Abnormalities in the upper gastrointestinal tract in inflammatory bowel disease.

The predominant histopathologic feature of inflammatory bowel disease is the infiltration of acute and chronic inflammatory cells, including polymorphonuclear neutrophils, macrophages and lymphocytes, in the affected intestine. Helicobacter pylori is recognized as the most common cause of upper gastrointestinal lesions, and Helicobacter pylori-associated gastritis is characterized by increased numbers of acute and chronic inflammatory cells. The pathogenesis of inflammatory bowel disease or Helicobacter pylori-associated gastritis involves immunological abnormalities, including the deficient or excessive expression of cytokines. The chronic inflammatory process in patients with Crohn's disease may affect any part of the gastrointestinal tract, whereas ulcerative colitis affects mainly the colon and rectum. Here, we discuss abnormalities in the upper gastrointestinal tract in inflammatory bowel disease. Although the prevalence rate of Helicobacter pylori infection is low in Crohn's disease, these patients often have abnormalities in the upper gastrointestinal tract.

The interaction of host genetic factors and Helicobacter pylori infection.

Helicobacter pylori plays an important role in the development of atrophic gastritis that represents the most recognized pathway in multistep gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of Helicobacter pylori infection. As to bacterial virulence factors, a high proportion of Japanese strains are cagA(+)vacAs1. The CagA protein is injected from attached Helicobacter pylori into gastric epithelial cells and the CagA-SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. Host cytokine gene polymorphisms and a frequent single nucleotide polymorphism in the PTPN11 gene that encodes SHP-2 may associate with gastric atrophy among Helicobacter pylori-infected subjects. Prevention of gastric cancer requires the development of better screening strategies for determining eradication candidates and further improvement of treatments of Helicobacter pylori infection.

Usefulness of an elemental diet in Crohn's disease.

Crohn's disease is a chronic relapsing disease for which no complete cure is available. Although drug therapy with agents such as corticosteroids and azathiopurine is useful, the long-term side effects of these drugs are problematic. The advent of infliximab has recently brought a change in treatment, but the long-term side effects of this agent remain uncertain. In contrast, nutritional therapy produces no drug-induced side effects and is effective in inducing and maintaining remission. However, sufficient efficacy cannot be expected in patients in whom compliance with nutritional regimens gradually decreases owing to unpalatability. In these cases, combination therapy with agents such as immunosuppressors and infliximab may be useful.

DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review.

DNA hypermethylation is one of major epigenetic changes. Hypermethylation of many genes has been reported to be related with carcinogenesis and tumor progression of colorectal cancer. Some genes including estrogen receptor is associated with ageing, and changes related with ageing may be accelerated in inflammatory bowel disease. Furthermore, fecal DNA methylation will be able to be used as a marker of colorectal cancer and inflammatory bowel disease. Evaluation of hypermethylation potentially contributes diagnosis of colorectal diseases.

Confocal endomicroscopy for the diagnosis of gastric cancer in vivo.

BACKGROUND AND STUDY AIMS: Advances in endoscopy have led to imaging of the details of the gastric mucosa, but the histological diagnosis usually has to be confirmed by endoscopic biopsy. A method of confocal endomicroscopy that has recently been developed allows the observation of living cells in vivo. Several investigators have reported that the technique is of value, but there have as yet been no studies describing its application in gastric cancer. PATIENTS AND METHODS: Twenty-seven patients with early gastric cancer underwent confocal endomicroscopy (Pentax EG-3870CIK; Pentax, Tokyo, Japan). After intravenous administration of fluorescein sodium, confocal images obtained from the normal mucosa and from cancerous lesions were interpreted by two pathologists independently and compared with the histological findings, including CD34 immunostaining of biopsy specimens or resected specimens from the same sites. RESULTS: Fluorescein yielded high-quality confocal images of the gastric mucosa; if cancer could be targeted (59%) images were mostly graded good. The images corresponded to the hematoxylin-eosin staining of transverse sections of specimens from the same sites. In the results for the interpretation by the two pathologists, the accuracy for the diagnosis of gastric cancer was 94.2% (pathologist A), and 96.2% (pathologist B), respectively. The accuracy decreased substantially when poor images and inaccessible lesions were included. CONCLUSIONS: Confocal endomicroscopy is useful in the diagnosis of gastric cancer but good quality images cannot always be obtained. In the future, it may allow virtual biopsy and help reduce unnecessary biopsies.

Pit patterns in rectal mucosa assessed by magnifying colonoscope are predictive of relapse in patients with quiescent ulcerative colitis.

BACKGROUND: Relapse of ulcerative colitis is difficult to predict by routine colonoscopy. A high-resolution video-magnifying colonoscope with chromoscopy enables the observation of colorectal mucosal pit patterns. AIMS: To investigate the association of pit patterns as assessed by magnifying colonoscopy (MCS) with histological inflammation and mucosal chemokine activity in patients with quiescent ulcerative colitis, and to prospectively analyse the prognostic factors that may predict exacerbations. METHODS: MCS was performed in 113 patients with ulcerative colitis in remission. Pit patterns in the rectal mucosa were classified into four MCS grades on the basis of size, shape and arrangement. Mucosal interleukin (IL) 8 activity was measured in biopsy specimens of rectal mucosa and the specimens were assessed for histological disease activity. The patients were then followed until relapse or for a maximum of 12 months. Multivariate survival analysis was carried out to determine the independent predictors of clinical relapse. RESULTS: A positive correlation was identified between MCS grade, histological grade (p = 0.001) and mucosal IL8 activity (p<0.001). Multivariate proportional hazard model analysis showed that MCS grade was a significant predictor of relapse (relative risk 2.06, p = 0.001). Kaplan-Meier estimate of relapse during 12 months of follow-up was found to increase with increasing MCS grade, with values of 0% for grade 1, 21% for grade 2, 43% for grade 3 and 60% for grade 4. CONCLUSION: MCS grading is associated with the degree of histological inflammation and mucosal IL8 activity in patients with quiescent ulcerative colitis, and may predict the probability of subsequent disease relapse in patients with ulcerative colitis in remission.

Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy.

BACKGROUND AND AIMS: The relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD) is controversial but it is accepted that GORD is associated with increased exposure to gastric acidity. The proinflammatory interleukin (IL)-1B polymorphisms increase the risk of hypochlorhydria and gastric atrophy. We examined the association between proinflammatory cytokine gene polymorphisms, presence of gastric atrophy, and risk of GORD in H pylori positive and negative subjects in Japan. METHODS: We studied 320 consecutive dyspeptic patients without peptic ulcers or cancers. GORD symptoms were scored using the Carlsson-Dent questionnaire and erosive oesophagitis was assessed endoscopically. H pylori infection was diagnosed by urea breath test, histological examination, and serology. Gastric atrophy was assessed histologically, and polymorphisms in the IL-1B, IL-10, and tumour necrosis factor alpha (TNF-A) genes were genotyped. RESULTS: Two hundred and eight patients were H pylori positive and 112 were negative. One hundred and eight (34%) were found to have erosive oesophagitis by endoscopic criteria (grade A: 78; grade B: 23; grade C: 6; grade D: 1). Erosive oesophagitis and GORD symptoms were significantly more common in H pylori negative compared with H pylori positive subjects (p<0.05). H pylori positive subjects were more likely to have corpus gastric atrophy than H pylori negative subjects (p<0.001). Among H pylori positive patients, those without erosive oesophagitis or GORD symptoms were significantly more likely to have corpus atrophy than subjects with erosive oesophagitis or GORD symptoms (p<0.05). Among H pylori positive patients, subjects homozygous for the proinflammatory allele IL-1B-511T had a significantly lower risk of erosive oesophagitis (odds ratio (OR) 0.06 (95% confidence interval (CI) 0.006-0.51); p=0.01) and GORD symptoms (OR 0.10 (95% CI 0.01-0.85); p=0.04) compared with those homozygous for the -511C allele, while none of the two other proinflammatory cytokine gene polymorphisms had significant correlations with erosive oesophagitis or GORD symptoms. CONCLUSIONS: A proinflammatory IL-1B genotype is associated with increased risk of atrophy and decreased risk of GORD in H pylori infected subjects in Japan. These data indicate that in some genetically predisposed subjects, H pylori infection may protect against GORD through induction of gastric atrophy.

Increased expression of dipeptidyl peptidase IV in human mesothelial cells by malignant ascites from ovarian carcinoma patients.

Cell surface aminopeptidases play an important role in biological processes through degradation of small peptides. There are many bioactive peptides in ascites and these peptides are involved in carcinoma cell dissemination and infiltration. In human mesothelial cells dipeptidyl peptidase IV (DPPIV) shows the highest expression mostly in four cell surface aminopeptidases: aminopeptidase A, neutral endopeptidase 24-11, aminopeptidase N and DPPIV. Since mesothelial cells are always in contact with ascites, we examined the influence of malignant ascites on DPPIV. DPPIV enzyme activity in mesothelial cells was enhanced by the addition of ascites obtained from ovarian carcinoma patients in a time- and concentration-dependent manner, and flow cytometry and immunocytochemistry also revealed an increased expression of DPPIV on the cell surface of mesothelial cells. The <3-kD fraction of malignant ascites increased the DPPIV enzyme activity to the same level as the total ascites. Northern hybridization demonstrated that DPPIV mRNA was increased 3-fold by the addition of the <3-kD malignant ascites. In conclusion, DPPIV is highly expressed in human mesothelial cells and was regulated by ascites.

[A case of adult Wilms' tumor].

Wilms' tumor is very rarely found in adults and there are no established treatment guidelines for such tumors in adults. A 56-year-old woman was referred to our hospital for further examination of macroscopic hematuria. Computed tomography scan revealed a large right renal mass with enlarged lymph nodes. Angiography showed a hypovascular tumor. She underwent right nephrectomy and resection of lymph node metastasis with a diagnosis of malignant renal tumor. Histopathological examination revealed nephroblastoma with lymph node metastasis. The disease was classified as stage III according to the National Wilms' Tumor Study classification. The patient received adjuvant chemotherapy consisting of ifosfamide, cisplatin, and etoposide. This protocol was selected because of the published poor results with the standard Wilms' tumor chemotherapeutic agents when used in adults. She remained without tumor recurrence as of six months after surgery. Development of better therapeutic approaches to adult Wilms' tumor is awaited.

Diagnostic efficacy of tumor markers, sonography, and intraoperative frozen section for ovarian tumors.

Using sonography, we classified the adnexal masses of 292 patients into 4 patterns. Pattern A was benign cystic tumors; B was benign mixed tumors (cysts with a smooth solid component); C was malignant mixed tumors (cysts with an irregular solid component or thickened septum), and D was solid tumors. We diagnosed tumors showing patterns A and B as benign, while patterns C and D represented tumors with low malignant potential or actual malignancy. The sensitivity and specificity of sonography was 82.2 and 82.1%, respectively, and these values were superior to those for tumor markers (CA125, CA19-9, CA72-4). Both the sensitivity and specificity of intraoperative frozen sections were the highest, showing that this is the most reliable examination. However, 15 of 191 patients undergoing frozen section were upgraded by the final pathological diagnosis. If sonography is performed by an experienced gynecologic oncologist, this examination is more reliable than tumor markers. However, intraoperative frozen section should still be performed during surgery for patients with ovarian tumors.

[A case of clinically multifocal renal cell carcinoma].

A 61-year-old woman was diagnosed with a renal tumor of the left kidney by ultrasound sonography during a health check-up. Computerized tomography (CT) and colored Doppler ultrasound sonography demonstrated two hypervascular tumors as typical renal cell carcinomas. A radically nephrectomized specimen was step-sectioned. Four tumor nodules were detected macroscopically, and 47 small nodules were detected microscopically, showing the clear cell type and alveolar growth pattern. Then all nodules including the 47 small nodules were diagnosed renal cell carcinoma.

Endoscopic ablation with cyanoacrylate glue for isolated gastric variceal bleeding.

BACKGROUND: Endoscopic ablation with cyanoacrylate glue may achieve gastric variceal obliteration. A prospective evaluation of its therapeutic effects on bleeding gastric varices was conducted, focusing on endoscopic features. METHODS: Thirty-seven patients with bleeding gastric varices underwent endoscopic ablation with cyanoacrylate. RESULTS: Patients with localized-type gastric varices (n = 14) had a better clinical course in terms of recurrent bleeding, variceal eradication, and survival than those with diffuse-type gastric varices (n = 23) after endoscopic ablation with cyanoacrylate. These clinical effects were related to the vascular anatomy of the gastric varices as determined by varicography and 3-dimensional CT. Type 1 vascular anatomy (one varicose vessel without noticeable ramifications) was much more common (86%) in localized-type gastric varices, whereas type 2 vascular anatomy (multiple varicose vessels with complex connecting ramifications) was found almost exclusively (91%) in diffuse-type gastric varices. CONCLUSIONS: Endoscopic ablation with cyanoacrylate is an effective and safe procedure for patients with bleeding gastric varices. Determination of variceal anatomy may be useful for improving treatment strategies for such patients.

Scirrhous cancer of the stomach which survived for more than five years after neoadjuvant chemotherapy with UFT (uracil and tegafur) and cisplatin.

A 68-year-old man was diagnosed as having a scirrhous cancer of the stomach. Carcinomatous peritonitis was suspected on abdominal CT examination. Three courses of uracil and tegafur (UFT)/cisplatin (CDDP) chemotherapy were administered. The primary foci were reduced in size, then total gastrectomy was performed. Histological findings revealed a poorly differentiated adenocarcinoma with scirrhous invasion into the subserosa. Histological efficacy of the chemotherapy was judged to be grade 2. The patient has been alive without disease for more than five years after total gastrectomy. Neoadjuvant chemotherapy with UFT and CDDP may have contributed to the favorable clinical outcome in this patient.

Clinical significance of nonpalpable prostate cancer with favorable biopsy features in Japanese men.

OBJECTIVE: To assess the clinical significance of nonpalpable localized prostate cancers with relatively favorable six sextant biopsy features in Japanese men. PATIENTS AND METHODS: 136 nonpalpable prostate cancers of which biopsy features confined to (1) a Gleason score of 6 or less, (2) one or two positive cores per six sextant cores, and (3) 50% or less involvement of any positive core were collected. The Gleason score, tumor extension, and cancer volume were compared with preoperative serum PSA and PSA density for the patients who underwent radical prostatectomy. PSA doubling time was measured for the patients who were treated expectantly. RESULTS: Treatments chosen for 136 patients with favorable biopsy features were radical prostatectomy alone for 48 and with preoperative androgen deprivation for 30, radiation to the prostate for 12, androgen deprivation therapy for 21, and watchful waiting for 25. Of 48 patients who underwent radical prostatectomy without androgen deprivation therapy, 25% had nonorgan-confined cancers. Seven cancers (14.6%) were Gleason score of 7, but no cancers were 8 or greater. Among 42 prostatectomy specimens for which cancer volume was measured, 22 (52.4%) had cancer volume >0.5 cm(3). Pretreatment serum PSA levels were correlated neither with the Gleason score, tumor extension nor cancer volume. There was only one nonorgan-confined cancer in the 23 cancers for which PSA density was <0.2 ng/ml/g. The ability of PSA density to predict cancer volume <0. 5 cm(3) was 0.61 using a cut-off of 0.2 ng/ml/g. Of the 25 patients treated expectantly, the PSA doubling time was less than 2 years for 3 patients, while it was stable or fluctuated for 13. CONCLUSIONS: Tumor extension can be predicted based on PSA density in nonpalpable prostate cancer with favorable biopsy features, but predictability of cancer volume based on PSA or PSA density is not satisfactorily high. New parameters or biomarkers that complement needle biopsy findings are needed to predict clinical significance of T1c prostate cancer with favorable biopsy features.

Incidence rate of satellite tumors in renal cell carcinoma.

BACKGROUND: Nephron-sparing surgery for incidentally detected small renal tumors has been performed. The main objection to such surgery concerns the incidence rate of satellite renal tumors. In this study, the authors analyzed the rate of incidence and proliferative potential of satellite renal tumors. METHODS: The tumors of 124 renal cell carcinoma patients with a clinically identified unilateral and single tumor measuring

[Renal oncocytoma with cystic degeneration: a case report].

A 45-year-old man was referred to our department because of a right renal mass which was incidentally found at a health screening. Ultrasound sonography, computerized tomography and magnetic resonance imaging showed a hypovascular tumor 3 cm in diameter with the fluid at the upper pole of the right kidney, implicating that the tumor was renal cell carcinoma originating from a renal cyst wall, or with central necrosis. A radical nephrectomy was therefore performed. The tumor was dark-brown and contained brown fluid. The histopathological findings showed renal oncocytoma with cystic degeneration.

Impact of tumor size on the clinical outcomes of patients with Robson State I renal cell carcinoma.

BACKGROUND: In the TNM classification of renal cell carcinoma released in 1997, T1 tumors were defined as organ-confined tumors 7.0 cm or less in size, and T2 as those larger than 7.0 cm. The consideration of tumor size should be predicated on its prognostic value in predicting survival, because the goal of clinical staging is to separate patients into similar classes of survival based on the extent of disease at presentation. The authors examined the impact of tumor size on the clinical outcomes of patients with Robson Stage I disease to determine a size cutoff that would maximize the predictive value of the TNM staging system. METHODS: Between 1962 and 1995, 382 patients with renal cell carcinoma were treated at the Department of Urology at the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, and the TNM staging of 350 of those patients was recorded. Of 350 patients, 157 (45%) were at TNM Stage I, 47 (13%) at Stage II, 65 (19%) at Stage III, and 81 (23%) at Stage IV, according to the TNM stages defined in 1997. Robson Stage I includes TNM Stages I and II, and 204 patients in these stages were analyzed in this study. This study group included 146 men and 58 women with a mean age of 57.8 years (range, 26-84 years). The mean follow-up period was 5.4 years. RESULTS: The patient survival periods were not significantly different for those with TNM Stages I and II. This finding indicated that the tumor size cutoff of 7.0 cm was not useful in predicting the prognosis. The patients at TNM Stages I and II were then divided into two groups at each size cutoff, from 2.5 cm to 9.0 cm, at 0.5-cm intervals. The tumor size cutoff of 5.5 cm was most predictive of patient survival (P = 0.0121). None of other patient characteristics varied significantly between the two groups at this dichotomous point. Tumor size and microscopic intrarenal venous invasion, but not grade or infiltration pattern, were found in univariate and multivariate analyses to be significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. CONCLUSIONS: The current data indicate that the tumor size cutoff of 5.5 cm was most significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. The tumor size cutoff of 5.5 cm was also shown to be significant in univariate and multivariate analyses.

[Results of chemotherapy and salvage surgery for advanced testicular cancer].

Since 1980, 73 patients with advanced testicular cancer have been treated with chemotherapy and 43 patients received post-chemotherapy (salvage) surgery. The median age of all patients was 31 years old, ranging from 17 to 63 years. The histology of the primary testicular tumor was pure seminoma in 23 patients and non-seminoma in 50 patients. According to the Japan Urological Association classification, 38 patients were classified as stage II and 35 patients as stage III. As first-line chamotherapy, 52 patients were treated with PVB regimen (cisplatin, vinblastin, bleomycin), 16 patients with PEB (cisplatin, etoposide, bleomycin) and 5 patients with VAB-6 (vinblastine, actinomycin-D, bleomycin, cisplatin, cyclophosphamide). Thirty (41%) of the 73 patients achieved a complete response (CR) with chemotherapy alone and 63 (86%) achieved no evidence of disease (NED) with salvage treatment. As second-line chemotherapy, 16 patients were treated with PE (cisplatin, etoposide), or VIP (etoposide, ifosfamide, cisplatin) or VeIP (vinblastine, ifosfamide, cisplatin). One of the 16 patients achieved CR and 11 (69%) patients achieved NED. As salvage surgery, retroperitoneal lymphnode dissection (RPLND) was performed in 22 patients, RPLND with thoracotomy in 7 cases and thoracotomy alone in 4 cases. Necrosis was found in surgical specimens of 24 (56%) patients, mature teratoma in 6 (14%) and residual cancer in 13 (30%). Ninety-six percent and 100% of the patients with necrosis and mature teratoma survived with NED, respectively, but only 54% of the patients with residual carcinoma survived despite further treatment. Residual cancer was still found in 8 of the 32 (25%) marker normalized cases. Residual cancer could not reliably be predicted or discriminated from necrosis or mature teratoma by the prognostic criteria. Therefore, salvage surgery remains essential in the treatment of advanced testicular cancer.

Effect of gadolinium chloride treatment on concanavalin A-induced cytokine mRNA expression in mouse liver.

The effect of Kupffer cell depression on concanavalin A (Con A)-induced cytokine mRNA expression in the liver was studied. Gadolinium chloride (GdCl3) is a commonly used Kupffer cell inhibitor. GdCl3 (40 mg/kg, i.p.) was injected into each mouse, and 24 hr later, Con A (0.2 mg/mouse) was administered. Plasma was obtained at 24 hr after Con A treatment for alanine aminotransferase (ALT) measurement. GdCl3 treatment inhibited Con A-induced elevation of ALT. However, it did not inhibit Con A-induced interleukin-2 or tumor necrosis factor-alpha mRNA expression. The present results suggest that Kupffer cells are not responsible for Con A-induced cytokine expression in the liver.

[Clinical significance of prostate specific antigen (PSA) and PSA density in the detection of T1a and T1b prostate cancer].

The clinical significance of preoperative prostate specific antigen (PSA) and PSA density (PSAD) in distinguishing stage T1a and T1b prostate cancer from benign prostatic hyperplasia (BPH) was studied retrospectively in men who had undergone surgery for BPH. A total of 202 clinically BPH patients underwent transurethral resection of prostate (TURP) or retropubic prostatectomy, and histopathological findings were BPH in 179 patients, T1a cancer in 10 patients and T1b cancer in 13 patients. The T1a cancer group was similar to the BPH group in all parameters. The PSA and PSAD values in the T1b cancer group were significantly higher than those in the BPH group (P < 0.001). Prostate volume and amount of tissue resected in the T1b cancer group were significantly smaller than those in the BPH group (p < 0.001). The cut-off values of PSA and PSAD were examined with T1a and T1b cancer as a positive control and histologically proven BPH as a negative control. When 8.0 ng/ml was used as the PSA cut-off value, the sensitivity was 65% and specificity was 70%. When 0.25 ng/ml/ml was used as the PSAD cut-off value, the sensitivity and specificity were 65% and 75%, respectively. PSAD was useful for improving the specificity. Almost all the cases undetected by using both cut-off values were of T1a cancer. The receiver operating characteristics curve demonstrated that at any point, PSAD was a better detector for distinguishing T1a, T1b cancer from BPH, focusing especially in the range of PSA level between 6.0 and 10.0 ng/ml. These findings suggest that PSA and PSAD are useful parameters in distinguishing T1b cancer from BPH before surgery.