Ranitidine therapy for gastroesophageal reflux disease. Results of a large double-blind trial.

In a multicenter, double-blind trial, 284 patients with gastroesophageal reflux disease were evaluated before, during, and after six weeks of treatment with either placebo or ranitidine (150 mg twice daily). Randomization resulted in two comparable patient groups. Ranitidine treatment was significantly more effective than placebo treatment in decreasing the frequency and the severity of heartburn during both daytime and nighttime assessment periods. There was a significant correlation between improvement in heartburn symptoms and decrease in antacid consumption; hence, patients receiving ranitidine consumed significantly fewer antacid tablets. Among patients with endoscopic esophagitis at baseline, the overall change in endoscopic classification after six weeks of therapy was significantly better for the ranitidine-treated patients. The ranitidine-treated group had less evidence of erosions and ulcerations as well as greater healing. There were no differences between the groups with respect to changes in esophageal mucosal sensitivity to acid perfusion or changes in histologic grading of esophageal mucosal biopsy specimens. The ranitidine safety profile was similar to that of previous studies. We conclude that, in patients with gastroesophageal reflux disease, ranitidine therapy, 150 mg twice daily, markedly reduced the heartburn symptoms of reflux disease and significantly improved the endoscopic appearance of the esophageal mucosa.

Diffusely infiltrating adenocarcinoma of the endometrium. A subtype with poor prognosis.

We studied cases of stage I endometrial adenocarcinoma encountered at our institution during the period 1970-80. Five out of 164 of these tumors showed a diffusely infiltrating pattern of growth. Two of the five patients died of cancer within 5 years, with a 5-year mortality of 40%. A control group of 15 patients seen over the same period showed a 5-year mortality of 13.3%. Thus, the diffusely infiltrating pattern of growth was indicative of poor prognosis in endometrial carcinoma in stage I disease.

Malignant mixed müllerian tumors of the uterus. A clinicopathologic assessment of 34 cases.

We have analyzed clinical and pathologic features of a series of 34 patients with malignant mixed müllerian tumors of the uterus. This study includes 17 homologous and 17 heterologous lesions. The most significant prognostic indicator in our patients was tumor extent (stage) at diagnosis. Of lesser importance were the presence of heterologous elements, especially chondrosarcoma, high grade of carcinoma and tumor size. Survival rates were 52% at 2 years and 36% at 5 years for homologous tumors; and 47% and 14%, respectively, for the heterologous variety.

Crohn's colitis with carcinoma and dysplasia. Report of a case and review of 100 small and large bowel resections for Crohn's disease to detect incidence of dysplasia.

A patient who developed invasive adenocarcinoma of the cecum after a 20-year history of Crohn's enterocolitis is reported. Histologic examination of the resected specimen showed widespread severe dysplasia in addition to the invasive carcinoma. An additional 100 randomly selected bowel resection specimens removed for Crohn's disease were reviewed to determine the frequency of epithelial dysplasia. Applying rigorous criteria, we found a 2% incidence of mild dysplasia; no instance of severe dysplasia was identified.

An immunohistochemical study of nasopharyngeal neoplasms using keratin antibodies: epithelial versus nonepithelial neoplasms.

Forty cases of nasopharyngeal neoplasia were analyzed using immunohistochemical staining employing keratin antibodies. Using this probe the tumors were classified as being keratin-positive or negative. In this study, all squamous cell carcinomas labeled with keratin antibodies whether they were classified as keratinizing or nonkeratinizing by usual staining methods. In contrast, lymphoid and mesenchymal tumors of the nasopharynx did not label with keratin antibodies. Thus, the presence of keratin proteins as detected by immunohistochemical means on paraffin-embedded tissues appears to be a useful, reliable, and sensitive method for aiding in the accurate diagnosis and classification of nasopharyngeal neoplasms.

Malignant mixed mesodermal tumors of the ovary: a clinicopathologic assessment of 12 cases.

Twelve women with mixed mesodermal tumors of the ovary were studied. These tumors grow rapidly and patients are frequently in an advanced state of their disease when the diagnosis is made. In 10 individuals the initial complaint was either an abdominal mass or increasing abdominal girth. With one exception, the patients were postmenopausal. The most important prognostic criterion was the stage of the tumor at the time of the diagnosis. Of nine women with Stage III and IV disease, only one is well and free of disease. No pathologic features were uncovered which could be related to prognosis.

The effects of early treatment of hereditary tyrosinemia type I in infancy by orthotopic liver transplantation.

Two infants with hereditary tyrosinemia secondary to fumarylacetoacetate hydrolase (FAH) deficiency underwent orthotopic liver transplantation at 14 and 16 weeks of age due to poor clinical and biochemical response to medical therapy. Prompt clearance of abnormal metabolites with improved mental alertness and appetite occurred with minimal perioperative complications. Both infants tolerated rapid institution of normal diets and have shown progressive growth and development in the first 36 months after transplantation. Early liver transplantation should be considered as an option for infants with certain inherited metabolic disorders with poor prognosis, such as tyrosinemia type I, who fail to respond to medical therapy.

The significance of intraepithelial eosinophils in the histologic diagnosis of gastroesophageal reflux.

Detection of intraepithelial eosinophils in esophageal mucosal biopsies has been suggested as histologic evidence of symptomatic gastroesophageal reflux (GER) disease in both children and adults. Previous studies have primarily examined symptomatic persons, and only one study included a comparison with normal controls. In the present study, the authors examined esophageal mucosal biopsies obtained by the hydraulic suction technic for the presence of intraepithelial eosinophils from 73 adult patients with subjective and objective evidence of GER disease and 12 asymptomatic adult volunteers in whom a series of esophageal function tests were normal. Intraepithelial eosinophils were identified in 23 (31.5%) of adult patients and in 4 (33.3%) of the asymptomatic volunteers. No clinical aspects in the GER patients correlated with the presence of eosinophils. By crude quantitation, rare eosinophils added little to more conventional assessment of histologic esophagitis and were present in one-third of normal subjects. The authors conclude that rare eosinophils in esophageal biopsies may not be a reliable criterion for the histologic assessment of GER disease.

Heterologous mixed müllerian tumor confined to an endometrial polyp.

Mixed müllerian tumors of the uterus, which have been divided into homologous and heterologous types, are considered neoplasms of high malignant potential. In the heterologous variety, the presence of rhabdomyosarcoma has been associated with an especially poor prognosis. We report the first case of a heterologous, malignant mixed mesodermal tumor (adenocarcinoma, stromal sarcoma, and rhabdomyosarcoma) confined to an endometrial polyp. The patient, treated by surgery only, remains clinically free of disease 11 years later. Mixed müllerian tumors of limited extent may not be associated with the dismal prognosis that usually accompanies such lesions.

Prognostic indicators for cancer. Gastric cancer.

The recent shift in the population from patients presenting with gastric cancer to patients presenting with early-stage lesions has led to renewed interest in identifying prognostic factors for this type of tumor. Conveniently for surgeons, prognostic factors can be divided into groups that are assessed preoperatively, intraoperatively, and postoperatively. Despite the explosion of interest in genetic and molecular markers for gastric cancer, the feature best correlated with patient survival continues to be tumor stage at the time of diagnosis.

Expression of steroid hormone receptors in benign hepatic tumors. An immunocytochemical study.

Many hepatic adenomas have been demonstrated to have a clear relationship with oral contraceptive use, and it is presumed that there may be hormone receptors within the cytoplasm or nucleus of adenoma cells that mediate tumor growth in response to hormonal stimulation. Only a small number of examples of benign hepatic tumors have been analyzed for the presence of estrogen and progesterone receptors, and there has been a lack of consensus with regard to the findings. All previous studies have determined receptor levels by biochemical methods. In a retrospective study, we employed specific monoclonal antibodies against estrogen and progesterone receptors in 10 benign paraffin-embedded hepatic lesions: five examples of hepatic adenoma and five examples of focal nodular hyperplasia. All patients were female, except for one male with adenoma and one male with focal nodular hyperplasia. No patient had received tamoxifen citrate or any other form of hormonal therapy for their hepatic lesion. Positive controls included benign and malignant breast tissue. No positive staining was seen in hepatic adenoma, focal nodular hyperplasia, or normal adjacent liver parenchyma. Intense positive staining was seen in all positive control tissues. This negative result with the use of specific monoclonal antibodies in an established immunohistochemical method for analysis of estrogen and progesterone receptors does not exclude the presence of these receptors in benign hepatic lesions, but does suggest that, if present, they occur in much smaller amounts than in benign and malignant breast tissue. The presence of hormone receptors in benign hepatic tumors deserves further study.

Congenital polycystic tumor of the atrioventricular node. Autopsy study with immunohistochemical findings suggesting endodermal derivation.

Atrioventricular node congenital polycystic tumor, a lesion that causes heart block and sudden unexpected death, has been postulated to arise from the lymphatics, foregut endoderm, cardiac mesoderm, and mesothelium since its initial description in 1911. No theory concerning the histogenesis of this tumor has been completely satisfactory, either from an embryologic or a clinical standpoint. Biologic studies including cell culture systems from the lesions as well as optimal ultrastructural examination have been compromised due to postmortem autolysis. We studied four examples of this entity by standard histochemical stains for mucopolysaccharides, and by modified immunohistochemical labeling for carcinoembryonic antigen, factor VIII, and keratin. Results suggest an origin from foregut endoderm. The lesion has not been reported to be outside the region of the atrioventricular junction, but was demonstrated in the thymus gland in one of our cases.

Renin in angiolymphoid hyperplasia with eosinophilia. Its possible effect on vascular proliferation.

A hypertensive man became normotensive after the surgical removal of two subcutaneous masses of angiolymphoid hyperplasia with eosinophilia. To demonstrate that angiolymphoid hyperplasia with eosinophilia is a renin-producing pathologic condition, Bowie stain for juxtaglomerular cell granules and immunohistochemistry for human renin were used. Bowie stain was positive in cells showing cytoplasmic granules similar to those found in the juxtaglomerular cells of the kidney. Immunohistochemical staining using antiserum against human renin showed the presence of renin-containing cells. This staining was not seen after substitution of the specific renin antiserum by preimmune serum, by the renin antiserum preabsorbed with pure human renin, or with plasma from a patient with high-plasma renin activity. Renin-containing cells were located in areas surrounding vascular structures and were apparently neither endothelial, mast, nor lymphoid cells. Six of eight additional cases of angiolymphoid hyperplasia with eosinophilia were positive for renin-containing cells. Renin has been described in several other histologically highly vascularized tumors. Since a product of renin, angiotensin II, has been found to have angiogenic properties, it is possible to postulate that renin, through angiotensin II, may stimulate the proliferation of vessels and, therefore, may be involved in the pathogenesis of angiolymphoid hyperplasia with eosinophilia.

Provocative testing for occult medullary carcinoma of the thyroid: findings in seven children with multiple endocrine neoplasia type IIa.

A rise in the serum calcitonin (CT) following provocative testing has facilitated making the diagnosis of occult medullary carcinoma of the thyroid (MCT) or C cell hyperplasia (CCH) in asymptomatic children of kindred with multiple endocrine neoplasia (MEN) type IIa. Findings were reviewed for seven children varying in age from 3 to 16 years screened at our institution between 1976 and 1986. Three had elevated basal calcitonin (S-CT). Six had significant elevation of calcitonin (delta-CT) after stimulation. Total thyroidectomy was performed in all seven. Five had MCT with bilobar involvement in three. CCH was present in all five. Two patients had no gross, microscopic, or immunohistochemical evidence of MCT or CCH. One of three had an elevated S-CT. The other had a significant delta-CT. All patients have normal postoperative S-CT and delta-CT. Our experience indicates the importance of beginning stimulation tests of affected kindred at less than 3 years of age. It appears, however, that neither elevated S-CT or positive delta-CT are perfect predictors of parafollicular cell pathology. Solitary parathyroid enlargement, second thyroid malignancy, and branchial pouch anomalies may occur with MEN IIa. One patient with MCT had a focus of papillary carcinoma. One patient with primary hyperparathyroidism had a solitary enlarged parathyroid adenoma. Additional findings were the presence of nodules of ectopic thymus in close association with the thyroid gland in three patients.

Gastrointestinal manifestations of multiple endocrine neoplasia, type IIB.

Multiple endocrine neoplasia, type IIB (MEN 2b), is comprised of medullary carcinoma of the thyroid, pheochromocytoma, diffuse ganglioneuromatosis of the gastrointestinal tract, and skeletal abnormalities. Alimentary tract manifestations, especially enlargement of the lips and tongue by proliferative neural tissue, are often the earliest clues to the presence of the syndrome. A patient is presented here who illustrates the chronicity and diversity of symptoms characteristic of MEN 2b. It is important to recognize the typical oral manifestations of this syndrome so that the thyroid gland can be evaluated before the development of disseminated medullary carcinoma.

The use of endoscopic biopsy in evaluation of polypoid lesions of the colon.

Use of flexible endoscopes affords biopsy sampling of polypoid lesions of the colon, especially within the rectum and sigmoid colon by flexible fiberoptic sigmoidoscopes. Histologic examination of colonic biopsies usually allows division of polyps into neoplastic and non-neoplastic categories. There are significant limitations to such biopsies, however, due to sampling error and inability to reach deep submucosal cores of polyps where malignant invasion may occur. When properly aware of its limitations, the endoscopist will find the endoscopic biopsy a valuable aid in planning the therapeutic approach to a polypoid lesion of the colon.

Juvenile polyps and ulcerative colitis.

Four children with ulcerative colitis, three of whom were in clinical remission of their disease, experienced rectal bleeding due to solitary juvenile polyps. Only one of the four polyps was detected radiologically. Two children passed their polyps spontaneously, one was identified at colonoscopy, and the fourth caused colocolic intussusception and was removed during surgery.

Use of avidin-biotin complex in an ELISA system: a quantitative comparison with two other immunoperoxidase detection systems using keratin antisera.

Three systems--the indirect, peroxidase-antiperoxidase (PAP), and avidin-biotin peroxidase complex (ABC) detection system--were compared in quantitative ELISA titration and inhibition assays and tissue labeling with keratin antisera. The ABC system was found to be the most sensitive of the three in ELISA titration assays, being approximately 4-fold more sensitive than the indirect method and 2-fold more sensitive than the PAP method. In addition, the ABC method demonstrated increased sensitivity when compared on tissue sections. Furthermore, the secondary and tertiary components of the PAP and ABC systems were titrated and optimal concentration ranges determined for use in ELISA inhibition assays. In ELISA inhibition assays the broadest usable inhibitor range and maximal sensitivity were obtained using the ABC system as compared with indirect and PAP detection systems. Finally, the effects of varying microtiter plate-coating concentrations on range and sensitivity were examined, and possible explanations are discussed including the possibility of surface-bound antigen being a competitor for the antibody of the solution phase antibody-antigen complex.

An immunohistochemical study of adenomatoid tumors utilizing keratin and factor VIII antibodies. Evidence for a mesothelial origin.

Fifteen adenomatoid tumors were examined immunohistochemically using antibody probes to keratin and factor VIII-related antigen. Cells lining adenoid structures labeled using keratin antibody in all 15 tumors but failed to label with factor VIII-related antigen antibodies in any case. In one case tissue was retrieved from a paraffin block and studied by immunoelectron microscopy using the two antibody probes. Immunoprecipitate was demonstrated in adenoid cells adjacent to desmosomes using keratin antibody but was absent using factor VIII-related antigen antibodies. Of the two prevailing theories of origin for adenomatoid tumors, based on ultrastructural and histochemical data to date, these results are additional evidence for a mesothelial origin and fail to support an endothelial origin.