An evaluation of the clinical implications of acid breakthrough in patients on proton pump inhibitor therapy.

BACKGROUND: Some patients with gastro-oesophageal reflux disease continue to experience symptoms despite therapy with proton pump inhibitors. One recently proposed cause is the occurrence of nocturnal acid breakthrough. AIM: : To investigate the relationship between acid breakthrough occurrence (nocturnal and daytime) and refractory symptoms among patients with gastro-oesophageal reflux disease on proton pump inhibitors. METHODS: Fifty-two consecutive patients with persistent symptoms of gastro-oesophageal reflux disease despite proton pump inhibitor therapy underwent 24-h pH study at the Mayo Clinic between January 1 and November 10, 1999. Relevant data were extracted and analysed. RESULTS: Fifty-two patients, 18 males and 34 females, were eligible for the study. The mean age was 53 +/- 2.2 years. Thirty-seven patients (71%) had nocturnal acid breakthrough, and 36 (69%) had daytime acid breakthrough. Sixty per cent of patients experienced both nocturnal and daytime acid breakthrough, whereas 19% had neither. Among those with nocturnal and daytime acid breakthrough, only 36% and 33% of symptoms, respectively, were associated with gastro-oesophageal reflux episodes. The proportion of patients with symptoms and the mean symptom scores were not significantly different between those with and without acid breakthrough. CONCLUSIONS: Gastric acid breakthrough occurs nocturnally and during the daytime in patients on proton pump inhibitor therapy. With less than 36% of refractory symptoms associated with gastro-oesophageal reflux, gastric acid breakthrough cannot explain symptom refractoriness to proton pump inhibitor therapy in a significant majority of patients evaluated by 24-h pH study.

Hereditary angioedema: a broad review for clinicians.

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

Clear cell carcinoma of the liver: a comparative immunohistochemical study with renal clear cell carcinoma.

Morphologic differentiation of clear cell hepatocellular carcinoma (HCC-CC) from clear cell renal carcinoma (RCC-CC) may not be possible without the aid of immunohistochemical stains. We performed a battery of immunohistochemical stains on 10 previously diagnosed HCC-CCs, and 10 RCC-CCs, in order to determine which single or combination of immunostains would be most useful in diagnosis. We concluded that a positive Hepatocyte immunostain (DAKO) is sufficient for a diagnosis of HCC-CC if enough tissue is available. This immunostain distinguishes HCC-CC from other clear cell malignancies with sensitivity of 90% and specificity of 100%, when biopsy material is adequate. Other tests were much less sensitive, although several had specificity of 100%. A negative immunostain does not exclude the diagnosis of HCC-CC (negative predictive value 91%, especially in small biopsy material) and should be followed by additional immunostains such as pCEA for demonstration of tumor canaliculi, ubiquitin for Mallory bodies, and several epithelial cell markers that are typically positive in RCC-CC (epithelial membrane antigen, Leu M-1, pancytokeratin) and negative in HCC-CC.

Malignant melanomas in the small intestine: a study of 103 patients.

OBJECTIVES: Malignant melanoma shows an unusual predilection to metastasize to the small intestine. A proportion of small bowel melanomas occur without history of an antecedent primary. We evaluated a group of patients with malignant melanoma in the small intestine to further our understanding of this disease. METHODS: We reviewed 103 cases of malignant melanoma in the small intestine (77 surgical resections and 26 autopsies) accessioned at the Armed Forces Institute of Pathology between 1945 and 1991 for demographic, chronological, and pathological features. RESULTS: Mean age at time of primary was 45.6 yr for surgical and 34.1 yr for autopsy cases (p = 0.01). Mean age at time of small intestinal involvement was 52.2 yr for surgical and 42.7 yr for autopsies (p = 0.03). Primary lesions preceded intestinal disease by an average of 5.6 yr for surgical and 2.1 yr for autopsies. The age distribution of surgical patients with and without known primary melanomas at the time of small intestinal melanoma was not significantly different. The same was true for autopsy patients. Using regression analysis, the linear relationship of age at primary melanoma (AAP) on age at small intestinal melanoma (AASI) was given by AAP = 2.30 + 0.85 (AASI), and that of AASI on AAP was given by AASI = 3.94 + 1.02 (AAP) (r = 0.93 and p < 0.0001 for both regressions). CONCLUSIONS: Our data and results support the concept that small bowel involvement by melanoma, even without a known primary, is most probably metastatic. The age at which an unknown primary occurred in cases of intestinal melanoma, or the age at which intestinal metastasis may appear in cases with known primary melanoma, can be estimated. There appear to be two subsets of primary melanoma: one that occurs among younger patients and is more aggressive with rapid metastasis and early death and one that occurs among older patients, is more indolent, and metastasizes less rapidly.

Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship.

OBJECTIVE: In a recent review of hepatocellular carcinoma (HCC) in North American residents, we were surprised to learn that 42.6% of these tumors in the 1980-1993 consultation files of the Armed Forces Institute of Pathology had arisen in noncirrhotic livers. We subsequently noted that the nonneoplastic livers of a number of these had nodular regenerative hyperplasia (NRH), a condition that has been associated with liver cell dysplasia, a putative premalignant lesion. To investigate the possibility that NRH might be a precursor of HCC, we studied those cases in which there was an association of HCC and NRH and examined the possible role of portal vein obstruction in NRH occurring in livers with HCC. METHODS: Subjects were selected based on study criteria and histological slides, clinical/autopsy records were reviewed, and features of neoplastic and nonneoplastic liver were noted. Simple statistical comparisons were made between the groups with and without NRH with respect to defined variables. RESULTS: Of 804 patients suitable for study, 342 were noncirrhotic, and 23 of these had NRH. Mean age of patients with NRH was 65 +/- 13.6 (SD) yr. Seventeen of these (73.9%) had liver cell dysplasia, and 16 (69.6%) had portal venous invasion. Liver cell dysplasia occurred in a significantly greater proportion of those with NRH than those without (p < 0.01), but there was no significant difference between both groups with regard to portal venous invasion. Three patients (13%) had received chemotherapy and/or radiotherapy before diagnosis of NRH. CONCLUSIONS: These findings may be due to the development of HCC within the dysplastic foci that occur in livers with NRH, but the findings do not exclude the converse possibility that NRH may also develop in a noncirrhotic liver with HCC, secondary to portal venous invasion with portal vein occlusion. The temporal relationship between HCC and NRH is probably determined in each case by the particular interaction of multiple pathogenetic factors. Among patients with HCC, factors other than the portal vein obstruction by tumor invasion may play a role in the pathogenesis of NRH.

Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients.

This study examined clinico-histopathologic differences between North American patients who developed hepatocellular carcinoma with and without cirrhosis. Histologic slides and clinical records of cases were reviewed. Cases were classified according to defined histopathologic criteria. Analyses were performed using appropriate tests. A total of 42.6% of cases were noncirrhotic. The trabecular type of hepatocellular carcinoma was the most common growth pattern in both groups. Patients with cirrhosis were significantly older, had high grade tumors, and local portal venous invasion significantly more often than patients without cirrhosis. Encapsulated tumors occurred in significantly more in patients without cirrhosis. Patients without cirrhosis survived longer than patients with cirrhosis (P < .0001) and had a better 5-year survival experience. On average, in patients with cirrhosis, serum aspartate transaminase and total serum bilirubin were significantly greater, and serum albumin was significantly lower. In general, hepatocellular carcinoma in North American patients with cirrhosis tended to be less well differentiated than those found among patients without cirrhosis. The pathology, natural history, and prognosis of this tumor is significantly influenced by the presence or absence of cirrhosis in the nonneoplastic liver, and the presence of cirrhosis portends a poorer prognosis.

Comparison of tumor pathology with duration of survival of North American patients with hepatocellular carcinoma.

BACKGROUND: Several of the large studies addressing prognosis and survival from hepatocellular carcinoma (HCC) have been from Europe and Asia, but only a few have emanated from North America. Survival statistics from other parts of the world may not be applicable to the North American population because of etiologic, demographic, cultural, lifestyle, and intangible differences. The current study investigated the survival experience and histologic correlates of North American patients with HCC and compared findings with similar studies from North America and other parts of the world. METHODS: One thousand sixty-three patients examined during a 14-year period, met inclusion criteria for this study. Each patient was placed in one of three categories based on the duration of survival from date of diagnosis of HCC. Each tumor was examined histologically and classified according to World Health Organization criteria. Patient's sex and age at diagnosis were obtained from case records. Survival analyses and comparisons were performed using appropriate methods. Variables were tested for association using chi-square tests and randomization tests as appropriate. RESULTS: Age, sex, tumor growth pattern, Edmondson and Steiner's nuclear grades, mitotic index, and presence or absence of tumor giant cells or portal venous invasion, were found to have statistically significant (P < 0.05) relationships with the duration of patient survival. Significantly better survival was found to be associated with female sex, low nuclear grade, low mitotic index, age at diagnosis younger than 50 years, absence of giant cells, and absence of portal venous invasion. CONCLUSIONS: Certain histopathologic features of HCC may be useful for predicting patient survival and, thus, for empiric prognostication of these patients.

Expression of proliferating cell nuclear antigen in hyperplastic polyps, adenomas and inflammatory cloacogenic polyps of the large intestine.

AIMS: To compare proliferating cell nuclear antigen (PCNA) immunoexpression in hyperplastic polyps, adenomas, and inflammatory cloacogenic polyps of the human colon and rectum using paraffin wax embedded tissue. METHODS: The monoclonal antibody PC10 was used to demonstrate PCNA immunoreactivity in 88 polypoid lesions from 68 patients. Cases in which immunoexpression was completely absent were excluded, leaving 32 hyperplastic polyps, 31 adenomas, and seven inflammatory cloacogenic polyps for analysis. Labelling indices for the upper and lower third of each lesion and for adjacent normal mucosa were calculated. RESULTS: The upper third labelling indices for adenomas were substantially higher than those for hyperplastic polyps or normal mucosa, whereas those for the upper thirds of hyperplastic polyps and normal mucosa did not differ greatly. The differences between the lower third samples were not significant. In 16 (50%) hyperplastic polyps positive cells persisted onto the luminal surface. Some adenomas showed the most intense staining and the highest labelling indices in the upper third, with strong staining of surface cells; this pattern was not seen in the other lesions. The inflammatory cloacogenic polyps did not show a consistent pattern of immunoexpression. CONCLUSIONS: Differences in cell kinetics between adenomas, hyperplastic polyps, and normal mucosa may be shown in formalin fixed, paraffin wax embedded tissue using PC10 as a marker of proliferative activity. PCNA expression also persists into the upper portions of hyperplastic polyps. Assuming that hyperplastic polyps are hypermature lesions with a slower rate of cell migration, this finding suggests that there may be an alteration in PCNA protein metabolism.

Association of hepatocellular carcinoma in North American patients with extrahepatic primary malignancies.

BACKGROUND: The finding of an association between one primary tumor and others is an area of continuing interest from clinical and pathologic viewpoints. The authors studied patients in North America with hepatocellular carcinoma associated with extrahepatic primary malignancies (EHPMs) and compared them with patients who had hepatocellular carcinomas not associated with other neoplasms. The authors know of only four other series that have investigated such cases, none of which was from North America. METHODS: The authors retrospectively reviewed 1349 consecutive cases of histologically diagnosed hepatocellular carcinoma (HCC) at the Armed Forces Institute of Pathology over a 14-year period. Seventy-four patients (5.5%) had an EHPM, and these were compared with the 1275 patients who did not have another primary malignancy. Statistical comparisons were made using the chi-square statistical or Fisher's exact test, as appropriate, and life-table survival analyses were performed. RESULTS: Significantly more men (P = 0.02) than women had EHPMs, and their mean age of 69.2 +/- 2.1 years was significantly older (P < 0.05) than that of those without EHPMs (59.9 +/- 1.0 years). Seventeen (19.8%) EHPMs occurred before HCC, 66 (76.7%) occurred synchronously, and 3 (3.5%) occurred metachronously. The probability of finding an EHPM increased if the nonneoplastic liver was cirrhotic or dysplastic. Mean survival for the HCC with EHPM group did not differ significantly from that for the group without EHPM. CONCLUSIONS: Extrahepatic primary malignancies do not significantly influence the survival of patients with HCC. The most common EHPMs associated with HCC are either diseases of old age or those already known to be common among North American populations.