Biomedical subjects
Publications and source records attributed to R Nascimbeni.
The authors describe the personal experience on colonic lavage cytology in neoplastic or inflammatory diseases. Although the presence of false negative results in the lesions of right colon, the method could be useful in the diagnosis of selected cases.
We described the morphological, histochemical and immunohistochemical findings of a polyp detected in the left colon (splenic flexure) in which the diagnosis was atypical hyperplastic polyp. The description is focused on the capability of a hyperplastic polyp to evolve into adenomatous tissue through different modalities.
Aberrant crypt foci (ACF) are microscopic clusters of altered colonic crypts considered premalignant lesions in the large bowel. Genomic instability at short tandem repeats in the DNA, referred to as microsatellite instability (MSI) is the hallmark of hereditary nonpolyposis colorectal carcinoma (HNPCC) caused by mutations in DNA mismatch-repair genes, mostly hMLH1 and hMSH2. In this study, we evaluated for MSI ACF (n = 16), adenomas (n = 18), carcinomas (n =22), and lymph node metastases (n = 3) from 17 patients with colorectal cancer positive for MSI. Ten patients were members of HNPCC families; 7 patients had no family history of cancer. MSI was found in 7 of 7 (100%) ACF and 11 of 12 (91%) adenomas from patients with HNPCC. MSI was not related to histology and size of ACF. A progressive increase in instability as estimated by the number of shifted bands was observed along the ACF-adenoma-carcinoma sequence. In contrast, two of nine (22%) ACF and none of six adenomas from patients with MSI sporadic carcinoma were unstable at microsatellite loci. hMLH1 or hMSH2 protein expression was altered only in MSI-positive premalignant lesions (ACF and/or adenomas), but not in all MSI-positive lesions in patients with HNPCC. These observations provide evidence of the premalignant nature of ACF in HNPCC and suggest that MSI is a very early event both in HNPCC and in sporadic colorectal carcinogenesis, although in the latter it seems infrequent.
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations of genes encoding for proteins of the mismatch repair (MMR) machinery. The majority of mutations occur in the MLH1 and MSH2 genes, and consist of splice-site, frameshift and nonsense changes, leading to loss of protein function. In this study, we screened 7 HNPCC families for MLH1/MSH2 mutations. Sequence changes were identified in 5 families. Four alterations were novel 1- or 2-bp deletions or insertions causing a frameshift and appearance of premature stop codons (MLH1: c.597-598delGA, c.1520-1521insT; MSH2: c.1444delA, c.119delG). The four small insertions/ deletions were located within stretches of simple repeated sequences. By reviewing the HNPCC mutation database, we found that the majority of 1-2 bp frameshift mutations similarly affects simple repetitive stretches, pointing to DNA polymerase slippage during replication as the most likely source of such errors. We also evaluated microsatellite instability (MSI) in a breast carcinoma (BC) from an MLH1 mutation carrier. While a colon cancer from the same individual showed MSI, the BC specimen was MSI-negative, indicating that development of the latter tumor was unrelated to MMR impairment, despite presence of a constitutional MLH1 mutation. Hum Mutat 17:521, 2001.
BACKGROUND: A causal association between acute diverticulitis of the sigmoid colon and arthritis has rarely been reported. CASE REPORT: We report the case of a 60-year-old patient who developed migrating arthritis of the knee and ankle during the recurring episode of acute diverticulitis of the sigmoid colon. Treatment with NSAIDs and antibiotics had little effect on joint disease, but medical treatment was successful in reducing the diverticulitis-related symptoms. Arthritis promptly improved after surgical resection of the sigmoid colon, and 30 months later the patient is free of symptoms in the previously affected joints. CONCLUSIONS: Five cases of diverticulitis-associated arthritis have been reported. The similar case reported here reconfirms that joint disease has a limited response to medical approaches. Colon resection is recommended for patients with diverticulitis-associated arthritis which does not respond promptly to antibiotic therapy.
Aberrant crypt foci are considered potential markers of colorectal cancer risk. The aim of this study was to analyze a large series of human aberrant crypt foci according to frequency, distribution, and histology. Aberrant crypt foci were identified in methylene blue-stained colonic mucosa from 103 patients undergoing surgery for colorectal cancer or diverticular disease. Foci were histologically classified into surface hyperplastic type, surface and glandular hyperplastic type, mixed hyperplastic and adenomatous type, and adenomatous type. The mean frequency of aberrant crypt foci (n = 720) was higher in the colorectal cancer group (0.20/cm2) than in the diverticular disease group (0.07/cm2), and in distal colonic segments than in proximal segments. Most of the histologically examined foci (n = 366) were hyperplastic (88.8%). Surface hyperplasia accounted for 30.6% and prevailed in small lesions. Surface and glandular hyperplasia accounted for 58.2% and prevailed in medium-sized to large foci. Partially or totally dysplastic foci accounted for 10.1% of examined lesions (10.8% and 2.8% in the colorectal cancer and diverticular disease groups, respectively). Most of them (94.6%) were composed of mixed hyperplastic and adenomatous crypts and prevailed in large lesions. The higher frequency of aberrant crypt foci in patients with colorectal cancer sustains their putative role as preneoplastic markers. The high rate of mixed hyperplastic and adenomatous lesions supports the possible adenomatous transformation of hyperplastic lesions.
Previous studies are consistent with the hypothesis that aberrant crypt foci (ACF) could be intermediate biomarkers in colorectal carcinogenesis. The present controlled experimental trial was performed to sequentially analyze ACF progression in rat colonic mucosa. F344 rats were administered 2-weekly doses of azoxymethane (15 mg/kg body weight, s.c.) and sacrificed 6, 12, 20, 30 and 36 weeks after the first carcinogen injection. Control groups of untreated rats were sacrificed at the same time points. The number of ACF per area, their multiplicity (number of crypts per focus), ACF frequency and multiplicity according to each colonic site, histology of ACF and macroscopic lesions were recorded. No ACF were found in control animals. In treated animals, the number of ACF per area and the multiplicity progressively and significantly increased throughout the study. ACF were prevalent in the mid colon. Lower frequencies were registered in the distal colon and rectum. ACF were rare in the proximal colon and cecum. By histology, ACF presented superficial and extensive hyperplasia. Tumors were found in the 30th and 36th week. Adenomas and well-differentiated adenocarcinomas were in the distal colon. All proximal neoplasms were signet ring cell carcinomas. In our study, ACF growing features and distribution are not correlated to adenoma and adenocarcinoma distribution. It is conceivable that signet ring cell carcinomas arising in the proximal colon, where ACF are rare, could present a different pathway of growth. The preneoplastic role of ACF and their function as intermediate biomarkers in colorectal carcinogenesis remain to be clarified.
Point mutations of the K-RAS gene at codon 12 are found in about 40% of cases with colorectal cancer. The diagnostic implications of the detection of these mutations and their clinical utility are still unclear. The aim of this study was to test both the feasibility of the detection of the mutated K-RAS gene in serum and its potential role in colorectal cancer detection and monitoring. Codon 12 K-RAS mutations were examined in DNA extracted from the serum of 35 patients with colorectal cancer and were compared with the K-RAS status in the corresponding primary tumor. Molecular detection was performed by the mutant-enriched PCR (ME-PCR) assay, a sensitive method capable of distinguishing a small quantity of mutated DNA in the presence of abundant wild-type DNA. The occurrence of mutations was compared with clinicopathological parameters as well as CEA and CA19.9 serum levels. We found codon 12 K-RAS mutations in the tissue of 13/35 (37%) patients. Serum mutations were detected in 5/13 (38.5%) patients with mutated K-RAS in the tissue. 26/35 (74%) patients showed an identical K-RAS pattern in tissue and serum. No codon 12 K-RAS alterations were found in serum samples of 22 patients with benign gastrointestinal diseases. Elevated serum CEA levels were detected in 16 patients, four of whom also presented serum RAS mutations. Our results confirm that K-RAS mutations can be found in circulating DNA extracted from serum samples of patients with colorectal cancer and show that there is a correspondence between serum and tissue K-RAS patterns.
While tissue KRAS2 mutations have been extensively investigated, the role of circulating mutant KRAS2 gene in patients with colorectal carcinoma remains obscure. The aim of the present study was to explore the prognostic significance of circulating KRAS2 gene mutational status in subjects undergoing primary treatment for colorectal cancer. Codon 12 KRAS2 mutations were examined in DNA samples extracted from the serum of 86 patients with colorectal cancer and were compared with the KRAS2 status of their primary tumors. Tissue and serum KRAS2 status was compared with other clinicopathological variables (including CEA and CA 19-9 levels) and with cancer-related survival. KRAS2 mutations were found in tissue samples of 28 patients (33%); serum KRAS2 mutations were detected in 10 of them (36%). Serum KRAS2 status was significantly associated with Dukes' stage D (p=0.001) and with preoperative CA 19-9 levels (p=0.01). At multivariate analysis, cancer-related survival was associated with Dukes' stage (p<0.0001), CEA level (p=0.02), and mutant circulating KRAS2 (p=0.01). All 7 stage D patients with serum KRAS2 mutations died of the disease within 24 months of primary treatment; cancer-related survival was significantly better in 9 stage D patients without serum KRAS2 mutations, with 5 patients (56%) alive after 24 months and 1 patient (13%) alive after 44 months. Residual disease after surgery was evident in all 7 stage D patients with mutant circulating KRAS2, and in 5 out of 9 stage D patients without serum mutations. Serum KRAS2 status may impact substantially on the management of stage D colorectal carcinoma, since it appears to cor-relate with prognosis in this patient subgroup.
Young age is believed to be a risk factor for hereditary or familial non-polyposis colorectal cancer. Present study analysed frequency, phenotype and familial cancer risk of 82 subjects with colorectal cancer under 55 years of age. According to age and family history, probands have been subdivided into 5 groups: Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (8.2% of cases); Suspected HNPCC (7.3%); Non-specific familial aggregation of colorectal cancer (AFACC) (19.5%); Early-onset colorectal cancer (diagnosis under 35 years of age) (CCG) (6.1%); Sporadic colorectal cancer (CCS) (58.5%). Proportions of probands with multiple colonic tumours were highest in HNPCC (57.1%), but present in AFACC (12.5%) and CCG (20.0%) groups, as well. Extracolonic, in particular endometrial and ovarian cancers have been found in HNPCC and AFACC probands. Tumours of proximal colon were most frequent in HNPCC, suspected HNPCC, CCG patients. Eleven-years survival rate was higher in HNPCC probands then in CCS group. Familial cancer risk in HNPCC was 3 times as much as in CCG + CCS groups. Diagnosis of colorectal cancer under 55 years of age is associated with an high frequency of hereditary or familial cases. Genetic tests, surveillance and screening programs in these patients must be based on extensive phenotype and pedigree analyses. HNPCC is widely represented in young colorectal cancer patients and is associated with a high risk of multiple synchronous or metacronous colonic and extracolonic tumours. Total colectomy and eventual hysterectomy with bilateral oophorectomy seem therefore recommendable options in these patients.
BACKGROUND AND AIMS: Epidemiological studies have shown that ulcerative proctitis represents 25-55% of ulcerative colitis. In western countries, the incidence of ulcerative proctitis has been increased, while the incidence of more extensive colitis remained unchanged. Compared with extensive ulcerative colitis, the idiopathic proctitis seems to be a benign disease, with an extension to proximal segments in less than 30% of cases, low surgical and cancer risk. On the basis of epidemiological studies, not confirmed by endoscopic and histological features, it has been hypothesized that ulcerative colitis and proctitis could represent two different clinical entities. The aim of the study was to evaluate some clinical and demographic features related to the two different localizations, colitis and proctitis, in the attempt to clarify the above mentioned issues. METHODS: Demographic data of 156 patients observed in our institution from 1982 to 1999, were retrospectively analysed. Diagnosis, extension and severity of ulcerative procto-colitis were based on endoscopic and histological criteria. Local and systemic symptoms, extraintestinal manifestations, surgical and cancer risk, were also recorded. RESULTS AND CONCLUSIONS: Ulcerative proctitis has shown to be a benign disease, with a prevalence of local symptoms, less systemic and extraintestinal manifestations, and low endoscopic grades of activity. Furthermore no surgical intervention and cancer development were recorded. Extension to proximal segments was observed in 10.25% of cases. Young age of onset of symptoms,-smoking and appendectomy were associated to an higher risk of extension of the disease.
The different diagnostic modalities (MIBI scan, ultrasound, CT, MNR) applied in the preoperative study of hyperparathyroidism, have given excellent sensitivity results, only slightly lower than those obtained by surgical exploration performed by experienced surgeons. Yet, their only limitation lies in a lower level of specificity. Other cervical tumours, such as thyroid nodules, lymphoadenopaties, vascular and macular lesions, can in fact be erroneously taken as hyperfunctioning parathyroids. The present paper shows a clinical experience of 27 patients affected by IPT (14 primary IPT, 10 secondary, 3 terziary) who underwent Color-Doppler Ultrasonography and US before surgical exploration. As a result, global sensitivity level reached 81.5%, specificity 100%. In IPT I and III, sensitivity reached 100% while in IPT II it was only 72.2%. In conclusion, Color-Doppler associated with conventional US increases the specificity rate of IPT pre-operative diagnosis.
In relation to DNA index we have studied 18 cases of differently evoluted carcinoma of the colon, some incoherently (8) other in agreement (10) with staging. Static and flow cytometric techniques have been employed, the first by means of densitometric study on paraffin sections with the Feulgen method, the second based on application of Hedley method on paraffin included material. DNA content, pressed by the DNA index, is inversely proportional to survival with similar results in both techniques, from which the possible prognostic significance is argued.
BACKGROUND AND AIMS: Improved medical therapy and bowel sparing and sphincter saving techniques have changed surgery for UC and CD. Collaboration between gastroenterologists and surgeons is necessary to uniform the indications for surgical treatment reducing emergency operations. GISMII multicentric study aimed to show indications, timing and impact of surgery, through retrospective analysis of cases observed between 1992 to 1996. METHODS: Data were obtained by 16 departments of General Surgery. RESULTS: 102 UC and 376 CD patients were analyzed. In UC patients surgery was performed for failure of medical therapy in 54%, complications in 28.4%, cancer or dysplasia in 10% of cases, 83.3% elective procedures. 30.4% ileo-anal pouch, 30.4% total procto-colectomies with definitive ileostomies, 32.4% total colectomies with ileo-rectal anastomosis, 6.8% segmental resections, were performed. In CD patients surgery was performed in 21% for medical therapy failure, in 79% for complications. 53.4% of patients were submitted to 1 operation, 84% elective procedures. Reoperations were performed in 46.6% of patients, 70.3% elective procedures. In the first operation bowel resection was performed in 79.1%, stricturoplasty in 14.3%; in the subsequent operations bowel resection 62.8%, stricturoplasty 21.7%, increasing number of temporary or definitive ileo-stomies. CONCLUSIONS: Collaboration between gastroenterologists and surgeons is necessary to obtain optimal results, reducing the incidence of emergency surgery, and complications. The short period observed between diagnosis and operation (21.4 months) is due to the increasing tendency of gastroenterologists to anticipate a surgical procedure when young patients with a chronic disease need a prolonged medical therapy.
Sixtysix patients were submitted to color Doppler ultrasonography, with flowmetric analysis, in the preoperative work up of their thyroid nodules. Three different groups (and two subsets) were so identified, corresponding to the different pathological nodule types: hyperplasia, adenoma, and cancer. The data obtained were then compared to the final pathological results. The color Doppler ultrasonography showed a diagnostic accuracy rate of 87.8%. An evaluation of the peak systolic velocity proved to be very useful in the differential diagnosis between adenomas and cancers. The color Doppler ultrasonography represents a sound method for evaluating thyroid nodules.
BACKGROUND AND AIMS: The mortality in severe episodes of ulcerative colitis (UC) has been reduced from 31-61% in the 1950 to 1-3%. Nevertheless it remains high in non specialist centers. Simple criteria are necessary to predict the outcome of severe ulcerative colitis. METHODS: 14 patients hospitalized for severe disease (Truelove and Witts criteria) from 1996 to 2000 were retrospectively analyzed. Patients were divided into two groups: 1. Group A: patients with severe disease surgically treated. 2. Group B: patients with severe disease responders to medical therapy Sex, age, length of steroids medical therapy, fever, stool frequency, CRP, ESR, haemoglobinemia, leukocytes, serum albumin values in the three days before the operation or during the hospitalization were collected. RESULTS: Total colectomy with ileostomy was necessary in 8 patients (57.1%), while 6 patients (42.90%) were responders to medical therapy. No perioperative mortality was recorded. Stool frequency, CRP, ESR, haemoglobinemia, serum albumin were significantly related to surgical operation. CONCLUSIONS: 1. No uniform criteria off severe attacks, are clearly defined in Literature. 2. The length of pre-operative medical therapy has a tendency to be too high (in our series 19 + 8.2 days). 3. Stool frequency, CRP, ESR, haemoglobinemia, serum albumin were significantly modified in operated patients.
Grave hypercalcemia may complicate primary hyperparathyroidism. This clinical condition is potentially life-threatening, if it is untreated. The emergency therapy consist in rehydratation, stimulation of diuresis and somministration of biphosphonates. A urgent surgery is required if conservative therapy is not successful. The Authors herein present a consecutive series of 6 cases with acute hypercalcemic crisis due primary hyperparathyroidism, successful treated with urgent parathyroidectomy after conservative treatment.