Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases.

Autoantibody against phospholipase A2 receptor (anti-PLA2R) is a sensitive and specific biomarker of idiopathic membranous nephropathy (iMN), being found in approximately 70% of iMN patients and only occasionally in other glomerular diseases. However, whereas its diagnostic specificity vs. normal controls and other glomerulonephritides (GN) has been firmly established, its specificity vs. membranous nephropathy associated with various diseases (sMN) has given inconsistent results. The aim of our study was to evaluate the prevalence of anti-PLA2R antibodies in iMN in comparison with various control groups, including sMN. A total of 252 consecutive iMN patients, 184 pathological and 43 healthy controls were tested for anti-PLA2R antibody using indirect immunofluorescence (PLA2R IIFT, Euroimmun). Anti-PLA2R autoantibodies were detectable in 178/252 iMN patients, 1/80 primary GN, 0/72 secondary GN, 9/32 sMN and 0/43 healthy controls, with a diagnostic sensitivity of 70.6%. The diagnostic specificity of anti-PLA2R antibody vs. normal and pathological controls was 100 and 94.6% respectively. However, when the diagnostic specificity was calculated only vs. secondary forms of MN, it decreased considerably to 71.9%. Interestingly enough, 9 out of 10 anti-PLA2R positive patients in the disease control groups had membranous nephropathy associated with various diseases (7 cancer, 1 Crohn's disease, 1 scleroderma). In conclusion, anti-PLA2R positivity in a patient with MN, should not be considered sufficient to abstain from seeking a secondary cause, especially in patients with risk factors for neoplasia. The causal relationship between tumors and anti-PLA2R-induced MN remains to be established, as well as the possible mechanisms through which malignancies provoke autoimmunity.

Expression of the ErbA-beta class of thyroid hormone receptors is selectively lost in human colon carcinoma.

Members of the erbA gene family are involved both in control of differentiation and in neoplasia. V-erbA, a retroviral oncogene, blocks avian erythroid differentiation. V-erbA-related transcripts are physiologically expressed in multiple normal tissues. They encode a family of transcriptional regulatory factors, some of which are thyroid hormone receptors. In man, two genes, erbA-alpha and erbA-beta, are transcriptionally active. We examined expression of erbA-related transcripts in normal and neoplastic colon. In normal colon mucosa, as well as in a colon polyp and in a colon polyp cell line, three characteristic erbA-related transcripts were consistently found. One transcript of 6 kb was erbA-beta related. Two transcripts of 2.7 and 5.2 kb were erbA-alpha related. In eight patients' colon carcinomas expression of the 6-kb erbA-beta transcript was absent or markedly diminished when compared with the same patients' noninvolved mucosa. In contrast, expression of the two erbA-alpha transcripts was the same in both colon carcinoma and noninvolved mucosa. No evidence was found of erbA-beta gene deletion in any of the tumors lacking erbA-beta expression. These data suggest that selective loss of normally present erbA-beta gene expression accompanies malignant transformation of the colonic epithelial cell.

Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium.

Autocrine stimulation of the epidermal growth factor receptor (EGF-R), by coexpression of transforming growth factor-alpha (TGF-alpha), causes malignant transformation of some fibroblast cell lines. TGF-alpha and EGF-R are both known to be expressed in colon carcinoma tissue and have been shown coexpressed in colon carcinoma cell lines. TGF-alpha autocrine activation of EGF-R has been suggested as a potential mechanism contributing to abnormal growth control in colon cancer. We now report coexpression of TGF-alpha and EGF-R transcripts in morphologically normal colonic epithelium from five individuals, in colonic adenomas from three individuals, and in a nontumorigenic colon adenoma cell line, VACO-330. Functional studies demonstrate VACO-330 growth is stimulated by exogenous TGF-alpha and is completely abolished by a blocking anti-EGF-R antibody. Autocrine stimulation of EGF-R by TGF-alpha is therefore required for growth of the adenoma cell line. Autocrine stimulation of EGF-R by TGF-alpha does not cause malignant transformation of the colonic epithelial cell. In normal and adenomatous human colon TGF-alpha, via either an autocrine or paracrine mechanism, is likely an important physiologic stimulant of epithelial proliferation.

Enzyme-altered foci in colons of carcinogen-treated rats.

The distal colon and rectum from male F344 rats treated with 15 mg/kg 1,2-dimethylhydrazine.2HCl (DMH) for 20 weeks were analyzed for focal areas of enzyme alteration. Tissues were embedded in methacrylate at 4 degrees C and cut in 2- to 4-micron serial sections. In DMH-treated rats, 8.8 +/- 2.4 foci/cm2 of examined mucosa were observed at 20 weeks and 7.7 +/- 1.1 foci/cm2 at 31 to 52 weeks, compared with 1.2 +/- 0.6 foci/cm2 in control rats (P = 0.01). The number of foci at 31 to 52 weeks compared with 20 weeks did not change significantly, but the area of altered rectal mucosa increased from 0.22 +/- 0.2% at 20 weeks to 1.47 +/- 0.6% at 31 to 52 weeks (P = 0.051). Most foci had decreased N-acetyl-beta-D-glucosaminidase, alpha-naphthyl butyrate esterase, and mucin in epithelial cells and increased gamma-glutamyl transpeptidase in the stroma. Morphologically, the foci varied from normal to overtly dysplastic. Grossly, tumors were identified in 5 of 20 DMH-treated rats killed at 31 to 52 weeks but not in 12 DMH-treated rats killed at 20 weeks or 30 control rats killed at 20 to 52 weeks. These data suggest but do not establish that enzyme-altered foci are putative preneoplastic lesions in the colon.

Aberrant crypts: putative preneoplastic foci in human colonic mucosa.

Aberrant crypts were identified for the first time in whole-mount preparations of normal-appearing human colonic mucosa after staining with methylene blue. The foci of aberrant crypts varied from single altered glands to plaques of greater than 30 crypts. The mean proportion of colonic mucosa altered and the number of foci with aberrant crypts per cm2 of colonic mucosa were (a) higher in patients with colon cancer than in patients without colon cancer or predisposing conditions and (b) highest in our single case of Gardner's syndrome. Aberrant crypts are postulated to be the earliest identifiable potential precursors of colon cancer. Analysis of aberrant crypts may facilitate the study of the early pathological and molecular changes that precede colon cancer.

Correlation of stromal cells by morphometric analysis with metastatic behavior of human colonic carcinoma.

The cellular compositions of the inflammatory infiltrates in human colonic carcinoma in well-defined compartments have not been quantified previously. Morphometric analysis of this tissue revealed several relationships between the concentrations of different kinds of cells that may be an important first approach to understanding the nature of the host reaction in different groups of patients. Primary tumors without metastases differ from those with metastases in that those without metastases contain higher concentrations of plasma cells (P = 0.0019) and eosinophils (P = 0.0098) in sections taken at a location remote from the margin (tissue located greater than 1 cm from the margin) and increased concentrations of eosinophils (P = 0.0224) in sections of tumor contiguous to the margin (tissue 0-4.5 mm from the margin). In sections contiguous to the margin, the concentration of plasma cells is related to the concentrations of lymphocytes (R = 0.55, P = 0.0014), eosinophils (R = 0.46, P = 0.0085), fibroblasts (R = 0.47, P = 0.0075), and neutrophils (R = 0.63, P = 0.0001). In sections remote from the margin, the concentration of plasma cells is related to the concentration of lymphocytes (R = 0.36, P = 0.0442), eosinophils (R = 0.36, P = 0.0457), mast cells (R = 0.38, P = 0.0375), and neutrophils (R = 0.38, P = 0.0371).

Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers.

PURPOSE: Carmustine (BCNU) resistance has been correlated with tumor expression of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT). It has been shown that streptozotocin will deplete AT activity of human colon cancer cells in vitro and potentiate BCNU cytotoxicity. This clinical trial was conducted to determine whether streptozotocin can be used as a modulator of AT in metastatic colorectal cancers and thereby overcome clinical resistance to BCNU. PATIENTS AND METHODS: Fifteen patients with fluorouracil-resistant metastatic colon or rectal cancers were treated sequentially with 2 g/m2 of streptozotocin followed 5 1/2 hours later by BCNU. Sequential biopsies of metastases before and after streptozotocin were conducted to determine whether streptozotocin depletes tumor AT. Peripheral-blood mononuclear cells (PBMCs) were evaluated as a surrogate tissue for prediction of baseline AT levels and streptozotocin posttreatment modulation of the AT in metastases. RESULTS: Streptozotocin treatment led to a 78% (range, 69% to 89%) decrease in the AT levels in colon cancer metastases; however, myelosuppression and hepatic toxicity limited the BCNU dose to 130 mg/m2. A similar decrease in AT levels of PBMCs was found; however, the absolute levels of AT in PBMCs at baseline and following streptozotocin were not predictive of the levels expressed in metastases from the same patient. Despite the decrease in tumor levels of AT, no clinical responses were observed. CONCLUSION: Streptozotocin decreases but does not fully deplete AT activity in metastatic colorectal cancers and the residual AT level in metastases is sufficient to maintain clinical resistance to BCNU. We have also demonstrated that sequential computed tomography (CT)-directed biopsies of colorectal cancer metastases can be used to evaluate strategies to investigate modulators of AT-directed repair. AT levels of PBMCs do not predict for the AT level or degree of modulation achieved in the metastatic tumor.

Laparoscopic liver biopsy to evaluate hepatic dysfunction in patients with hematologic malignancies: a useful tool to effect changes in management.

Hepatic dysfunction is common in patients who receive intensive chemotherapy and it is important to determine the etiology in order to institute appropriate therapy. The role of laparoscopic liver biopsy in patients with neutropenia, thrombocytopenia, or both was evaluated as a mean of making treatment decisions and as a determinant of clinical outcome. Laparoscopic liver biopsy was performed in 29 subjects who were receiving intensive cytotoxic therapy with or without bone marrow transplantation. One to three direct-vision laparoscopic liver biopsies were performed in each patient using a Tru-cut needle during general anesthesia. Platelet concentrate transfusions were usually given before, during, and immediately after biopsy. Bleeding was controlled with spatula electrocautery. Thirty-two biopsies were obtained in 29 patients. At the time of liver biopsy, white blood cell and platelet counts ranged from 0 to 14,300/microliters (median: 2500/microliters), and 1000 to 47,000/microliters (median: 20,000/microliters), respectively. Bleeding at the liver biopsy site was readily controlled during the procedure without clinical evidence of significant bleeding; no procedure-related complications were noted and no patients required re-exploration. All biopsies were informative and the lesions observed in 32 biopsies revealed graft-versus-host disease (n = 5), hepatic candidiasis (n =1), hepatic veno-occlusive disease (n = 3), cholestasis (n = 19), hemosiderosis (n = 26), toxic injury (n = 8), hepatic steatosis (n = 4), granuloma (n = 1), viral infection (n =1), and malignancy (n = 1). Laparoscopic liver biopsy has been proven to be an effective means of assessing the cause of liver dysfunction in patients who were thrombocytopenic and immunosuppressed. The diagnosis obtained at laparoscopic liver biopsy altered therapy in nine of 29 (31%) patients.

Direct central vein puncture for silicone rubber catheter insertion. An alternative technique for Broviac catheter placement.

The indications for placement of the Broviac catheter have been expanded. Although cephalic vein cutdown has become the accepted technique for placement of the catheter, cannulation of this vein is not always possible. A technique is described for direct placement of the Broviac catheter into the subclavian or internal jugular vein. Formal venous cutdown is not required, and the technique does not sacrifice a vein. We have performed 21 consecutive catheter insertions in 20 patients without complications. It is a safe alternative method for silicone rubber catheter placement.

The role of fluorodeoxyglucose and positron emission tomography in the evaluation of pancreatic disease.

BACKGROUND: The difficulties involved in the timely and accurate diagnosis of pancreatic disease are well known. The usual imaging modalities usually identify abnormalities but may not always differentiate malignancy from other condition such as scar tissue or chronic inflammation. The purpose of our study was to determine if fluorodeoxyglucose positron emission tomography (FDG PET) can accurately diagnose pancreatic disease. METHODS: The records of 15 patients presenting with pancreatic disease were retrospectively reviewed. The diagnosis suspected by imaging modalities was compared with the final tissue diagnosis. Two patients were excluded because no tissue was obtained. RESULTS: Adenocarcinoma was diagnosed in 9 patients. A mass consistent with this diagnosis was seen in 8 of 9, 6 of 9, 6 of 8, and 5 of 5 patients by PET, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS), respectively. Chronic pancreatitis (CP) was diagnosed in 2 patients. The unique appearance on FDG PET made the diagnosis in both these patients. Both patients with CP were thought to have a malignancy by CT and EUS and 1 of 2 by ERCP. Neuroendocrine tumors were diagnosed in 2 other patients. One of 2 was seen by FDG PET and both by CT. CONCLUSIONS: FDG PET can accurately differentiate a pancreatic adenocarcinoma from chronic pancreatitis in a patient with a suspicious pancreatic mass. Thus, FDG PET may help in establishing a diagnosis and subsequently managing a patient with pancreatic disease.

Percutaneous endoscopic gastrostomy. Review of 150 cases.

Percutaneous endoscopic gastrostomy was performed on 50 children and 100 adults from June 1979 to May 1982 at Case Western Reserve University Hospitals and the Mt Sinai Medical Center in Cleveland. Morbidity was low (10%), and there were no procedure-related deaths. Complications included minor wound infections in seven patients early in the series, extrusion of the tube in three, unnecessary laparotomy in two suspected of having problems with the tube early in the series, a partial separation of the gastrostomy from the abdominal wall in one adult, and gastrocolic fistula in one adult and one child. The last condition disappeared after removal of the gastrostomy tube in both patients. No leakage around the catheter, hemorrhage, peritonitis, or gastric outlet obstruction was encountered. This procedure provided a rapid, safe, and effective method for creating a feeding gastrostomy and did not require general anesthesia and laparotomy. Percutaneous endoscopic gastrostomy should become the method of choice for the creation of a feeding gastrostomy.

Splenectomy and the induction of murine colon cancer.

The influence of a functional spleen on induction and growth of cancer is unknown. Both beneficial and detrimental results have been observed in tumor-bearing hosts following splenectomy. We examined the effect of splenectomy, splenic autotransplantation, and splenic preservation on the induction and growth of 1,2-dimethylhydrazine (DMH)-induced murine colon cancer. Following splenectomy there was a significant increase in malignant tumors but no increase in benign tumors. To rule out the possibility that splenectomy increased the carcinogenicity of DMH by decreasing the capacity for DNA repair in colon cells, the units of 06-alkylguanine DNA alkyltransferase were measured in tumor-free and malignant colon tissue from both splenectomized and control rats. This repair protein was chosen because it is known to protect cells from the mutagenic effects of methylating agents. There was no significant difference in the alkyltransferase activity of tumor-free colon vs malignant tumor or between treatment regimens. Thus, the ability of the spleen to protect rats from the induction of malignant colon tumors induced by DMH is most likely due to preservation of immunologic surveillance in the host.

Moxalactam vs tobramycin-clindamycin. A randomized trial in secondary peritonitis.

One hundred five patients with peritonitis were randomized to receive either tobramycin sulfate plus clindamycin phosphate or moxalactam alone before surgical intervention. Fifty-nine patients were evaluable. A mean of 3.1 (moxalactam) and 3.5 (tobramycin-clindamycin) pathogens per patient were identified. Overall success rate was 85% (tobramycin-clindamycin, 24/30; moxalactam, 26/29). When patients with appendicitis were excluded, there was an observed but not statistically significant advantage of moxalactam over tobramycin-clindamycin (85% vs 67%). There were five deaths (tobramycin-clindamycin, four; moxalactam, one). Other complications included hypoprothrombinemia (tobramycin-clindamycin, five; moxalactam, five), renal dysfunction (tobramycin-clindamycin, three; moxalactam, one), and superinfection (tobramycin-clindamycin, nine; moxalactam, six). More wound infections were noted in the group given tobramycin-clindamycin. These data suggest that moxalactam is as safe and efficacious as tobramycin plus clindamycin. The observed benefits of this agent warrant study in a larger sample to verify advantages of moxalactam over combination therapy.

Effects of muramyl dipeptide and core body temperature on peritoneal bacterial clearance.

To examine the interaction between muramyl dipeptide (MDP) and core body temperature in murine peritonitis, 120 Sprague-Dawley rats were randomized to receive either 0, 1, or 4 micrograms/g body weight of MDP. Twenty-four hours later a sublethal intraperitoneal inoculation of Escherichia coli was given after core body temperature regulation at 32 degrees C to 40 degrees C, which was maintained for 30 minutes. Killing of the rats at 1, 3, or 6 hours later allowed evaluation of peritoneal white blood cell and bacterial counts. Results demonstrated that MDP (independent of core body temperature) caused an increased peritoneal white blood cell response at one and six hours and an increased peritoneal bacterial clearance at three hours. Increasing core body temperature adversely affected peritoneal bacterial clearance. High-dose MDP was clearly significant in acceleration of peritoneal bacterial clearance. No interaction between MDP and core body temperature was seen.

Hepatic dysfunction in patients with carcinoma who are severely thrombocytopenic and immunosuppressed.

BACKGROUND: The use of intensive cytotoxic drug therapy for malignant disorders often results in hepatic dysfunction. It is important to determine the cause of hepatic injury to institute appropriate therapy; however, neutropenia and thrombocytopenia may prevent performance of hepatic biopsy to establish a cause. STUDY DESIGN: We prospectively evaluated the cause of hepatic dysfunction using laparoscopic biopsy of the liver in 20 consecutive patients who were receiving intensive cytotoxic therapy, with or without bone marrow transplantation, or who were being treated for severe aplastic anemia. One to three direct-vision laparoscopic biopsies were performed in each patient during general anesthesia and bleeding was controlled with spatula electrocautery. Platelet concentrate transfusions were given before, during, and immediately after the biopsy. RESULTS: Platelet and leukocyte counts at the time of hepatic biopsy ranged from 1,000 to 83,000 per microL (median of 23,500 per microL) and zero to 14,300 per microL (median of 2,200 per microL), respectively. Nineteen of 20 patients had platelet counts of less than 68,000 per microL. Bleeding at biopsy site was controlled during the procedure without evidence of bleeding or complications after biopsy. Biopsy specimens revealed graft-versus-host disease (n = 2), hepatic veno-occlusive disease (n = 1), steatosis (n = 5), cholestasis (n = 19), hemosiderosis (n = 19), and granuloma (n = 1). CONCLUSIONS: In several patients, the knowledge derived from hepatic biopsy results altered the therapeutic strategy. The use of laparoscopic hepatic biopsy to assess the cause of hepatic dysfunction should be encouraged because it is a safe procedure, even in patients who are severely thrombocytopenic and immunocompromised.

Electrical activation of the diaphragm.

The physiology of electrical activation of the diaphragm is reviewed, with emphasis upon the respiratory mechanics of the diaphragm and its action upon other respiratory structures. The application of diaphragm pacing is discussed in terms of candidate selection, evaluation, and its future as a treatment modality for respiratory insufficiency.

Randomized trial of imipenem-cilastatin versus gentamicin plus clindamycin in the treatment of polymicrobial infections.

The comparative efficacy of imipenem-cilastatin versus clindamycin and gentamicin in the treatment of polymicrobial infections was evaluated. Eleven patients completed treatment with the former and nine with the latter. Conditions treated included infected extremity ulcers, peritonitis, perirectal abscess, soft-tissue abscess, abdominal abscess, and acute diverticulitis. Similar rates of bacteriologic and clinical cure or improvement were achieved with the two treatments. Superinfection occurred in two patients who received imipenem-cilastatin and one who received clindamycin and gentamicin. No significant difference in adverse effects was noted. Imipenem-cilastatin appears to be an effective antibiotic in treating polymicrobial infections; however, a much larger patient population would be required to detect a significant difference in the efficacy rates or frequency of adverse effects when comparing the two regimens.

Percutaneous approaches to enteral alimentation.

Feeding gastrostomy and jejunostomy provide effective access for long-term enteral nutrition. Traditional operative techniques for the performance of these procedures requires laparotomy and often, general anesthesia. This report describes our experience with two relatively new methods, percutaneous endoscopic gastrostomy and percutaneous endoscopic jejunostomy. Results of percutaneous gastrostomy and jejunostomy to date in 323 cases include a morbidity of 5.9 percent and a 0.3 percent operative mortality. Percutaneous endoscopic gastrostomy and jejunostomy should become the procedures of choice for the establishment of enteral access in patients requiring long-term enteral alimentation.

Role of surgery in antibiotic-induced pseudomembranous enterocolitis.

With the increased use of prophylactic and broad-spectrum antibiotics, pseudomembranous colitis has emerged as a significant clinical problem. Management with specific anti-Clostridium difficile therapy (vancomycin or metronidazole) has reduced mortality to less than 2%. Nevertheless, the disease may progress to a fulminant toxic colitis or colonic perforation. Additionally, another subset of patients will present with a dramatic clinical picture, suggesting acute peritonitis, eventuating in unnecessary laparotomy. This report reviews both the medical and surgical literature during the past 15 years of patients treated for pseudomembranous colitis. Analysis of this clinical data has provided us with the opportunity to both define the role of surgery in this disorder and illustrate the necessity for a combined medical and surgical cooperative approach in the early management of this iatrogenic disease.

A critical analysis of the largest reported mass fecal occult blood screening program in the United States.

Fecal occult blood testing for the detection of colon cancer remains controversial. We performed a mass screening program from January 24, 1988, to February 19, 1988, with intensive media promotion, including 121 minutes of televised air time. A total of 5,000 primary practitioners were notified by mail. Hemoccult-II tests were distributed to 156,000 individuals; 55,051 (35%) were returned. Ninety-five percent of the respondents were informed of the program by television. A total of 3,375 persons (6%) tested positive for fecal occult blood; of these, 2,469 (73%) informed the center that they saw their physician to initiate a work-up. Information from physicians regarding work-ups was returned on only 1,356 (55%) patients. Diagnostic tests numbered 2,227 (1.6 tests per patient). However, 5% had no testing, 16% had a repeat Hemoccult only, and 35% had neither a barium enema nor colonoscopy performed. Thirty-six colorectal cancers and 212 polyps were identified. The predictive value (i.e., number of cancers per number of patients who tested positive) increased directly by decade. Thirty-three of 36 patients (92%) with cancer underwent either a barium enema or colonoscopy versus only 185 of 438 (42%) patients with a "negative" work-up. Cancers found were carcinoma in situ in 10 patients (29%), Dukes A in 12 (35%), Dukes B in 4 (12%), and Dukes C in 8 (24%); distant metastases were not found in any participant. Thirty-six percent of the tumors were located in either the right or transverse colon. We conclude that: (1) Screening identified early cancers. All were potentially curable and 64% were limited to the bowel wall. (2) Massive Hemoccult distribution was possible over a short interval, but patient and physician compliance was disturbingly low. (3) Total colonic evaluation is mandatory, since at least 36% of tumors were beyond the reach of the flexible sigmoidoscope. (4) Many work-ups were unnecessary (repeat Hemoccults) or inadequate, indicating a need for physician education.