Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet.

Given the clinical prevalence of type 2 diabetes and obesity and their association with high mortality linked to cardiovascular disease, the aim of the study was to investigate the effects of feeding type 2 diabetic Goto-Kakizaki (GK) rats either high- or low-fat diets on cardiomyocyte structure and function. The GK rats were fed either a high-fat diet (HFD) or a low-fat diet (LFD) from the age of 2 months for a period of 7 months. The GK-HFD rats gained more weight, ate less food and drank less water compared with GK-LFD rats. At 7 months, non-fasting blood glucose was higher in GK-LFD (334 ± 35 mg dl(-1)) compared with GK-HFD rats (235 ± 26 mg dl(-1)). Feeding GK rats with a HFD had no significant effect on glucose clearance following a glucose challenge. Time-to-peak (t(peak)) shortening was reduced in myocytes from GK-HFD (131.8 ± 2.1 ms) compared with GK-LFD rats (144.5 ± 3.0 ms), and time-to-half (t(1/2)) relaxation of shortening was also reduced in myocytes from GK-HFD (71.7 ± 6.9 ms) compared with GK-LFD rats (86.1 ± 3.6 ms). The HFD had no significant effect on the amplitude of shortening. The HFD had no significant effect on t(peak), t(1/2) decay, amplitude of the Ca(2+) transient, myofilament sensitivity to Ca(2+), sarcoplasmic reticulum Ca(2+) content, fractional release of Ca(2+) and the rate of Ca(2+) uptake. Structurally, ventricular myocytes from GK-HFD rats showed extensive mitochondrial lesions, including swelling, loss of cristae, and loss of inner and outer membranes, resulting in gross vacuolarization and deformation of ventricular mitochondria with a subsequent reduction in mitochondrial density. Expression of genes encoding various L-type Ca(2+) channel proteins (Cacnb2) and cardiac muscle proteins (Myl2 and Atp2a1) were downregulated in GK-HFD compared with GK-LFD rats. Structural lesions and changed expression of genes encoding various cardiac muscle proteins might partly underlie the altered time course of myocyte shortening and relaxation in myocytes from GK-HFD compared with GK-LFD rats.

Venous invasion may predict lymph node metastasis in early rectal cancer.

AIM: The aim of this study was to evaluate the role of histopathological and demographic characteristics in predicting lymph node metastasis in patients with adenocarcinoma of the rectum confined to the mucosal and submucosal layers. METHODS: Fifty-nine patients with early rectal cancer underwent resection of the rectum including lymph nodes and five showed lymph node metastasis (8.6%). Pathology slides of these patients were reviewed by a single pathologist. Demographic and clinical characteristics of these 59 patients were correlated with the existence of nodal metastasis. Formal tests of comparability were carried out by using Fisher's exact test. Logistic regression models were fitted to data to examine possible relationships with 12 covariates measured from each patient and to obtain corresponding odds ratios (as well as a 95% confidence interval for the odds ratios). These covariates included age at surgery, gender, morphology, histology, degree of differentiation, Haggitt's classification for polyps according to the level of invasion, lymphatic and venous invasion, desmoplastic reaction, degree of lymphocytic invasion, presence of lymphoid follicles and presence of infiltrating or pushing margins. RESULTS: A significantly higher rate of lymph node metastasis occurs in the presence of venous invasion (P < 0.01). Venous invasion was present in three of five (60%) patients with lymph node metastasis and only four of 54 (7%) patients without lymph node metastasis. Other variables did not achieve statistical significance. CONCLUSIONS: Only the presence of venous invasion was found to be highly significant. The odds ratio of lymph node metastasis increased 18-fold for a patient who had venous invasion compared with a patient who did not. This suggests that the presence of venous invasion in early rectal cancer may provide valuable information to determine which patients would benefit from radical surgery, or adjuvant radiation therapy after sphincter-sparing surgery owing to an increased risk of lymph node metastasis.

Intra-abdominal desmoplastic small round cell tumor.

BACKGROUND: Intra-abdominal desmoplastic small round cell tumor is a rare malignancy with a predilection for young males. Unique histological and immunocytochemical features distinguish the tumor from other members of the family of small round cell tumors of infancy and childhood. The aggressive nature of tumor spread, relative insensitivity to chemotherapy, and generally incomplete resectability result in a very poor prognosis. The authors report a case of a 39-year-old man with diffuse abdominal and pelvic involvement of intra-abdominal desmoplastic small round cell tumor treated with aggressive chemotherapy and surgery. METHODS: Computed tomography (CT)-guided biopsy of an omental mass was performed. Histologically, discrete nests of uniform closely packed malignant cells were distributed in a background of focally desmoplastic stroma. Immunocytochemistry demonstrated positivity for epithelial, mesenchymal, and neural markers. On the basis of these unique histological and immunohistochemical characteristics, the diagnosis of desmoplastic small round cell tumor was made. The patient was treated with aggressive neoadjuvant chemotherapy consisting of a high-dose alkylator -based combination regimen, followed by surgery. RESULTS: The patient had a 10 to 15 percent regression in tumor mass in response to chemotherapy. Laparotomy revealed two large omental masses, another large mass adherent to the left colon and pelvic sidewall, and diaphragmatic, peritoneal and mesenteric studding with small nodules. Complete surgical resection was not possible. CONCLUSIONS: Intra-abdominal desmoplastic small round cell tumor remains an aggressive malignancy with an extremely poor prognosis. Although some response to chemotherapy may be possible, complete resection is rare, and surgical efforts are generally palliative.

Foreign body reaction to a metal clip causing a benign bile duct stricture 16 years after open cholecystectomy: report of a case.

We present herein a case where a benign bile duct stricture developed 16 years after an open cholecystectomy and without any prior symptoms. The patient was thought to have a Klatskin tumor both pre- and intraoperatively and was treated with a resection of the mass and bile duct confluence, while hepaticojejunostomies were also performed to both ducts separately. A pathologic examination of the specimen revealed extensive fibrosis, chronic inflammation, and a nonnecrotizing granulomata. Any hilar mass presenting after upper abdominal surgery should therefore be considered to be potentially a benign bile duct stricture, even with a long symptom-free interval.

Colonic melanoma, primary or regressed primary.

Primary melanoma originating in the gastrointestinal tract is very rare and the majority of these tumors arise in the mucosa of the anus or rectum. A case of solitary colonic melanoma in a 79-year-old man is described with a review of pertinent literature. The surgically excised neoplasm was evaluated by routine histology and immunohistochemistry stains. Pathologic examination of the excised cecal mass revealed an 8 x 5-cm tan-pink mass with a central green-black necrotic area. Histologically, there were solid sheets of S100- and HMB-45-positive pigmented cells extending from the mucosal ulcerated surface through the bowel wall. The patient had no evidence of cutaneous or ocular primary melanoma. He remained free of recurrent disease 5 years after surgical resection of the colonic melanoma. The unique pathologic features and clinical outcome support the diagnosis of primary colonic melanoma in this patient.

A simplified technique for laparoscopic jejunostomy and gastrostomy tube placement.

BACKGROUND: Percutaneous endoscopic gastrostomy and jejunostomy tube placement have long been considered the standard for supplying enteral nutrition when oral intake is not possible. Both have well-documented roles and limitations and are associated with a higher than generally appreciated incidence of aspiration. A distally placed tube in the jejunum decreases the chance of this morbid complication. Additionally, when percutaneous endoscopic gastrostomy is indicated but cannot be done for technical reasons, a minimally invasive alternative is desirable. METHODS: In prior series, the techniques suggested for laparoscopic enteral access have characteristics that are either difficult for the average surgeon to duplicate, or use nonstandard anchoring techniques of the bowel to the abdominal wall. A simple, laparoscopically directed, percutaneous technique utilizing cost-effective appliances is described, and suggested indications are outlined. RESULTS: This technique has been successfully applied in 46 patients with minimal complications. CONCLUSIONS: A simplified technique for laparoscopic jejunostomy and gastrostomy tube placement is described. This has been successfully deployed in 46 patients with minimal morbidity. The procedure lessens the need for sophisticated suturing skills and duplicates standard small bowel to abdominal wall fixation methods.

Biliary tract obstruction secondary to mycosis fungoides: a case report.

Mycosis fungoides is a cutaneous T-cell lymphoma that can disseminate to multiple organs. We report a patient who presented with obstructive jaundice caused by isolated involvement of the extrahepatic biliary tree by mycosis fungoides. Initially, endoscopic examinations and biopsies of the biliary tree and liver failed to reveal a cause for the obstructive symptoms. Finally, surgical resection of the gallbladder and extrahepatic ducts was performed. Examination revealed a dense, mixed lymphocytic infiltrate with atypical cells within the mucosa. Gene rearrangement studies confirmed the presence of a monoclonal T-cell population. The pattern of the gene rearrangement in the biliary tree was identical to that found in a previous skin biopsy that showed mycosis fungoides. Although liver involvement by mycosis fungoides is not uncommon, disease isolated to the extrahepatic biliary tree has not previously been reported. This case should alert clinicians and pathologists to yet another cause of obstructive jaundice.

A clinical-pharmacological evaluation of percutaneous isolated hepatic infusion of doxorubicin in patients with unresectable liver tumors.

A dose escalation study of hepatic arterial infusion of doxorubicin during hemodynamic isolation of the liver (the Delcath system) was conducted to: 1) study the pharmacokinetics of regional doxorubicin therapy, and 2) define therapeutic efficacy in the treatment of unresectable liver tumors. Eighteen patients with unresectable primary or metastatic tumor in the liver were treated with 57 procedures. Pharmacokinetic studies were performed on all treatments. Hepatic extraction ratio of doxorubicin remained constant at 60.3+/-12.1%. independent of the dose escalation. The calculated intrahepatic concentration of doxorubicin ranged from 30 to 88 microg/ml when the dosage of doxorubicin was escalated from 50 to 120 mg/m2. Dose-limiting systemic toxicity (grade 4 myelosuppression) was observed at 120 mg/m2. Twelve of 14 patients who received more than one treatment at 90 or 120 mg/m2 were evaluable for disease response: there were 4 partial responses, 3 minor responses, I stable disease, and 4 progressive disease. The median overall survival of responders was 23 months, and for nonresponders it was 8 months. We have demonstrated a dose-response effect of hepatic infusion of doxorubicin at 90 and 120 mg/m2 in advanced hepatic malignancies. The isolated hepatic perfusion system improves the therapeutic index of doxorubicin and provides pharmacologic justification for its use in the treatment of unresectable hepatic malignancies, especially metastatic melanoma and sarcoma.

Intra-abdominal desmoplastic small round cell tumor.

BACKGROUND: Intra-abdominal desmoplastic small round cell tumor is a rare malignancy with a predilection for young males. Unique histological and immunocytochemical features distinguish the tumor from other members of the family of small round cell tumors of infancy and childhood. The aggressive nature of tumor spread, relative insensitivity to chemotherapy, and generally incomplete resectability result in a very poor prognosis. The authors report a case of a 39-year-old man with diffuse abdominal and pelvic involvement of intra-abdominal desmoplastic small round cell tumor treated with aggressive chemotherapy and surgery. METHODS: Computed-tomography (CT)-guided biopsy of an omental mass was performed. Histologically, discrete nests of uniform closely packed malignant cells were distributed in a background of focally desmoplastic stroma. Immunocchemistry demonstrated positivity for epithelial, mesenchymal, and neural markers. On the basis of these unique histological and immunohistochemical characteristics, the diagnosis of desmoplastic small round cell tumor was made. The patient was treated with aggressive neoadjuvant chemotherapy consisting of a high-dose alkylator -based combination regimen, followed by surgery. RESULTS: The patient had a 10 to 15 percent regression in tumor mass in response to chemotherapy. Laparotomy revealed two large omental masses, another large mass adherent to the left colon and pelvic sidewall, and diaphragmatic, peritoneal and mesenteric studding with small nodules. Complete surgical resection was not possible. CONCLUSIONS: Intra-abdominal desmoplastic small round cell tumor remains an aggressive malignancy with an extremely poor prognosis. Although some response to chemotherapy may be possible, complete resection is rare, and surgical efforts are general palliative.

Transrectal sonography in staging rectal carcinoma: the role of gray-scale, color-flow, and Doppler imaging analysis.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of combining gray-scale sonography with color-flow imaging and pulsed Doppler transrectal sonography in the staging of rectal carcinoma. SUBJECTS AND METHODS: Thirty-nine patients with primary rectal carcinoma underwent transrectal sonography. The rectal masses were staged T1-T2 or T3-T4 on the basis of gray-scale imaging. The local nodes were classified as benign or malignant on the basis of size and echogenicity. In 22 patients, color-flow imaging and pulsed Doppler imaging of the rectal mass and of the local lymph nodes were performed. The peak systolic velocity (PSV) and end diastolic velocity were documented, and the resistive index was calculated. RESULTS: Gray-scale imaging alone was used to stage T1-T2 masses with 88% sensitivity and 82% specificity. T3-T4 masses were staged with 82% sensitivity and 88% specificity. Overall accuracy was 85%. Gray-scale imaging of lymph nodes using a discriminatory size of less than or equal to 5 mm for benign nodes and greater than 5 mm for malignant nodes yielded a sensitivity of 100%, a specificity of 28%, and an accuracy of 52%. Using receiver operating characteristic curve analysis, we determined that a size of greater than or equal to 7 mm was optimal for characterizing nodes. Such a size provided an accuracy of 83%. PSV of less than 25 cm/sec distinguished T3-T4 from T1-T2 rectal masses with 75% sensitivity, 80% specificity, and 77% accuracy. A PSV of greater than 20 cm/sec classified a node as malignant with 100% sensitivity, 62% specificity, and 76% accuracy. A resistive index of greater than 0.61 classified a node as malignant with 71% sensitivity, 85% specificity, and 80% accuracy. CONCLUSION: Color-flow imaging and pulsed Doppler imaging are useful additions to gray-scale transrectal sonography in staging primary rectal carcinomas. The combination has most value when evaluating perirectal nodes.

Incidence of recurrent bladder cancer in patients requiring admission for abdominal pain long after cystectomy.

BACKGROUND: Malignant disease is often considered in the workup of the acute abdomen, especially when there is a history of intra-abdominal, neoplastic disease. The treatment of bladder cancer frequently involves intra-abdominal procedures, but the incidence of recurrent bladder cancer as the cause of an acute abdomen is unknown. METHODS: In a retrospective, 13-year study, the cause of abdominal pain in 29 patients with a history of surgery for bladder cancer was reviewed. Evaluations included analysis of all clinical, laboratory, radiologic, and pathologic data prior to and during hospitalization, where available. RESULTS: Fourteen of 18 patients 38.9 +/- 10.8 months after cystectomy and 10 of 11 patients 18.9 +/- 10.8 months after noncystectomy procedures had recurrent bladder cancer. Computed tomography, when used, identified all cases of recurrent cancer prior to exploratory surgery. CONCLUSION: Abdominal pain requiring admission in patients with a remote history of cystectomy for bladder cancer is likely due to recurrent disease.

Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vascular malformations.

A case of multiple focal nodular hyperplasia of the liver occurring in a 22-year-old woman with musculoskeletal hemihypertrophy and anomalous vascular supply to the liver is described. The patient had Klippel-Trénaunay-Weber syndrome and abdominal pain and tender massive hepatomegaly. Visceral angiography showed marked dilatation of the celiac axis and both the main trunk and peripheral branches of the hepatic artery. Large abdominal veins drained from the dome of the liver into the hepatic veins. The vascular anomalies were evident on contrast-enhanced computed tomography and magnetic resonance imaging. Multiple focal nodular hyperplasia was confirmed by laparoscopic liver biopsy. The findings in this patient support the concept that multiple focal nodular hyperplasia characteristically occurs in a syndromic form and is induced by an irregular arterial supply in the liver, with localized hyperfusion that leads to nodular areas of hepatocyte hyperproliferation.

Sphincter of Oddi dysfunction caused by an ampullary neoplasm.

The case of a 50-year-old man with abdominal pain and abnormal liver test results is described. Endoscopic retrograde cholangiopancreatography with manometric studies showed biliary dilatation, poor ductal drainage, and sphincter of Oddi dysfunction. Clinical and radiographic clues suggested the possibility of an ampullary lesion; a small ampullary adenoma was detected after endoscopic sphincterotomy, and ampullary carcinoma was found in the operative specimen. Malignancy can cause sphincter dysfunction not only in the esophagus (as pseudoachalasia) but in the ampulla of Vater as well.

Intraoperative ultrasonography of liver: detection of occult liver tumors and treatment by cryosurgery.

A prospective study of 110 patients undergoing liver surgery was undertaken to evaluate the usefulness of intraoperative ultrasonography (IOUS) and cryosurgery in treating primary and metastatic liver tumors. The diagnoses were colorectal cancer (n = 72), hepatocellular carcinoma (n = 15), ovarian cancer (n = 8), cholangiocarcinoma (n = 4), and other tumors (n = 11). IOUS results were compared with preoperative CT scan angioportography. IOUS detected 37 lesions not seen on CT in 21 patients (19%) and 13 lesions not detected by bimanual palpation in 6 patients (5%). IOUS-assisted cryosurgery was carried out to ablate unresectable liver tumors in 21 patients (19%). At median follow-up of 14 months, 5/21 patients (24%) achieved complete response; 24 and 52% of patients recurred in the liver and systematically, respectively. Thus, IOUS is useful in detecting occult liver tumors and in providing assistance in tumor ablative therapies. Cryosurgery is useful in controlling some of the unresectable liver tumors, but the 76% recurrence rate implies the need for an effective regional and systemic chemo/immunotherapy.

A new peripherally implanted subcutaneous permanent central venous access device for patients requiring chemotherapy.

PURPOSE: A peripherally implanted central venous access device (P.A.S. Port; Pharmacia Deltec Inc, St Paul, MN) was evaluated for ease of insertion, functionality, acceptance, and complications in patients who required long-term venous access. A hand-held tracking system (Cath-Finder; Pharmacia Deltec Inc) used to determine catheter tip location was also evaluated. PATIENTS AND METHODS: A P.A.S. Port was placed in 47 patients who required long-term intravenous access. The median follow-up duration has been 32 weeks (range, 2 to 112). Total usage has been 2,028 catheter-weeks. The Cath-Finder was used to determine catheter tip location during insertion. Nursing staff and patient satisfaction were polled and functionality and complications were recorded. RESULTS: The device was found to be simple to insert, the procedure well tolerated, and, with one exception, the Cath-Finder accurately predicted catheter tip location. There was a 6.4% incidence of transient phlebitis and a 6.4% incidence of symptomatic axillary or subclavian vein thrombosis. There were no infectious complications. Access was simple in all but two obese patients. The device functioned well in all patients, except three in whom blood aspiration was difficult and two in whom fluid administration was slow. The device was well tolerated by all patients and nursing staff satisfaction was high. CONCLUSION: This device provides a highly acceptable, additional method of implantable, permanent central venous access for chemotherapy patients with a low complication rate. The successful use of the Cath-Finder and minor extent of the procedure may allow this device to be inserted in a clinic procedure room without sedation and fluoroscopy.

Expression of colorectal carcinoma-associated antigens in colonic polyps.

Immunohistologic techniques were used to study the expression of colorectal carcinoma-associated antigens in colonic polyps and to compare this with expression in the normal colonic epithelium. Forty-nine polyps were studied using monoclonal antibodies to 16 different blood group and differentiation antigens and carcinoembryonic antigen epitopes. With the Lewis(a) antigen and the two epitopes of CEA recognized by 3D6 and COL-4 expression in polyp tissue was the same as that in the normal colon. Five types of alteration of antigen expression in polyps were seen. The blood group antigens A, B, and Lewis(b), which are expressed only on the right side of the normal adult colon, were detected in both neoplastic and nonneoplastic polyps from the distal colon. The Lewis(x) antigen and the antigen epitopes detected by the antibodies COL-12, CA19-9, ME491, and GA73.3 showed an increased frequency of expression in all types of polyps in comparison with the normal colonic epithelium, while H-type 2, ND4, and the antigen epitope detected by CO29.11 showed a slightly decreased frequency of expression in polyp tissue. The X-like antigen which was expressed in only 7% of normal colon specimens showed increased frequency of expression in polyp tissue with significantly greater expression in neoplastic than hyperplastic lesions (P = 0.003). The TAG-72 antigen was detected only in adenomas with severe dysplasia (P = 0.01), correlating well with premalignant histology. These findings have helped us clarify the variation of antigen expression in colonic polyps and allowed us to define which antigens are worthy of further investigation as markers of possible malignant transformation.

The influence of immunosuppression on peptic ulceration following renal transplantation and the role of endoscopy.

Peptic ulceration is common in patients undergoing renal transplantation. With a change in routine immunosuppression from azathioprine and steroids to cyclosporin, or cyclosporin and low-dose steroids and azathioprine, less peptic ulceration might be expected. This was investigated in two groups of patients undergoing renal transplantation. Group 1 (n = 90) received azathioprine and prednisolone; Group 2 (n = 44) received cyclosporin and low-dose azathioprine and prednisolone. Patients from both groups were endoscoped 7-14 days after operation, when peptic ulceration, oesophagitis, gastritis, and duodenitis were assessed. Whilst Group 2 differed significantly in receiving more methylprednisolone than Group 1 (P less than 0.05), there was no difference between the two groups with regard to the incidence of peptic ulceration or inflammatory lesions. In both groups there was a trend for those treated with methylprednisolone for rejection to develop ulcers or inflammatory lesions when a total dose of more than 2 g had been given by the time of endoscopy. Any possible reduction in the incidence of peptic ulceration after transplantation is outweighed by the continued use of high-dose methylprednisolone to treat episodes of rejection. The true incidence of peptic ulceration after transplantation is much higher than if presenting symptoms alone are the starting point for investigation. Regular post-transplantation endoscopy allows prompt diagnosis and treatment, with attainment of a very low mortality rate (0.75% overall, or 4% in those with peptic ulcers) from peptic ulceration in patients undergoing renal transplantation.

Detection of the tumor-associated glycoprotein antigen (TAG-72) in premalignant lesions of the colon.

We used monoclonal antibody B72.3 to study the expression of the colorectal carcinoma-associated antigen TAG-72 in premalignant colonic lesions with the immunoperoxidase technique. This antigen, which is rarely detectable in the normal colonic epithelium, was expressed in 13 of 19 adenomas with moderate to severe dysplasia and nine of nine cases of inflammatory bowel disease. The antibody reacted with the normal-appearing mucosa adjacent to a carcinoma in 10 of 12 cases, although only eight of the tumors expressed the antigen. The expression of the TAG-72 antigen in the colonic epithelium may be an early marker of malignant transformation.

The expression of colorectal carcinoma-associated antigens in the normal colonic mucosa. An immunohistochemical analysis of regional distribution.

Immunohistologic studies were performed to evaluate the expression and regional distribution of 20 colorectal carcinoma-associated antigens in the colonic mucosa of 12 normal adults. A distinct regional variation was seen in the expression of blood group A, B, Lewis(b), and extended Lewis(y) antigens, which were expressed predominantly in the right colon, whereas Lewis(a), Lewis(y), and H-type 2 were prevalent throughout. Lewis(x) and X-like antigens were only occasionally expressed. Two antibodies against sialylated Lewis(a) showed different staining patterns, with CA19.9 positive in only two biopsies and CO29.11 intensely positive in most. Two of the three antibodies detecting carcinoembryonic antigen epitopes (3d6 and COL-4) stained many biopsies, whereas COL-12 was rarely detected. No regional gradient was found in the expression of the other antigens studied (B72.3, ME491; GA73.3, ND1, and ND4). This mapping data will provide an important baseline for future studies of epitope distribution in the colon in premalignant and neoplastic conditions.