[Role of endoanal ultrasound in the evaluation of fistula-in-ano treated with a seton]. / L'ecografia endoanale nella valutazione delle fistole trattate con setone.

AIM: The aim of this study was to define the role of endorectal ultrasound in the evaluation of transphincteric fistula-in-ano treated with a seton. METHODS: Fifty-one patients affected by complex fistula-in-ano and treated with the application of a drain seton at the Second Unit of General Surgery of the University of Cagliari were recruited for the study. Clinical and ultrasonographic (US) evaluation, with transanal scans, were performed in each case before operation. Intraoperative demonstration of a transphincteric track was an indication for a partial fistulotomy with the application of a seton, tied up loosely around the external sphincter. If clinical and US evaluation, during follow-up, revealed a good drainage of the fistula by the seton and its superficialization, definitive fistulotomy was performed. RESULTS: Endoanal US had an 88.2% accuracy. Sclerosis around the seton was observed in 9 patients (17.6%); in other 9 cases a surgical toilette of the track was necessary because of the bad drainage carried out by the seton. Definitive fistulotomy was performed in 35 patients, whilst 16 are still bearer of the seton. After a mean follow-up of 39.5 months, 1 recurrence (2.9%) has occurred. Functional results were satisfactory: 55.9% of the patients has a perfect continence and 88.2% has a Wexner's incontinence score of up to 5. CONCLUSIONS: At skilled institutions, endoanal ultrasound allows to optimize the therapy of transphincteric fistula-in-ano treated with a seton and contribute to obtain good results in terms of recurrence and functional outcomes.

[Surgical treatment of pilonidal disease. Results with the Bascom's technique]. / Il trattamento del sinus pilonidalis: esperienza con la tecnica di Bascom.

AIM: Pilonidal sinus is a considerable source of problems in young patients both in terms of discomfort and in time off to work. Many procedures have been proposed for its treatment but most of them present substantial persistence/recurrence rates. Surgical procedures avoiding a wound in the midline are most likely to succeed. Bascom's technique is the simplest and successful method. The aim of this study is to retrospectively evaluate the results of the Bascom's procedure performed by the authors as to healing time and recurrence rate. All patients with chronic pilonidal disease, treated with Bascom's technique were re-viewed. Complications, healing time and long-term follow-up were considered. RESULTS: A total of 74 patients (52 males, and 22 females), were admitted to the study. The mean age was 26 years; 69 had a small sinus with 1-2 tracks. Three patients (4%) had postoperative bleeding or wound infection. Mean healing time was 39 days but all patients were able to return to work within 1 week from the operation. The mean period of follow-up was 45 months. Six patients developed recurrence (9,2%). Only 3 of them, (because symptomatic) required a second operation. CONCLUSION: Bascom's technique is simple and suitable for one-day surgery with local anesthesia. It also gives favorable results as to return to work and rate of recurrence. Therefore, it is suggested as the procedure of choice in the initial treatment of symptomatic pilonidal disease.

[Surgical treatment for colorectal cancer in patients over 80 years. Short and long term results]. / Il trattamento chirurgico del cancro colorettale nel paziente ultraottantenne. Risultati a breve termine e a distanza.

AIM: To determine the results of elective surgical treatment for colo-rectal cancer in the elderly. METHODS: A total of 746 patients were consequently operated on in elective conditions for colorectal cancer. Patients were divided into 4 groups, according to patient's age: Group A > or =80; Group B=70-79; Group C=60-69; Group D < or = 60. RESULTS: Between older patients there was a higher percentage of right colon cancers (A: 26.3%; B: 13.9%; C: 16.6%; D: 20.6%) and stage D tumors (A: 34.4%; B: 28.3%; C: 21.4%; D: 26%), explaining the greater proportion of palliative surgical treatment in this group of patients (A: 34.7%; B: 28.2%; C: 28.6%; D: 25.7%). There were no differences in term of morbidity (A: 12.6%; B: 9.2%; C: 5.1%; D: 6.4%), mean hospital stay (A: 18.9+/-16.2 days; B: 17.2+/-15.8; C: 15.2+/-8.6; D: 16.8+/-21.8) and postoperative mortality (A: 3.1%; B: 2.3%; C-D: 0.4%); on the contrary, survival curve in group A was significantly shorter than in the other groups. CONCLUSION: Advanced age is not per se a negative prognostic factor and consequently does not represent a contraindication to surgery. In fact, long-term results have been proved to be similar both in young and old patients. Nevertheless, elderly patients have a lower capacity to react to postoperative complications; this needs an accurate evaluation of single patient, considering different parameters such as disease stage, possibility of cure or palliation, quality and expectancy of life.

Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases.

BACKGROUND: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 215) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. PATIENTS AND METHODS: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MSI+ tumour tissues, respectively. RESULTS: The MSI+ phenotype was detected in 75 (24%) patients, with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial [18/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria; (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. CONCLUSIONS: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis.

Prevalence and prognostic role of microsatellite instability in patients with rectal carcinoma.

BACKGROUND: Association between microsatellite instability (MSI) and favorable postoperative survival in patients with colorectal cancer receiving adjuvant chemotherapy has been indicated. To evaluate whether an analogous positive prognostic role of MSI could be present in rectal carcinoma (RC; most RC patients receive adjuvant radiotherapy), PCR-based microsatellite analysis of archival RCs and statistical correlation with clinico-pathological parameters were performed. PATIENTS AND METHODS: DNA from paraffin-embedded paired samples of tumors and corresponding normal tissue from 91 RC patients was analyzed for MSI using five microsatellite markers (tumors were classified as MSI(+) when two or more markers were unstable). RESULTS: Seventeen (19%) RC patients exhibited a MSI(+) phenotype. Prevalence of instability was found in patients with earlier RC onset (28% in cases with diagnosis age < or =55 years versus 15% in cases >55 years), whereas similar MSI frequencies were observed in patients with different disease stage or receiving different adjuvant therapies. While MSI was detected in seven (64%) of 11 familial patients, a remarkably lower MSI incidence was observed in sporadic cases (10/80; 12.5%). A significant association with better disease-free survival (DFS) and overall survival (OS) was found for MSI(+) patients (median DFS/OS, 30/32 months) in comparison to MSI(-) ones (median DFS/OS, 18/21 months) (P <0.001). CONCLUSIONS: MSI was demonstrated to be a strong molecular prognostic marker in rectal carcinoma, independent of the administered treatment (radiotherapy, chemotherapy or both).

[Levels of cytokines in mucosal biopsies of Crohn's colitis. Physiopatological observations]. / Contenuto delle citochine IL-1beta, IL-6 e IL-8 su prelievi bioptici di colite di Crohn. Considerazioni fisiopatologiche sull'estensione panintestinale della malattia.

BACKGROUND: It is well known that mucosal concentrations of many pro and anti-inflammatory cytokines are elevated in diseased segments of colon in Crohn's colitis. The present study, showing preliminary results, aims to determine whether the IL-1beta, IL-6 and IL-8 levels are increased throughout the entire colon in patients with Crohn's colitis. METHODS: Five patients with active Crohn's colitis and five controls were studied by mucosal biopsies. In the diseased patients IL-1beta, IL-6 and IL-8 levels have been measured in both pathologic and normal appearing colonic mucosa. The concentration of these cytokines was assessed using ELISA and compared. Histological sections were also performed to confirm diseased segment of colon. RESULTS: The concentrations IL-1beta and IL-8 were much more higher in patients with Crohn's colitis when compared to controls. Moreover IL-1beta and IL-8 were more elevated in uninvolved colonic segments than on diseased segments. CONCLUSIONS: Our results confirm the finding of other authors that, although Crohn's colitis is a segmental disease, the concentration of IL-1beta and IL-8 in mucosal biopsies is increased throughout the entire colon. In particular our study shows that the concentrations of IL-1b and IL-8 is higher in uninvolved than involved colonic segments. These appearances favour the physio-pathologic hypothesis that Crohn's colitis involves the entire colon even when is not clinically or histologically apparent, and they suggest that uninvolved parts of colon may not be free of disease. Further studies are required to better understand the higher levels of cytokines found in macroscopically normal when compared to pathological mucosal in patients with Crohn's colitis.

Neuromuscular and vascular hamartoma of the small intestine.

Neuromuscular and vascular hamartoma is an extremely rare stricturing condition of the small bowel. It consists of abnormal mixtures of intestinal tissues: disorganized fascicles of smooth muscle derived from the submucosa, bundles of nonmyelinated nerve fibers with scattered abnormal ganglion cells and hemangiomatous vessels, occurring focally and causing recurrent obstructive symptoms or occult chronic gastrointestinal bleeding. In this paper we report our experience with this tumor.

[Neuromuscular and vascular hamartoma of the small intestine. Report of a clinical case and review of the literature]. / L'amartoma neuromuscolare e vascolare dell'intestino tenue. Presentazione di un caso clinico e revisione della letteratura.

We present the case of a 50-year old patient, operated on for three adjoining annular strictures in the jejunum with proximal dilatation. He presented with a one-year history of recurrent cramping in the upper abdomen and vomiting, with two episodes of intestinal obstruction. Microscopic examination of the stricture revealed, in the submucosa, disorganised fascicles of smooth muscle derived from the muscularis mucosae, bundles of non-myelinated nerve fibres with scattered abnormal ganglion cells and haemangiomatous vessels. The pathological findings observed were similar to those described as neuromuscular and vascular hamartoma, a rare stricturing condition of the small intestine. Many authors have questioned the hamartomatous nature of this disorder, since identical features may be seen in Crohn's disease, in ischaemic enteritis, in radiation enteritis and in non-steroidal antiinflammatory drug-induced small intestinal strictures. On the basis of a review of the 5 previously described cases and of our own experience, we believe that neuro muscular and vascular hamartoma of the small bowel should be considered as a distinct entity if histological hallmarks of Crohn's disease are absent, in patients with no history of gastrointestinal disease, or of chronic ingestion of non-steroidal antiinflammatory drugs.

[Clinical relevance of unusual metastases from colorectal neoplasms]. / Implicazioni cliniche delle metastasi in sede inusuale del cancro colo-rettale.

BACKGROUND: The aim of the study was to evaluate the clinical relevance of isolated metastases (MII) in unusual sites (different from liver and lung), synchronous and metachronous, in patients operated on for colorectal carcinoma (CCR). METHODS: The study was performed on 655 patients who underwent surgery for CCR during the period 1985-2000. Work out for distance metastases was performed (both during preoperative evaluation and follow-up) with physical examination and other few exams (CEA, chest X-ray, abdominal US scan). Other investigations were carried out if requested by clinical features. Metastases localized in sites different from liver and lungs were considered unusual. RESULTS: Metastases in unusual sites usually are observed in patients with terminal neoplastic disease. MII was found in only 7 (1.07%) patients, all submitted to resection of the primary tumor. Sites of unusual metastases were bones (3), CNS (2), adrenal gland and anus; such lesions were easily diagnosed by clinical features or by few examinations. Curative treatment was feasible in only three patients, and actually it did improve neither survival, nor quality of life. CONCLUSIONS: Extra-abdominal MII are rare, generally they cannot be treated; therefore particular tests for early diagnosis of such lesions appear useless. Potentially curative surgery for splenic and adrenal metastases is described in the literature; anyhow these lesions are usually shown by routine investigations.

The impact of an incomplete preoperative colonoscopy in patients with colorectal cancer.

Total large bowel evaluation remains an essential step in the treatment of patients with colorectal cancer (CRC). Colonoscopy is the gold standard in the evaluation of the colon for colorectal tumors, but may be incomplete due to tumor obstruction, which is a frequent event in distal cancers. Double-contrast barium enema has a lower accuracy and is not ideal in the presence of signs of obstruction. In theory, intraoperative colonoscopy is a valid alternative, but its routine use is impeded by various practical limitations. Preoperative survey of the colon in 521 consecutive patients treated for CRC in our department was based on colonoscopy (92.5%). Our series was characterised by a high percentage of distal lesions (76.4%) and therefore by a high percentage of incomplete preoperative colonoscopies (50.4%) due to tumor obstruction. In the presence of an incomplete preoperative colonoscopy, we evaluated the entire colon with a double-contrast barium enema in selected cases (36.7%) and with a postoperative colonoscopy within 3 months of surgery in almost all patients (93.4%). The overall rate of complete endoscopic evaluation, either pre- or postoperatively, was 96.7%. The incidence of adenomas was significantly higher in the preoperative examinations as compared to early postoperative colonoscopy. This means that in distal cancer the vast majority of polyps will be located in the distal colon and therefore included in a standard resection. Four patients (0.8%), required a second operation for treatment of a missed lesion (2 benign and 2 malignant). The need for a repeat surgery apparently did not affect the therapeutic results in these four patients. On the basis of our experience, intraoperative colonoscopy would not appear to be a mandatory procedure in all cases of incomplete preoperative evaluation of the colon. However, in the absence of prospective, randomised trials comparing intraoperative vs early postoperative colonoscopy, the dilemma as to the strategy of choice remains.

Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations.

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most potent inhibitor within the series (EC(50) = 0.14 microM, IC(50) = 0.4 microM, and SI > 1429), was then selected as a lead compound for a synthetic project based on molecular modeling studies. Using the three-dimensional structure of RT cocrystallized with the alpha-APA derivative R95845, we derived a model of the RT/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogues. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. Among the compounds synthesized and tested, 20 was the most active one, with EC(50) = 0.045 microM, IC(50) = 0.05 microM, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based and enzyme assays, respectively, together with the highest selectivity achieved so far in the PAS series.

[Colonoscopic screening in first-degree relatives of patients with sporadic colorectal cancer]. / Screening colonscopico nei parenti di primo grado di pazienti operati per carcinoma colorettale sporadico.

UNLABELLED: Colonoscopic screening has been recommended in asymptomatic first-degree relatives of patients with colorectal cancer. In fact this population is believed to have an increased risk in developing colorectal neoplasia. The purpose of this study is to report the impact of colonoscopy in a series of completely asymptomatic first-degree relatives of patients operated on for colorectal cancer at our institution. A total of 480 individuals was requested to participate in a screening program based on faecal occult blood testing (FOBT) and colonoscopy in those with positive FOBT. Colonoscopy was also suggested to persons with negative FOBT. After the first 195 examined relatives, FOBT was abandoned because of continuously increasing acceptance of colonoscopy. RESULTS: Two hundred fifty four subjects (52.4%) accepted to participate at the screening program. After the first 195 examined relatives, FOBT was abandoned because of continuously increasing acceptance of colonoscopy. A total of 142 colonoscopies was performed. Colonoscopy was completed in 112 relatives (78.9%). Thirty-three subjects (23.2%) had a positive colonoscopy: one had invasive adenocarcinoma, one had large villous adenoma and 31 had 54 polyps. Twenty-three lesions (40.3%) were located proximal to the splenic flexure. Of the 54 polyps, 45 (83.3%) were less than 1 cm in size. These findings confirm the utility of colonoscopic screening in asymptomatic first-degree relatives of patients with colorectal cancer. However, its feasibility with the current endoscopic facilities remains an unsolved question.

Direct hyperplasia does not enhance the kinetics of liver repopulation in a new model of hepatocyte transplantation in the rat.

BACKGROUND/AIMS: We have recently developed a new model of extensive liver repopulation by transplanted hepatocytes following exposure to pyrrolizidine alkaloids. In the present study, the effect of 2/3 partial hepatectomy (PH) and that of a potent direct liver mitogen, lead nitrate, were compared in their ability to modulate the kinetics of liver repopulation. METHODS: Fischer 344 rats deficient in enzymatic activity for dipeptidyl-peptidase IV (DPPIV-) were used as cell transplantation recipients. They were given 2 doses of the pyrrolizidine alkaloid retrorsine (30 mg/kg, i.p.), 2 weeks apart, followed 2 weeks later by transplantation of 2 x 10(6) hepatocytes (via the portal vein), freshly isolated from a normal congeneic DPPIV+ donor. PH was carried out or a single injection of lead nitrate (100 micromol/kg, i.v.) was administered 2 weeks post-transplantation. Liver samples obtained at different time points post-treatment were processed histochemically for DPPIV activity. RESULTS: The percent of liver sections occupied by DPPIV+ hepatocytes was <1% at the time of PH or lead nitrate administration. In animals which underwent PH, it increased to 33.4+/-5.7% at 2 weeks and to 55.6+/-8.5% at 1 month. However, in animals receiving lead nitrate, these percentages were only 3.3+/-1.3% at 2 weeks and 16.2+/-3.9% at 1 month. Repeated injections of lead nitrate had no additional effect. Further experiments indicated that an acute mitogenic response to lead nitrate was present in transplanted cells, while resident hepatocytes were inhibited by retrorsine. CONCLUSIONS: These results indicate that direct mitogenic signals (such as those induced by lead nitrate), and compensatory signals (such as those elicited by PH), are not equally effective on kinetics of liver repopulation in this system. The possible reasons for these differential effects are discussed.

[Recurrent esophageal obstruction by a foreign body: a case report and review of the literature]. / Ostruzione esofagea ricorrente da corpo estraneo: caso clinico e revisione della letteratura.

The Authors report a clinical case of a patient endoscopically treated for recurrent oesophageal obstruction by a foreign body. A review of the recent medical literature confirms that immediate endoscopic treatment is the best approach in the oesophageal retention of foreign bodies.

In vitro and in vivo antiproliferative activity of IPCAR, a new pyrazole nucleoside analog.

IPCAR is a pyrazole nucleoside analog which belongs to a class of compounds structurally related to the inosine monophosphate (IMP) dehydrogenase (IMPDH) inhibitors ribavirin, selenazofurin and tiazofurin. Unlike other anticancer drugs, IPCAR showed a potent and broad-spectrum antiproliferative activity in vitro coupled with low cytotoxicity for resting PBL and CFU-GM. IPCAR proved fully inhibitory against human nasopharyngeal carcinoma KB cells expressing the MDR phenotype, whereas IPCAR-resistant renal adenocarcinoma ACHN/R1 cells were fully susceptible to inhibition by a number of anticancer drugs, with the exception of 6TG, 6MP and 5FU towards which they showed a partial cross-resistance. In combinations studies, IPCAR proved synergistic with 6MP, 6TG, 5FU and ribavirin, and additive with ara-A, MTX, doxorubicin, taxol and tiazofurin. Antagonistic effects were never observed. Although the precise molecular target of IPCAR remains to be identified, the data presented herein suggest that, unlike ribavirin and tiazofurin, this drug inhibits a step of the de novo purine biosynthesis different from the conversion of IMP into GMP. In vivo, IPCAR showed low acute toxicity (DL10 > 1000 mg/kg) and was active against the L1210 murine lymphocytic leukemia model. Drug doses of 125 and 250 mg/kg on a day-1, -3 and -5 dosing schedule increased the life span (ILS) relative to untreated control mice of 36.4 and 68.2%, respectively, whereas administration of 500 mg/kg on days 1 and 3 resulted in a ILS of 86.4% and also increased the 30-day survival rate (25% of the mice).

[Lithiasis of the vermiform appendix. Remarks on a clinical case]. / Calcolosi dell'appendice vermiforme. Considerazioni su un caso clinico.

The authors present a case of a 36 year old male, admitted with a 3 year history of cramping abdominal pain, fever, and transient finding of a right lower quadrant mass. The abdominal roentgenogram revealed a large opacity located on the right side of the fifth lumbar segment. The patient underwent laparotomy: an enlarged appendix was removed. The specimen had 4 calculi completely obstructing the lumen of the appendix. The diameter of calculi were 0.5 (in 3 instances) and 3 cm. The case herein described is rather uncommon, due to: 1) the rarity of multiple appendiceal calculi; 2) the size of the larger stone; 3) the inconstant finding of right lower quadrant mass; 4) the non development of acute appendicitis. Differential diagnosis involved several diseases presenting with palpable mass of the lower quadrant of the abdomen and/or laminated densities at the plain abdominal roentgenogram.

Glycosidopyrroles. Part 1. Acyclic derivatives: 1-(2-hydroxyethoxy)methylpyrroles as potential anti-viral agents.

Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1 replication at concentrations that were very close to those cytotoxic for MT-4 cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations slightly below those cytotoxic for Vero cells. However for this series of glycosidopyrroles some relationship between calculated log P values and the observed cytotoxicity was found.

Antitumor activity of 4,5,6,7-tetrathiocino (1,2-b: 3,4-b') diimidazolyl-1,3,8,10-tetrasubstituted-2,9-dithiones (R4-todit).

A series of derivatives belonging to a new class of compounds (R4-todit) were highly cytotoxic to a panel of leukaemia- and solid tumour-derived cell lines (IC50 = 0.06-20 microM). The most potent compound was the butyl4 derivative (IC50 = 0.06-5.1 microM); T leukaemia and melanoma cells were the most susceptible cells to this inhibitor (IC50 0.06 microM and 0.1 microM, respectively). The effect of butyl4-todit was irreversible, and led to progressive cell death. The compound showed a comparable potency against exponentially growing and stationary phase cells, and against cell lines expressing the MDR phenotype. The cytotoxicity of butyl4-todit in human normal PBL was up to 20 fold lower than that shown against T leukaemia cells. When tested for antiangiogenic activity in vivo, 1.5 mg/Kg butyl4-todit resulted in over 70% inhibition of the angiogenesis process induced in mice by Kaposi's sarcoma cell secreted products.