In search of the grail: A race for acid suppression. / La búsqueda del Grial: una carrera por la supresión ácida.

Proton pump inhibitors are the reference standards for the treatment of acid-related diseases. Acid suppression in gastroesophageal reflux disease is associated with a high rate of mucosal cicatrization, but symptom response differs among endoscopic phenotypes. Extraesophageal manifestations have a good clinical response in patients that present with abnormal acid exposure (diagnostic test) in the esophagus. Proton pump inhibitors have shown their effectiveness for reducing symptom intensity in nighttime reflux and sleep disorders, improving quality of life and work productivity. That can sometimes be achieved through dose modifications by splitting or increasing the dose, or through galenic formulation. Proton pump inhibitors are not exempt from controversial aspects related to associated adverse events. Technological development is directed at improving proton pump inhibitor performance through increasing the half-life, maximum concentration, and area under the curve of the plasma concentrations through galenic formulation, as well as creating safer and more tolerable drugs. The present review is focused on the mechanisms of action, pharmacokinetic properties, and technological advances for increasing the pharmacologic performance of a proton pump inhibitor.

Post-fundoplication symptoms and complications: Diagnostic approach and treatment. / Síntomas y complicaciones posfunduplicatura: abordaje diagnóstico y tratamiento.

Laparoscopic Nissen fundoplication is currently considered the surgical treatment of choice for gastroesophageal reflux disease (GERD) and its long-term effectiveness is above 90%. Adequate patient selection and the experience of the surgeon are among the predictive factors of good clinical response. However, there can be new, persistent, and recurrent symptoms after the antireflux procedure in up to 30% of the cases. There are numerous causes, but in general, they are due to one or more anatomic abnormalities and esophageal and gastric function alterations. When there are persistent symptoms after the surgical procedure, the surgery should be described as "failed". In the case of a patient that initially manifests symptom control, but the symptoms then reappear, the term "dysfunction" could be used. When symptoms worsen, or when symptoms or clinical situations appear that did not exist before the surgery, this should be considered a "complication". Postoperative dysphagia and dyspeptic symptoms are very frequent and require an integrated approach to determine the best possible treatment. This review details the pathophysiologic aspects, diagnostic approach, and treatment of the symptoms and complications after fundoplication for the management of GERD.

Clear-cell adenofibroma can be a clonal precursor for clear-cell adenocarcinoma of the ovary: a possible alternative ovarian clear-cell carcinogenic pathway.

Several studies have reported that ovarian clear-cell adenocarcinoma can be derived from endometriosis. Although the clear-cell adenofibroma (CCAF), a major form of benign and borderline ovarian clear-cell tumour, has been suggested as another precursor for clear-cell adenocarcinoma (CCA), there is no supportive genetic evidence for this presumption. To examine the genetic linkage between CCAF and CCA of the ovary, we conducted allelotype analysis for both CCAF and adjacent CCA components in 14 cases of CCA associated with benign CCAF and/or borderline CCAF. DNA isolated from laser-microdissected tissue was subjected to polymerase chain reaction and analysis for loss of heterozygosity (LOH), using 17 polymorphic markers located on 11 chromosomal arms: 1p, 5q, 8p, 9p, 9q, 10q, 11q, 13q, 18q, 19p and 22q. For all informative loci, the frequency of LOH in adenocarcinoma was 49% (54/110 loci), and was significantly higher than those in the components of benign CCAF (22%, 20/92 loci) and borderline CCAF (30%, 25/83 loci) (chi(2) test; p<0.05, respectively). The concordance rate in allelic patterns at all informative loci was 74% between benign CCAF and adenocarcinoma components, 81% between borderline CCAF and adenocarcinoma components, and 95% between benign CCAF and borderline CCAF components. Furthermore, between CCAF and adenocarcinoma components, an identical LOH pattern, involving the same alleles, was found in 13 (93%) of 14 cases at one or more chromosomal loci, and estimation of probability indicated that these events were very unlikely to have occurred by chance. Among the markers examined, LOHs on 5q, 10q and 22q were frequent in both CCAF and adenocarcinoma components, whereas LOHs on 1p and 13q were rare in CCAF components but frequent in adenocarcinoma components. These findings suggest that CCAF can be a clonal precursor for ovarian clear-cell adenocarcinoma.

A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci.

AIMS: Tumour budding is an adverse prognostic factor in colorectal cancer (CRC). We have investigated the significance of cytoplasmic fragments occurring in the immediate vicinity of tumour budding foci. METHODS AND RESULTS: Seventy-three CRCs with high-grade budding (> 10 budding foci in a x 20 objective field) were classified according to extent of budding (10-19 versus 20+ foci) and by the presence or absence of cytoplasmic fragments identified by immunostaining for cytokeratin. In serial sections, cytoplasmic fragments were shown to be dendritic cell processes in continuity with budding tumour cells and were renamed pseudo-fragments. Cytoplasmic pseudo-fragments, but not extent of budding, were associated with aberrant expression of beta-catenin (P = 0.045) and laminin-5 gamma2 (P < 0.0001), and with absent peritumoral lymphocytic infiltration (P = 0.0077). Cytoplasmic pseudo-fragments had a stronger association with infiltrating growth pattern (P = 0.0014) than extent of tumour budding (P = 0.014). There was no association between extent of budding and cytoplasmic pseudo-fragments (P = 0.12). CONCLUSIONS: Cytoplasmic pseudo-fragments may be a marker for an activated budding phenotype that is associated with cell motility and increased invasiveness in CRC and is independent of the extent of budding.

Apoptosis as an independent prognostic indicator in squamous cell carcinoma of the esophagus.

Apoptosis plays a crucial role in determining net cell proliferation and cell turnover in various tumors. The rate of apoptosis in tumor cells has been reported to be a useful prognostic indicator in colorectal carcinoma. We examined apoptosis in 72 specimens of esophageal squamous cell carcinoma, by the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) digoxigenin-nick end labeling (TUNEL) method. We examined correlation of apoptosis with outcome, clinicopathological features, and expression of the apoptosis-related proteins p53 and Bcl-2. The percentage of apoptotic cells, or apoptotic index (AI), ranged from 0.8 to 9.4 (mean: 3.47; SD: 2.02). Overall, 5-year survival of patients with high AI (AI > or = 5.0; n = 18) tumors was significantly higher than that of patients with low AI tumors (AI < 5.0; n = 58; 76.9% versus 44.9%; P = 0.042). AI did not correlate significantly with the clinicopathological features of patient age and sex, depth of tumor and histological differentiation, lymph node metastasis, lymphatic invasion, or venous invasion. In p53-negative tumors, the AI was significantly higher than in p53-positive tumors. We concluded that AI may be a useful prognostic indicator in esophageal squamous cell carcinoma following curative surgery, and that apoptosis in this tumor is related to relative underexpression of p53 protein.

Enhanced expression of mRNAs of antisecretory factor-1, gp96, DAD1 and CDC34 in human hepatocellular carcinomas.

To identify differentially expressed genes in hepatocarcinogenesis, we performed differential display analysis using surgically resected hepatocellular carcinoma (HCC) and adjacent non-tumorous liver tissues. We identified four cDNA fragments upregulated in HCC samples, encoding antisecretory factor-1 (AF), gp96, DAD1 and CDC34. Northern blot analysis demonstrated that these mRNAs were expressed preferentially in HCCs compared with adjacent non-tumorous liver tissues or normal liver tissues from non-HCC patients. The expression of these mRNAs was increased along with the histological grading of HCC tissues. These mRNA levels were also high in three human HCC cell lines (HuH-7, HepG2 and HLF), irrespective of the growth state. We also demonstrate that sodium butyrate, an inducer of differentiation, downregulated the expression of AF and gp96 mRNAs, supporting in part our pathological observation. Immunohistochemical analysis revealed that gp96 and CDC34 proteins were preferentially accumulated in cytoplasm and nuclei of HCC cells, respectively. Overexpression of these genes could be an important manifestation of HCC phenotypes and should provide clues to understand the molecular basis of hepatocellular carcinogenesis.

The role of cyclin-dependent kinase inhibitor p27 in squamous cell carcinoma of the esophagus.

The level of p27 expression decreases during tumor development and progression. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, stomach and lung carcinomas. We generated a new polyclonal antibody against p27 and carried out immunohistochemical analysis of p27 expression in 61 specimens of esophageal squamous cell carcinoma, 10 carcinoma in situ specimens, and 5 squamous epithelial dysplasia specimens of the esophagus. We examined the correlation of p27 expression with various clinicopathologic features and prognosis. In squamous epithelial dysplasia, the p27-positive cells were located in the superficial normal-appearing cells, not in the atypical cells. In carcinoma in situ, the expression of p27 was markedly lower than in normal esophageal epithelium. In advanced squamous cell carcinomas, high p27 correlated significantly with the degree of differentiation (p = 0.0002) and the depth of tumor invasion (p = 0.001) was statistically significant. The high p27 expression group had a better prognosis than did the low or negative p27 expression groups, but these differences were not statistically significant. These observations may imply that a decrease in p27 expression occurs early on in the carcinogenesis of esophageal carcinoma. In addition, p27 expression may correlate with the histologic differentiation of squamous cell carcinoma of the esophagus.

Primary small cell (oat cell) carcinoma of the breast: report of a case and review of the literature.

A case of primary small cell (oat cell) carcinoma of the breast in a 41-year-old woman is presented. The patient was alive and well without disease 16 months after modified radical mastectomy and subsequent chemotherapy. The tumor cells revealed morphologic similarity to oat cell carcinoma of the lung and immunohistochemical expression of neuroendocrine markers. In ultrastructural examination, the tumor cells had neurosecretory granules. Review of nine previously reported cases and this case of primary small cell carcinoma of the breast has revealed that this type of tumor shows prominent vascular invasion, frequent lymph node metastasis, infrequent expression of estrogen receptor, and also very poor prognosis. Immunohistochemical study for the c-kit proto-oncogene product, which has been reported to be a specific marker for pulmonary small cell carcinoma, demonstrated positive reactivity in approximately 80% of the tumor cells of this case, which is the first report according to our knowledge. The expression of c-kit might be some aid to the diagnosis of primary small cell carcinoma of the breast.

Thymic hyperplasia as a source of ectopic ACTH production.

A 26 year-old man with suspected Cushing's disease underwent transsphenoidal exploration of the pituitary without any evidence of microadenoma or hyperplasia. Progressive hypercortisolism necessitated bilateral adrenalectomy. Postoperatively, skin pigmentation gradually developed with a marked elevation of plasma ACTH levels, and CT scanning uncovered a thymic mass. Following removal of the thymic mass, skin pigmentation disappeared and plasma ACTH levels fell to normal. The excised mass was found to be a benign thymic hyperplasia without epithelial or carcinoid tumor cells. However, gel chromatography showed that the thymic tissue extract contained high ACTH content comparable to that of ectopic ACTH-producing tumors with a major component corresponding to ACTH(1-39). Northern blot analysis and in situ hybridization revealed the expression of proopiomelanocortin transcripts in lymphocytes of thymic hyperplasia. This report suggests that lymphocytes in thymic hyperplasia are the most likely site of deregulated ACTH expression causing ectopic ACTH syndrome.

Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes.

Although usual interstitial pneumonia (UIP)-like IP has been known as the most serious complication of Hermansky-Pudlak syndrome (HPS), its pathologic features and pathogenesis are poorly understood. We investigated biopsied and autopsied lung tissues from five patients who died of UIP-like IP associated with HPS (HPSIP). The salient histopathologic features of HPSIP observed were: (1) alveolar septa displaying florid proliferation of type-2 pneumocytes (2PCs) with characteristic foamy swelling/degeneration; (2) patchy fibrosis with lymphocytic and histiocytic infiltration centered around respiratory bronchioles, occasionally showing constrictive bronchiolitis; and (3) honeycomb change without predilection for the lower lobes or subpleural area. Those peculiar 2PCs were histochemically characterized by the over accumulation of phospholipid, immunohistochemically by a weak positivity for surfactant protein, and ultrastructurally by the presence of numerous giant lamellar bodies that compressed the nucleus with occasional cytoplasmic disruption, together suggesting a form of cellular degeneration with an over accumulation of surfactant (giant lamellar body degeneration). The present study strongly indicates that there is a basic defect in the formation/secretion process of surfactant by the 2PCs in HPS, which may well be the triggering factor for the HPSIP development. Other factors, such as macrophage dysfunction, may be working synergistically for further acceleration of the inflammatory process.

Extracellular superoxide dismutase in tissues from obese (ob/ob) mice.

We have examined the protein content and gene expression of three superoxide dismutase (SOD) isoenzymes in eight tissues from obese ob/ob mice, particularly placing the focus on extracellular-SOD (EC-SOD) in the white adipose tissue (WAT). Obesity significantly increased EC-SOD level in liver, kidney, testis, gastrocnemius muscle, WAT, brown adipose tissue (BAT), and plasma, but significantly decreased the isoenzyme level in lung. Tumor necrosis factor-alpha and interleukin-1beta contents in WAT were significantly higher in obese mice than in lean control mice. Immunohistochemically, both WAT and BAT from obese mice could be stained deeply with anti-mouse EC-SOD antibody compared with those from lean mice. Each primary culture per se almost time-dependently enhanced EC-SOD production, and overtly expressed its mRNA. The loss of heparin-binding affinity of EC-SOD type C with high affinity for heparin occurred in kidney of obese mice. These results suggest that the physiological importance of this SOD isoenzyme in WAT may be a compensatory adaptation to oxidative stress.

Ovarian leiomyosarcoma: an autopsy case report.

Primary non-specific sarcoma of the ovary is extremely rare, and only 22 reported cases of pure leiomyosarcoma (LMS) are known to the authors. We present an autopsy case of a primary ovarian leiomyosarcoma in a 73-year-old woman. She had noticed an abdominal mass after difficulty in defecating for several months. The excision of tumor with bilateral salpingo-oophorectomy and hysterectomy was carried out. A diagnosis of pure leiomyosarcoma of the left ovary was made on pathological examination with immunohistochemistry. Adjuvant radio-chemotherapy was not given. At 18 months' follow up, abdomino-pelvic sonography revealed an abdominal tumor and hepatic metastasis. The patient died 3.5 years after the initial surgery. The post-mortem examination revealed a peritoneal recurrent tumor and extensive distant metastases of the liver, lungs, pancreas, gastric mucosa, muscle and skin. The prognosis of the ovarian LMS is poor from the pertinent literature. Several prognostic indicators on histology including mitotic activity, proliferative activity and p53 status of the tumor are discussed.

Immunocytochemical localization of metallothionein in human pancreatic islets.

Metallothioneins (MTs) are small intracellular proteins that bind to metal ions and are involved in heavy-metal homeostasis and detoxication. Pancreatic islets were previously reported to contain zinc-containing matrix metalloproteinases (MMPs) and inhibitors of metalloproteinases (TIMPs) by immunocytochemical staining. The immunolocalization of MMPs and TIMPs in pancreatic islets prompted us to investigate further the link between zinc and MTs. Both beta and nonbeta islet cells were found to contain MTs by this immunocytochemical staining, suggesting that MTs may be involved in pancreatic hormone synthesis and secretion, in addition to their roles in zinc homeostasis and detoxification.

[A questionnaire survey of surgical lung biopsy in patients with diffuse lung diseases].

A nationwide questionnaire survey was conducted to investigate the indications, diagnostic yield, complications, outcome, and benefit of surgical lung biopsy for diffuse lung diseases. Surgical lung biopsies were performed in 410 patients at 132 institutes in 1998, 94% of them as video-assisted thoracoscopic surgery (VATS). Interstitial lung diseases of unknown etiology formed the largest diagnostic group, and consisted of 194 patients. The clinical diagnosis prior to lung biopsy was inconsistent with the final diagnosis in 32.8%. Complications were seen in 32 patients, and mortality was 1.2%. Acute exacerbation of the underlying disease was seen in 9 patients, four of whom died. Patients with nonspecific interstitial pneumonia and even usual interstitial pneumonia who were treated following biopsy showed better outcomes than those untreated. The physician in charge judged that 82.2% of the patients received clinical benefits from the biopsy procedure. We concluded that VATS lung biopsies are indicated in more cases to confirm diagnoses and as a reference for treatments in patients with diffuse lung disease.

Identification and characterization of genes associated with human hepatocellular carcinogenesis.

Eight cDNAs encoding galectin 4 (Gal-4), UGT2B4 (UDP-glucuronosyltransferase), ribosomal phosphoprotein P0 (rpP0), dek, insulin-like growth factor binding protein (IGFBP) 1, vitronectin, retinoic acid-induced gene E (RIG-E), and CYP3A4 (cytochrome P450 nifedipine oxidase) were identified as differentially expressed genes between human hepatocellular carcinoma (HCC) and matched nontumorous liver tissues. Higher levels of UGT2B4, rpP0, dek, vitronectin, Gal-4, and IGFBP-1 mRNAs combined with a lower level of RIG-E mRNA were observed in at least four of five primary HCCs compared to matched nontumorous liver tissues. Furthermore, a pathological study suggested that the levels of UGT2B4, rpP0, dek, and vitronectin increased and the level of RIG-E decreased with the histological grading. On the other hand, the expression of CYP3A4 mRNA and CYP3A7 (P-450 Fla) mRNA, a transcript found in the fetus and highly homologous to CYP3A4, was higher in all nontumorous liver and some of the carcinoma tissues from five HCC patients, whereas it was significantly lower in normal liver tissues from two non-HCC patients. The examination using HCC cell lines HuH-7 and HepG2 under different growth conditions suggested that the expression of dek mRNA was growth-associated. In contrast, the expression of Gal-4, UGT2B4, IGFBP-1, and RIG-E mRNAs was regulated in a cell density-dependent manner: the levels of Gal-4, UGT2B4, and IGFBP-1 were undetectably low, whereas the level of RIG-E was high in rapidly proliferating, subconfluent HCC cells in 10% serum; however, the expression levels were reversed in dense, overcrowded cultures. In addition, IGFBP-1 and Gal-4 mRNAs were also induced by reducing the serum concentration to 0.1%. We also demonstrated that sodium butyrate, an inducer of differentiation, up-regulated and down-regulated RIG-E and dek mRNAs, respectively, in a dose-dependent manner in HuH-7 cells, supporting, in part, our pathological observation. In summary, therefore, high expression of Gal-4, UGT2B4, rpP0, dek, IGFBP-1, and vitronectin, together with low expression of RIG-E, was correlated with the malignant potential of HCC. CYP3A4 and CYP3A7 could be induced in HCC-bearing livers. These transcripts are differentially regulated depending on cell-cell contact, serum growth factors, growth and differentiation status, and/or other mechanisms in premalignant and malignant liver cells.

[Hypereosinophilic syndrome associated with antineutrophil cytoplasmic antibody].

A 68-year-old man was admitted to our hospital with complaints of fever, cough, and shortness of breath. He had several erythematous maculae on the trunk and experienced hypesthesia in his lower extremities. Laboratory data showed marked eosinophilia (20,235/mm3) and enhanced hepatobiliary enzymes. Chest X-ray films and computed tomographic scans revealed diffuse patchy infiltrative changes in the lungs. Histologic findings confirmed eosinophilic infiltration of the skin, liver, and lungs. A diagnosis of hypereosinophilic syndrome (HES) was made in accordance with clinical criteria proposed by Chusid et al. The patient was positive for antineutrophil cytoplasmic antibodies (a marker for vasculitis). This suggested a clinical picture resembling Churg-Strauss syndrome (CSS) despite the lack of bronchial asthma. The findings in this report could contribute to a better understanding of the diversity of HES cases, several of which are considered to represent a continuum of pathologies sharing an etiology similar to that of CSS.

Production of endothelin by canine prostatic epithelial cells and its stimulatory effects on their growth.

The current study has been designed to explore expressions of endothelin (ET) receptors and ETs in the canine prostate and the effect of ETs on canine prostatic epithelial cells. ET receptors were characterized by biotinylated ET-1 binding in frozen sections of the prostate. Canine prostatic epithelial cells in primary culture were used for demonstration of ET-1 expression by reverse-phase HPLC coupled with radioimmunoassay and Northern blotting and were subjected to growth assay. Biotinylated ET-1 binding was localized in the epithelial component, and the binding was also blocked with an antagonist specific for ET(B) subtype receptors. ET-1 and ET-3 stimulated canine prostatic epithelial cell growth in vitro. The effect was also reversed in the presence of an antagonist specific for ET(B) subtype receptors. Elution profile of epithelial cell culture medium revealed two peaks, corresponding to ET-1 and big ET-1. Epithelial cells in culture expressed pre-pro-ET-1 mRNA. Canine prostatic epithelial cells expressed ET(B) receptors and ET-1. It appears most likely that the expressed ET-1 acts as an autocrine/paracrine proliferative factor on canine prostatic epithelial cells via ET(B) receptors.

Infantile disseminated visceral giant cell arteritis presenting as sudden infant death.

The rare clinicopathological entity 'disseminated visceral giant cell arteritis' (DVGCA) was first described in 1978. It is characterized by widespread small-vessel giant cell angitis and extravascular granulomas. A normal and healthy 7-month-old boy who presented unexpectedly with sudden infant death syndrome (SIDS) is reported. Histological examination at autopsy revealed giant cell angitis of the aorta, common carotid, coronary, pulmonary, celiac, mesenteric and common iliac arteries. There were also granulomas in the tracheal wall and liver. To our knowledge, this is the first documented case of DVGCA occurring in an infant younger than 12 months of age. A review of the literature on DVGCA is presented in this report, and the differential diagnosis is discussed.

Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis.

Tissue factor (TF) is an initiator of the extrinsic cascade of blood coagulation. Although recent studies have revealed a relationship between metastatic properties and TF expression in some neoplastic cells, the significance of TF in lung cancer, especially in non-small-cell lung cancer (NSCLC), is still unclear. In this study, TF was detected in NSCLC cell lines by functional study, Western blot analysis and immunocytochemical staining. TF levels in eight NSCLC cell lines were also quantitated by enzyme-linked immunosorbent assay (ELISA), and TF expression was evaluated in 55 specimens of surgically resected NSCLCs. NSCLC cell lines derived from metastatic lesions produced high levels of TF (48.3+/-23.5 ng 10(-6) cells, mean +/- s.e.m.), whereas those derived from primary lesions produced low levels of TF (0.2+/-0.1 ng 10(-6) cells). Immunohistochemical studies disclosed significantly stronger staining for TF in cells from NSCLC patients with metastasis than in those without metastasis. Among the 28 patients with metastasis, ten were strongly positive, 16 were moderately positive and two were negative for TF. In contrast, among the 27 patients without metastasis, only two were strongly positive, 18 were moderately positive and seven were negative for TF. Therefore, malignant cells from patients with lung cancer produce various levels of TF, and TF may play an important role in the metastatic process.

[Chronic hypersensitivity pneumonitis due to isocyanate in a patient presenting with acute symptoms 1 month after environmental exposure].

A 51-year-old man who had been working for 10 years with polyurethane paint containing isocyanate (MDI) was admitted to our hospital with complaints of fever and exertional dyspnea. Fine crackles were heard in both bases, and the patient had clubbed fingers. A chest X-ray film and computed tomograms of the lungs revealed patchy infiltrative shadows in both lung fields and subpleural honeycombing associated with irregular linear areas. Examination of bronchoalveolar lavage fluid showed increased T lymphocytes and a decreased CD 4/8 ratio. Specimens obtained by transbronchial lung biopsy revealed lymphoplasmacytic infiltration into the thickened alveolar walls, macrophage accumulation, and micro-epithelioid cell granulomas in the alveolar sacs. Hypersensitivity pneumonitis was suspected although the causative antigen was not identified because the results of short-term environmental provocation tests were negative in the patient's home and workplace. After discharge, the patient continued working as a paint sprayer. His acute symptoms recurred 1 month after exposure to isocyanate. Similar episodes occurred on two separate occasions. In addition, the patient tested positive for antibody to MDI-HSA in bronchoalveolar fluid. From the above observations, the patient was given a diagnosis of chronic hypersensitivity pneumonitis due to isocyanate (MDI). This condition is extremely rare. Furthermore, it is interesting that acute symptoms recurred 1 month after environmental exposure to the causative antigen.