: in these cases, CK20 was either focally or diffusely expressed. Our study suggests that the expression of cytokeratins under specific stimuli can be different from normal tissues, and that sometimes CK20 expression can be related to and precede the occurrence of metaplastic alterations.

Resolution of Ménétrier’s Disease after Helicobacter pylori Eradicating Therapy

Some cases of Ménétrier’s disease associated with Helicobacter pylori (HP) have recently been reported in the literature. We report here the case of a 51-year-old man with a diagnosis of Ménétrier’s disease who had previously been unsuccessfully treated with H2 antagonists. A subsequent demonstration of HP infection led us to treat the patient with an eradicating therapy which prompted complete regression of clinical symptoms, resolution of the gastric endoscopic picture, and absence of HP on gastric histology. This result, in accordance with others in the literature, indicates an eventual association of HP infection with Ménétrier’s disease and that consequent therapy is mandatory.

Evaluation by ultrasound of abdominal lymphadenopathy in chronic hepatitis C

Objective:Abdominal ultrasound has shown a frequent association between abdominal lymphadenopathy (LA) and chronic liver disease, but contradictory data have been reported on its relationship with the main parameters of hepatic function. The aim of this study was to correlate the prevalence of LA in patients who were chronic hepatitis–anti-hepatitis C virus positive prospectively followed-up over the last 3 years and its relationship with biochemical and histological data.Methods:136 RIBA II confirmed positive patients with ALT levels >2N were included. None of these had been or was at the time of study on interferon treatment. Ultrasound was performed using a Toshiba SSA 240 A apparatus with a 3.75 MHz convex probe; the operator was unaware of the other results. Diagnosis of chronic hepatitis in all cases was made on biopsy specimens; the histological activity index (HAI) score, according to Knodell, and the grading (G) and staging (S) scores, according to Desmet, were also evaluated.Results:LA was found in 54 out of 136 patients (40%); accordingly, patients were divided into two groups: the LN + ve group included 54 patients (M 33, mean age 48.1 ± 11.7 yr) and the LN-ve group included 82 patients (M 69, mean age 45.3 ± 11.9 yr). LN + ve patients showed significantly higher serum levels of AST (p < 0.0005), ALT (p < 0.001), γGLO (p < 0.05) and γGT (p < 0.02) than LN − ve patients. There was a more severe degree of liver disease in LN + ve patients, expressed by the higher HAI (p < 0.002), G (p < 0.002), and S (p < 0.005). The χ2 test for linear association analysis confirmed the trend toward greater histological severity in LN + ve patients (χ2 MH = 10.2; p < 0.002). Logistic regression confirmed the association between the presence of LA and AST (p < 0.02), ALT (p < 0.03), G (p < 0.02), and S (p < 0.02).Conclusion:This study showed a moderate prevalence of LA in chronic hepatitis C, lower than that reported in other studies. LA was associated with serum parameters of cytolysis, and above all, with the severity of histological damage.

The pathology of bladder cancer: an update on selected issues

To achieve a closer relationship between urologists and pathologists and to use a common language and identical objectives in the pathology of bladder cancer.

Octreotide prevents the pathological alterations of bowel obstruction in cancer patients.

Dear Editor, In cancer patients with bowel obstruction operative mortality and morbility are high. As luminal contents accumulate proximal to the obstruction, the bowel becomes distended and the increase in intraluminal pressure stimulates intestinal fluid secretion, which further stretches the bowel wall [3]. The consequent pathological findings are an accumulation of fluids and gases above the obstruction with altered motility producing distension, wall oedema, vessel congestion, necrosis and perforation of the bowel above the obstruction and the presence of peritoneal fluids. Obstructed patients are hypovolaemic, tachycardiac and frequently hypotensive as a result of fluids and electrolytes sequestered in the gut wall and in its lumen. Successful surgery may be compromised by these alterations and higher morbility and mortality are expected [5]. We studied the effect of octreotide preoperatively administered in three patients undergoing surgery for bowel obstruction due to cancer. The patients were managed by an intravenous replacement of fluids and electrolytes, nasogastric tube and antibiotics. All the patients were put on octreotide at a daily dose of 300 ~g, 5, 2 and 5 days respectively before surgery (14, 5, 13 administrations of octreotide respectively). After opening the abdomen it was discovered that the obstruction was the result of constriction by an intrinsic neoplasm of the colon. The diameter of the bowel above the obstruction was normal and no local gross pathological findings due to the accumulation of fluids in the lumen, such as oedema, vessel congestion or necrosis of the bowel above the obstruction were observed. Samples of intestine (2 cm x 2) 2, 5, and 10 cm above and below the obstruction, formalin-fixed and paraffin-embedded, sectioned and stained with EE, Van Gieson, Gomori, periodic acid/Schiff and alcian stains and a special stain of sulphurosialomucin revealed a normal anatomical (Fig. 1) and biochemical pattern. Intestinal anastomosis after resection was successful. The rationale for the use of octreotide in such situations derives from its known actions. It has also been shown to have a role in the medical management of bowel obstruction [2, 4]. Octreotide acts at the intestinal epithelium intracellu-

Multiplicity and History Have a Detrimental Effect on Survival of Patients With T1G3 Bladder Tumors Selected for Conservative Treatment

PURPOSE In the absence of Tis tumor we assessed whether history and multiplicity have a detrimental effect on conservative treatment in carefully selected patients with T1G3 bladder carcinoma. MATERIALS AND METHODS Between January 1976 and December 1999, 165 select patients with T1G3 bladder tumors were conservatively treated with transurethral resection plus adjuvant intravesical therapy. Patients with concomitant or previous Tis, previous T1G3, tumor size greater than 3 cm and more than 3 lesions were excluded from analysis. Repeat transurethral resection was not routinely performed. However, cytology had to be negative for atypia before the start of adjuvant intravesical therapy. RESULTS Recurrence-free survival at 1, 3 and 5 years was 71.8%, 55.6% and 45%, respectively. Of the cases 14 (8.4%) progressed with a median progression-free survival of 149 months. A total of 23 patients (14%) died. The 5-year recurrence-free survival rate was 52%, 34% and 15% in cases of single and/or primary, multiple and recurrent tumors, respectively. Median overall survival was 144 months. The 5-year disease-free overall survival rate was 85%, 83%, 79% and 69% in cases of primary, single, multiple and recurrent tumors, respectively. An intact bladder was maintained in 137 patients (83%) with a mean disease-free overall survival of 102.7 months. Patients with recurrent and/or multiple T1G3 tumors showed worse survival (p = 0.0021 and 0.0142, respectively). CONCLUSIONS History and multiplicity are relevant predictors of survival even in highly selected patients with TIG3 bladder tumors that are conservatively treated.