Healthy and tumoral tissue resistivity in wild-type and sparc-/- animal models.

Despite the technological improvement of radiologic, endoscopic and nuclear imaging, the accuracy of diagnostic procedures for tumors can be limited whenever a mass-forming lesion is identified. This is true also because bioptical sampling cannot be properly guided into the lesions so as to puncture neoplastic tissue and to avoid necrotic areas. Under these circumstances, invasive and expensive procedures are still required to obtain diagnosis which is mandatory to plan the most appropriate therapeutic strategy. In order to test if electrical impedance spectroscopy may be helpful in providing further evidence for cancer detection, resistivity measurements were taken on 22 mice, 11 wild-type and 11 sparc-/- (knock out for the protein SPARC: secreted protein acidic and rich in cysteine), bearing mammary carcinomas, by placing a needle-probe into tumor, peritumoral and contralateral healthy fat areas. Tumor resistivity was significantly lower than both peritumoral fat and contralateral fat tissues. Resistivity in sparc-/- mice was lower than wild-type animals. A significant frequency dependence of resistivity was present in tissues analyzed. We conclude that accurate measurements of resistivity may allow to discriminate between tissues with different pathological and/or structural characteristics. Therefore, resistivity measurements could be considered for in vivo detection and differential diagnosis of tumor masses.

Malignant pheochromocytoma and paraganglioma: future considerations for therapy.

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors. Knowledge about such neoplasms ameliorated in the last 10-15 years with the discovery of increasing number of germ line mutations even in apparently sporadic cases. Seemingly, genetic tests are going to be an integral part of diagnostic procedures. Standard therapies (advanced surgery, radiometabolic therapy, chemotherapy and radiotherapy) have revealed suboptimal results in tumor size reduction and survival. Currently, there is no standard therapeutic protocol and thus some patients end up with overtreatment while others are undertreated. An effective molecular target therapy aiming at permanent control of these highly complex neoplasms should be the aim of future efforts. In clinical setting investigatory trials with multiple drug therapies targeting a variety of different parallel pathways should be available. Successful management requires a multidisciplinary teamwork.

Detection of tissue abnormalities in normal mucosa surrounding colorectal cancer using an endocytoscopy system.

The endocytoscopy system is a novel diagnostic technique that provides extremely high-magnification imaging of the gastrointestinal mucosa. We are currently using a prototype Olympus endocytoscope for clinical research in gastrointestinal tumors. In one surgical specimen obtained after resection of a cancer of the transverse colon, focal abnormalities of colonic glands were detected 7 cm away from the primary tumor, within macroscopically normal mucosa. Our finding, which was confirmed by histopathological examination, suggests the need for further clinical investigation to assess whether endocytoscopy is able to identify premalignant changes in apparently normal mucosa. This could potentially be useful for accurate evaluation before planning minimally invasive therapy.

Pre-operative endoscopic ultrasonography can optimise the management of patients undergoing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocholithiasis: a prospective study.

BACKGROUND: Pre-operative endosonography has been proposed as a cost-effective procedure in the management of patients who undergo laparoscopic cholecystectomy having an intermediate risk of common bile duct stones. We prospectively evaluated the impact of pre-operative endosonography on the management of patients facing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocolithiasis. METHODS: Among 587 consecutive patients scheduled for laparoscopic cholecystectomy, 47 (8%) patients having one or more abnormal liver function tests but a normal appearance of common bile duct at abdominal ultrasound, underwent pre-operative endosonography. In patients with endosonography-detected common bile duct stones, a pre-operative endoscopic retrograde cholangiography was performed, or an intra-operative endoscopic retrograde cholangiography was scheduled. In all endosonography-negative patients, an intra-operative trans-cystic cholangiography was performed. RESULTS: Endosonography detected common bile duct stones in nine patients (19%) but only in five of them stones were radiologically confirmed (PPV 0.55). Endosonography-detected stones were confirmed in four of four (100%) patients in whom cholangiography was performed within 1 week, but only in one of five (20%) patients in whom radiology was further delayed (P < 0.05). In three of four cases (75%), stones detected at endosonography but not confirmed at X-rays, were smaller than 2.0 mm. Among 38 patients with negative endosonography, common bile duct stones were found in two patients (NPV 0.95), whereas unplanned endoscopic stone extraction was needed only in one patient (NPV 0.97). CONCLUSIONS: Pre-operative endosonography can spare unnecessary pre-operative endoscopic retrograde cholangiography as well as inappropriate scheduling of intra-operative endoscopic retrograde cholangiography in patients undergoing laparoscopic cholecystectomy with abnormal liver function tests. To maximise the impact of endosonography on the management of these patients, the procedure should be performed immediately before laparoscopic cholecystectomy.

Results of EUS in detecting perirectal lymph node metastases of rectal cancer: the pathologist makes the difference.

BACKGROUND: Accurate preoperative staging of primary rectal cancer is mandatory because the result may affect therapeutic decisions. Endoscopic ultrasonography (EUS) is considered the most accurate method for locoregional staging, but the issue of possible variations in the assessment of its accuracy related to technical aspects of pathologic staging has never been raised. The aim of this study was to assess EUS results as determined by two different methods of dissection of surgical specimens. METHODS: Among all cases with primary rectal cancer staged with EUS from April 1991 to April 1997, 131 patients underwent surgery without preoperative radiotherapy; EUS results for nodal staging were compared with those obtained by pathology. Resected specimens were examined using two different techniques (conventional vs. special dissection). RESULTS: There was a significant decrease in diagnostic accuracy of EUS according to pathologic technique. Overall accuracy, sensitivity, specificity, positive and negative predictive values for conventional versus special dissection were as follows: 74.6% vs. 43. 3% (p = 0.0001), 67.8% vs. 21.8% (p = 0.0002), 79.1% vs. 67.8% (p = 0.14), 67.8% vs. 43.7% ( p = 0.02), and 79.1% vs. 43.2% (p = 0.0003), respectively. EUS sensitivity according to size of metastatic lymph nodes was significantly lower for nodes smaller than 5 mm in diameter (p = 0.025) when special dissection was performed because of a larger number of lymph nodes harvested. CONCLUSIONS: Our findings raise concern about the results of EUS staging of lymph node metastases in rectal cancer. Further prospective studies on a node-by-node basis could clarify the real diagnostic yield of EUS.

[Non-invasive lymphatic staging of lung neoplasms: comparative study with computerized tomography and endoscopic ultrasonography]. / La stadiazione linfonodale non invasiva delle neoplasie polmonari: studio comparato tomografia computerizzata-ecoendoscopia.

INTRODUCTION: A prospective comparative study with pathology was performed at the National Cancer Institute, Milan, to assess the clinical value of Computed Tomography (CT) and endoscopic ultrasound (EUS) for nodal staging in lung cancer. MATERIAL AND METHODS: In three years, 71 patients with histological diagnosis of non-small-cell lung cancer were operated on. They underwent CT and EUS examinations to identify mediastinal lymphadenopathies after major nodal involvement had been excluded by chest X-ray. Diagnostic staging was completed in two weeks prior to treatment. Patients received complete tumor removal and radical lymphadenectomy (55 patients), invasive staging with node resection and sampling (11 patients), or mediastinoscopy (5 patients). Blinded interpretation of CT alone, EUS alone, and CT and EUS together were performed, with systematic correlation of imaging findings and pathological results. RESULTS: The frequency of mediastinal involvement was 42.2%. A total of 329 nodal stations were dissected or sampled and 755 lymph nodes were examined at histology. On a per-station basis, CT had greater sensitivity (74%) than EUS (56%), but EUS was more specific (83.4% vs 92.7%). The accuracy rates of the two techniques were similar (CT 81%, EUS 83%). A site by site analysis showed highest sensitivity (100%) in the lower right paratracheal nodes for CT, and in the superior left paratracheal and subcarinal nodes for EUS. When the EUS and CT images were studied together by specialists on a per-station basis, sensitivity, specificity, and accuracy increased to 85%. CONCLUSIONS: Endoscopic ultrasound should be part of the routine preoperative diagnostic approach to non-small-cell lung cancer, because of its high specificity. Results can be improved when EUS and CT are combined, which suggests that these imaging modalities should be used together in selected patients for the noninvasive staging of non-small-cell lung cancer to identify local lymphatic spread.

Observation of thoracic duct morphology in portal hypertension by endoscopic ultrasound.

BACKGROUND: Thoracic duct dilation has been demonstrated in portal hypertension and hepatic cirrhosis by lymphangiography and laparotomy and at autopsy. It is thought to be secondary to increased hepatic lymph flow and has been described in the absence of ascites or esophageal varices. The aim of the present study was to observe thoracic duct morphology by endoscopic ultrasound in various subsets of patients with portal hypertension and hepatic cirrhosis and also to validate existing radiologic/surgical data. METHODS: The thoracic duct of 33 patients with cirrhosis and portal hypertension was studied by endoscopic ultrasound. Patients were divided into four groups: 1, patients with ascites and esophageal varices; 2, esophageal varices without ascites; 3, without esophageal varices or ascites; 4, extrahepatic portal hypertension due to pancreatic malignancy. The thoracic duct diameter was also measured in 14 control subjects (group 5). RESULTS: When the thoracic duct diameter for the five groups was compared with analysis of variance, significance was p < 0.0001; by pairwise comparison, group 1 differed from the other four groups (p < 0.05). Thoracic duct dilation (5.61 mm) was seen in group 1 patients, whereas no dilation was present in groups 2 through 4. Additionally, thoracic duct diameter in 33 portal hypertensive and/or cirrhotic patients was significantly different from that in the 14 control subjects (p = 0. 003). CONCLUSION: The thoracic duct can be reliably identified by EUS in patients with hepatic cirrhosis and portal hypertension. Dilation of the duct is seen only in patients with hepatic cirrhosis, ascites, and esophageal varices. No thoracic duct dilation is present in extrahepatic portal hypertension. Contrary to existing radiologic/surgical data, thoracic duct dilation is not seen in all patients with hepatic cirrhosis and portal hypertension signifying advanced disease. A dilated thoracic duct by endoscopic ultrasound should be considered yet another sign of portal hypertension.

Cytogenetic and interphase cytogenetic analyses reveal chromosome instability but no clonal trisomy 8 in Dupuytren contracture.

The results of cytogenetic and FISH analysis performed in 26 cases of Dupuytren contracture are reported. Clonal or sporadic chromosome changes were found in 18 cases (69%). Clonal changes consisted of: +2, +16, -10, -Y, add(1)(p23), del(2)(q21), t(3;16)(p21;q24), add (3)(p24), del(18)(q21), t(Y;14)(p12;q24), +mar. The results differ from those obtained in normal palmar fascia used as control, in which -Y and +Y were the only clonal changes found in 2 of 11 analyzed cases (18%). No clonal trisomy 8 was found. FISH analysis performed in 11 cases (centromeric probe specific for chromosome 8) failed to show the presence of a cell population with +8. Clonal and sporadic structural changes were different from case to case and no clustering breakpoint was observed. The significance of the chromosome instability leading to clonal and sporadic chromosome changes not specific to Dupuytren contracture are discussed.

Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients.

PURPOSE: This prospective phase II study was designed to test the activity and toxicity of a regimen of fluorouracil (5-FU) and cisplatin (CDDP) in combination with radiation therapy in the treatment of epidermoid cancer of the anal canal. PATIENTS AND METHODS: Thirty-five consecutive patients with untreated epidermoid cancer of the anal canal were candidates for chemoradiation therapy (CRT). Staging of cancer was as follows: T1, 26%; T2, 60%; T3, 14%; and N1, 2,3, 26%. No patient had distant metastases. The treatment protocol consisted of two to three cycles of chemotherapy starting on days 1 and 21 and concurrent radiotherapy at a daily dose of 1.8 Gy up to a total dose of 36 to 38 Gy in 4 weeks, delivered to the anal region, perineum, middle and lower pelvis, and inguinal and external iliac nodes. Radiotherapy was then delivered to the anoperineal region and metastatic inguinal nodes to a total dose of 18 to 24 Gy in 10 fractions. Chemotherapy consisted of 24-hour intravenous (IV) infusion of 5-FU 750 mg/m2 on days 1 to 4 and CDDP 100 mg/m2 by 60-minute IV infusion on day 1. RESULTS: All patients received two cycles of chemotherapy; the second was delayed in three patients because of leukopenia that was evident in 11 (31%). In eight patients, a third cycle was added. They all experienced nausea or vomiting; one patient showed signs of cardiotoxicity and one developed proctitis, dermatitis, and diarrhea (grade 3). Complete regression (CR) was assessed in 33 patients (94%); nine patients with metastatic lymph nodes also had CR. Two patients had a partial response (PR); both underwent abdominoperineal resection, which was not curative in one. Two patients (6%) had a local recurrence; in one, this was associated with hepatic metastases. One of these patients underwent surgery and is alive after about 4 years, while the other is undergoing chemotherapy. After a median follow-up duration of 37 months, 94% of patients are alive without evidence of disease and 86% are colostomy-free. CONCLUSION: This regimen is well tolerated; its toxicity does not exceed that observed with the combination of 5-FU and mitomycin (MMC). Compared with our previous experience based on the classic CRT (5-FU, MMC, and radiation), the objective response rate observed with this new combination was similar. However, the local recurrence rate, observed in patients treated with the new regimen, was lower (6% v 24%). According to more recent data from the literature, primary CRT is the elective indication in epidermoid cancer of the anus and replacement of MMC with CDDP seems an effective and logical evolution.

Manual dissection of adenocarcinoma of the lower third of the rectum specimens for detection of lymph node metastases smaller than 5 mm.

BACKGROUND: The question of whether manual dissection when searching for metastatic lymph nodes from rectal cancer (less than 5 mm) is a reliable method remains controversial. METHODS: We examined 50 consecutive cases of primary adenocarcinoma of the rectum treated with a sphincter-sparing total rectum resection, total mesorectum excision, and coloanal anastomosis. We used a manual method for the detection of lymph nodes. RESULTS: One thousand seven hundred ninety-three lymph nodes were found (mean, 36 per patient). One hundred seventy-four contained metastases. Seventy-nine (45.4%) of the affected lymph nodes were less than 5 mm in greatest dimension. The percentage of metastases to small lymph nodes was similar to the percentage reported by Kotanagi (50%), but lower than the report of Herrera (78%), who used a clearing technique to search for regional lymph nodes. CONCLUSIONS: A median 17 months follow-up in these patients demonstrated that metastases in small lymph nodes are important in the accurate staging of rectal tumors and that a manual method of searching for small lymph nodes is reliable.

Preoperative radiotherapy for resectable cancer of the middle-distal rectum: its effect on the primary lesion as determined by endorectal ultrasound using flexible echo colonoscope.

20 patients with rectal cancer within 8 cm of the anal verge were studied. Endoscopic endosonography was carried out before and after pre-operative radiotherapy (45 Gy over three weeks). The local extent (tumour stage and diameter) was compared with the results of histopathological examination of the resected specimen after anterior resection or total rectal excision. The Tumour Regression Grade (TRG) and lymph node status were also estimated. Two patients were not evaluated endosonographically. Two (11%) of the remaining 18 patients showed ultrasound evidence of down staging (14/18 uT3/4 pre-radiotherapy: 12/18 uT3/4 after) and tumour diameter was significantly reduced. Tumour Regression Grade estimation showed evidence of response to treatment, showing regression of more than 50% in 13 (65%) of cases. Involved nodes were less than 5 mm in diameter in 45% of cases. Histopathological evidence of nodal metastatic regression was seen in 13 (28%) of all involved nodes found. The ultrasonically determined response to radiotherapy may offer useful information in predicting outcome and possibly in selecting surgery.

Non-small-cell lung cancer: detection of mediastinal lymph node metastases by endoscopic ultrasound and CT.

In this prospective study endoscopic ultrasound (EUS) and computed tomography (CT) were evaluated to compare diagnostic accuracy of the two methods. They were performed for nodal staging in selected patients admitted to our institution for non-small-cell lung cancer (NSCLC). From February 1992 to July 1993, 45 patients were recruited for the study when N3 and N2 nodal involvement were excluded on standard chest X-ray. All the patients completed EUS and CT exams for staging before treatment. The results of sensitivity, specificity and accuracy were obtained in 30 patients who underwent surgical treatment with macroscopically radical resection of T and N, which allowed a complete surgical and histological comparison of CT and EUS findings. On a per-patient basis CT results were: sensitivity 63.6%, specificity 78.9% and accuracy of 73.3%; on a nodal station basis sensitivity, specificity and accuracy were 70.0%, 85.1% and 81.6%, respectively. The EUS evaluation showed, on a per-patient basis, values of sensitivity 45.5%, specificity 57.9% and overall diagnostic accuracy of 53.3%. On a nodal station basis the results were 50.0%, 86.6% and 78.2%, respectively. The results obtained in the 30 patients when both techniques were taken in association regarding sensitivity (90.9%), specificity (73.7%) and accuracy (80.0%) on a per-patient basis suggest that the association of EUS and CT offers the best approach for preoperative staging of NSCLC.

Prevention and treatment of complications after endoscopic prostheses placement in tumors of the upper gastrointestinal tract.

Endoscopic intubation is a popular palliative method to resolve immediately malignant dysphagia. However, the complication rate is still high. Between 1978 and 1993, at the Division of Diagnostic and Surgical Endoscopy of Istituto Nazionale Tumori in Milan, 305 patients suffering from malignant dysphagia, were endoscopically treated by insertion of an endoprosthesis. We report the analysis of data regarding our complication rate, compared with the literature, and our experience in preventing managing complications related to this endoscopic procedure.

Clonal chromosome changes in non-neoplastic ureters.

Cytogenetic analysis was performed on 23 samples from non-neoplastic ureters. Clonal chromosome abnormalities were found in eight. They were: loss of Y chromosome, as a single abnormality (five cases) or associated with trisomy 10 and 20 (one case) or with trisomy 2 (one case); and duplication of Y chromosome (one case). Different numerical and structural sporadic abnormalities were found in nine cases. Immunohistochemical analysis and direct observation using the inverted microscope showed that the cells were mainly of the fibroblastic type. FISH analysis with chromosome 7 alpha-satellite probes failed to detect the presence of trisomy 7 in three epithelial cases tested.

Endoscopic stent placement for cancer of the lower esophagus and gastric cardia.

We reviewed our results of using stents for palliation of cancer of the lower third of the esophagus and gastric cardia. During a 14-year period, 76 patients with either lower third esophageal cancer (n = 43) or cancer of the gastric cardia (n = 33) received stents for palliation of malignant dysphagia. Successful endoscopic placement was initially achieved in all patients, with 71 patients available for follow-up. Of these, 40 (56%) were subsequently able to eat solid or semi-solid food, 25 (35%) could swallow only liquids, and 6 (8%) were unimproved. The combined early and late complication rate totalled 22%. Early complications included perforation (n = 3) and stent migration (n = 4); late complications consisted of dislodgment (n = 6), obstruction by tumor (n = 2), and severe esophagitis (n = 1). There were no procedure-related deaths, but survival at 1 year was estimated to be only 1.5%, with a median survival of 2.5 months after stent insertion. The endoscopic placement of prosthetic stents for cancer of the distal esophagus and gastric cardia entails a higher complication rate, less successful palliation, and shorter survival time compared to similar treatment for more proximal esophageal cancer.