Synchronous and subsequent lesions of serrated adenomas and tubular adenomas of the colorectum.

The characteristics of synchronous and subsequent lesions of serrated adenomas (SAs) of the colorectum are still unclear. This study aimed to clarify the characteristics of synchronous and subsequent lesions of SAs compared with tubular adenomas (TAs) of the colorectum. Patients were divided into 2 groups: SA (127 patients) and TA (158 patients). The mean follow-up durations in the SA and TA groups were 39.7 and 42.7 months, respectively. The number and clinical features of the synchronous and subsequent lesions of both groups were examined. In the SA group, 19 (15%) patients had synchronous lesions and 3 (2%) patients had subsequent lesions. In the TA group, 68 (43%) patients had synchronous lesions and 14 (9%) patients had subsequent lesions. The frequencies of patients with synchronous and subsequent lesions in the SA group were significantly lower than those in the TA group (p < 0.0001 and p = 0.02, respectively). The most frequent synchronous lesion was SA (67%) in the SA group and TA (95%) in the TA group. The most subsequent lesion was SA (62%) in the SA group and TA (100%) in the TA group. The histology of the index polyp and synchronous and subsequent lesions tended to be identical. No invasive colorectal carcinomas were observed in either group. Our data suggest that the colonic tumorigenesis potential of patients with SA may differ from that of patients with TA.

Preoperative MRI for predicting pathological changes associated with surgical difficulty during laparoscopic cholecystectomy for acute cholecystitis.

BACKGROUND: Severe inflammation with necrosis and fibrosis of the gallbladder in acute cholecystitis increases operative difficulty during laparoscopic cholecystectomy. This study aimed to assess the use of preoperative MRI in predicting pathological changes of the gallbladder associated with surgical difficulty. METHODS: Patients who underwent both preoperative MRI and early cholecystectomy for acute cholecystitis between 2012 and 2018 were identified retrospectively. On the basis of the layered pattern of the gallbladder wall on MRI, patients were classified into three groups: high signal intensity (HSI), intermediate signal intensity (ISI), and low signal intensity (LSI). The endpoint was the presence of pathological changes of the gallbladder associated with surgical difficulty, such as necrosis, abscess formation and fibrosis. RESULTS: Of 229 eligible patients, pathological changes associated with surgical difficulty were found in 17 (27 per cent) of 62 patients in the HSI group, 84 (85 per cent) of 99 patients in the ISI group, and 66 (97 per cent) of 68 patients in the LSI group (P < 0·001). For detecting these changes, intermediate to low signal intensity of the gallbladder wall had a sensitivity of 90 (95 per cent c.i. 84 to 94) per cent, specificity of 73 (60 to 83) per cent and accuracy of 85 (80 to 90) per cent. CONCLUSION: Preoperative MRI predicted pathological changes associated with surgical difficulty during laparoscopic cholecystectomy for acute cholecystitis.

ANTECEDENTES: La inflamación grave con necrosis y fibrosis de la vesícula biliar en la colecistitis aguda aumenta la dificultad quirúrgica durante la colecistectomía laparoscópica. Este estudio tuvo como objetivo evaluar el uso de la resonancia magnética preoperatoria (magnetic resonance imaging, MRI) para predecir los cambios patológicos de la vesícula biliar asociados con la dificultad quirúrgica. MÉTODOS: Los pacientes que se sometieron tanto a MRI preoperatoria como a colecistectomía precoz por colecistitis aguda entre 2012 y 2018 fueron identificados retrospectivamente. En base a la distribución en capas de la pared de la vesícula biliar en la MRI, los pacientes se clasificaron en tres grupos: (1) intensidad de señal alta (high signal intensity, HSI), (2) intensidad de señal intermedia (intermediate signal intensity, ISI) y (3) intensidad de señal baja (low signal intensity, LSI). El objetivo final fue la presencia de cambios patológicos en la vesícula biliar asociados con la dificultad quirúrgica, tales como necrosis, formación de abscesos y fibrosis. RESULTADOS: De los 229 pacientes elegibles, se documentaron cambios patológicos asociados con dificultad quirúrgica en 17 (27,4%) de 62 pacientes en el grupo HSI, 84 (84,8%) de 99 pacientes en el grupo ISI y 66 (97,1%) de 68 pacientes en el grupo LSI (P < 0,001). Para detectar estos cambios, la intensidad de señal de intermedia a baja de la pared de la vesícula biliar tuvo una sensibilidad del 89,8% (i.c. del 95% 84,2%-94,0%), una especificidad del 72.6% (i.c. del 95% 59,8%-83,1%) y una precisión del 85,2% (i.c. del 95% 79,9%-89,5%). CONCLUSIÓN: La MRI preoperatoria predijo los cambios patológicos asociados con la dificultad quirúrgica durante la colecistectomía laparoscópica por colecistitis aguda.

Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) has been applied to the treatment of superficial esophageal squamous cell carcinoma (SCC). The incidence and characteristics of metachronous multiple esophageal SCCs and Lugol-voiding lesions (LVLs) were investigated in a retrospective study in patients who had undergone EMR for superficial esophageal SCC. PATIENTS AND METHODS: 96 patients with esophageal SCC who had been treated by EMR were followed up by endoscopy for 12 months or longer. Clinicopathologic parameters such as tumor size and location and presence of LVLs were examined. RESULTS: 10 patients (10 %) had synchronous multiple SCCs, and 12 (13 %) developed metachronous multiple SCCs. The mean annual incidence of newly diagnosed tumor was 4.4 %. The incidence of a speckled pattern of LVLs was 20/74 (27 %) in patients with solitary SCC, 5/10 (50 %) in synchronous multiple SCC, and 10/12 (83 %) in metachronous multiple SCC. The incidence of the presence of speckled pattern of LVLs was significantly higher in patients with multiple SCCs than in those with solitary SCC (68 % vs. 27 %, P = 0.0004). CONCLUSIONS: Patients who have undergone EMR for esophageal SCC, especially those with metachronous multiple LVLs in the background mucosa, should undergo follow-up with close endoscopic observation using Lugol staining.

Randomized clinical trial of single skin sterilization with a povidone-iodine applicator versus conventional skin sterilization in abdominal surgery.

Background: The efficacy of widely used povidone-iodine applicators for skin sterilization in abdominal surgery is unclear. The aim of this trial was to evaluate whether sterilization with a povidone-iodine applicator was not inferior to a conventional sterilization method. Methods: Patients undergoing elective abdominal surgery were assigned randomly to receive single sterilization with the applicator or conventional sterilization. The primary endpoint was wound infection rate. Secondary endpoints were rate of organ/space surgical-site infection (SSI), adverse effects of povidone-iodine, amount of povidone-iodine used and total cost of sterilization. Results: Of 498 patients eligible for the study between April 2015 and September 2017, 240 were assigned and analysed in the applicator group and 246 in the conventional group. Wound infection was detected in 16 patients (6·7 per cent) in the applicator group and 16 (6·5 per cent) in the conventional group (absolute difference 0·0016 (90 per cent c.i. -0·037 to 0·040) per cent; P = 0·014 for non-inferiority). There was no difference between the groups in the organ/space SSI rate (11 patients (4·6 per cent) in the applicator group and 16 (6·5 per cent) in the conventional group. Both the amount of povidone-iodine used and the total cost of sterilization were higher in the conventional group than in the applicator group (median 76·7 versus 25 ml respectively, P < 0·001; median €7·0 versus €6·4, P < 0·001). Skin irritation was detected in three patients in the conventional group. Conclusion: In abdominal surgery, this povidone-iodine applicator was not inferior to conventional sterilization in terms of the wound infection rate, and it is cheaper. Registration number: UMIN000018231 (http://www.umin.ac.jp/ctr/).

Comparison between dexmedetomidine and midazolam as a sedation agent with local anesthesia in inguinal hernia repair: randomized controlled trial.

PURPOSE: In Japan, inguinal hernia repair is widely performed with local anesthesia. The objective of this study was to evaluate safety and efficacy of intravenous dexmedetomidine as a sedation agent with local anesthesia in inguinal hernia repair. METHODS: We performed this randomized, single-blind study for 200 patients who were scheduled to undergo inguinal hernia repair with local anesthesia. Patients were randomly divided into two groups (dexmedetomidine group: Group D, midazolam group: Group M). The primary outcome was to evaluate the safety of intravenous dexmedetomidine. Secondary outcomes were to analyze results of operators' surveys and patients' questionnaires and evaluate implementation of conscious sedation. RESULTS: Incidence of respiratory depression was significantly higher in Group M than Group D (p = 0.03). Other adverse events examined did not differ significantly. All three operators' questionnaires indicated that results were better in Group D than Group M. More than 70% of patients in both groups were satisfied with the surgery. More than 80% of Group D patients and 74% of Group M patients achieved a state of conscious sedation. CONCLUSION: This study demonstrated that intravenous dexmedetomidine during hernia repair with local anesthesia is safe and the results were satisfactory to both operators and patients.

Emergence of complex rearrangements at translocation breakpoints in a transgenic mouse; implications for mechanisms involved in the formation of chromosome rearrangements.

Cryptic complex rearrangements as a result of a reciprocal chromosome translocation have been characterised in a transgenic mouse strain. Analysis of the breakpoint junctions in our previous studies showed that the ada transgene was integrated at the breakpoint forming a fusion gene with Golga3 (Mea2). In this study, further detailed analysis around the translocation junctions revealed that the surrounding regions were composed of 13 fragments of defined transgenic chromosome origins over approximately 1.9-Mb areas. Exactly the same cluster structure of these 13 breakpoint fragments already existed in the second generation of the transgenic mice. Our results show that this highly complex rearrangement has been conserved as the incipient form without any additional changes for 18 years up to the present generation, suggesting simultaneous occurrence of multiple events in the founder mouse.

Helicobacter pylori-associated gastritis is related to babA2 expression without heterogeneity of the 3' region of the cagA genotype in gastric biopsy specimens.

BACKGROUND: Cytotoxin-associated gene A (cagA) is the major virulence factor of Helicobacter pylori strains and affects the clinical outcome of patients. Blood group antigen binding adhesin (BabA) helps the strains adhere to the epithelial cell layer and is the most important adhesin of H. pylori. OBJECTIVES: We tried to study the association between the status of babA2 and cagA in H. pylori strains and histological gastritis. methods: Thirty-six patients were included. RNA was extracted from two frozen biopsy samples of the antrum and corpus, respectively, and cagA/babA2 genotypes were analyzed with reverse transcription polymerase chain reaction and direct sequencing. Two gastric specimens of the antrum and corpus, respectively, were also stained with hematoxylin and eosin to analyze H. pylori-related gastritis. RESULTS: In the antrum, 56% of the specimens were babA2 positive and in the corpus 53%. The gastritis scores of activity and inflammation were associated with the presence of babA2 in antrum specimens but not in corpus specimens. cagA gene encoding in the CagA EPIYA-D region was detected in all samples, and the sequence was completely identical between those from the gastric corpus and antrum. CONCLUSION: babA2 expression is heterogeneous and correlated with the extent of gastritis in the antrum, but not in the corpus, whereas cagA shows a monotonous genotype.

Ultraviolet light induces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases.

The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30-40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UV-mediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.

Incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type I carriers in Saga, Japan.

Using a population-based cancer registry, we tabulated 69 definite adult T-cell leukemia/lymphoma cases (36 males and 33 females) and 2.20 expected cases (0.95 for males and 1.25 for females) diagnosed from 1981 to 1983 in Saga, Japan. The number of human T-lymphotropic virus type I carriers was computed by applying sex- and age-specific anti-human T-lymphotropic virus type I antibody positive rates among blood donors at the blood center in 1986 to the whole population of Saga Prefecture in 1982. The age-specific incidence rates among male human T-lymphotropic virus type I carriers from 40 to 79 yr of age per 100,000 were significantly higher than those of female carriers (P less than 0.05), and the rates from 60 to 69 yr of age were the highest in both sexes. The annual crude incidence rates among carriers were 115.9 for males and 66.4 for females. The summary incidence rates with 95% confidence intervals were 115.9 (58.4 to 193.0) for males and 65.9 (30.0 to 115.9) for females. The cumulative risks were 4.5% (0.8 to 11.0) for males and 2.6% (0.3 to 7.0) for females. These morbidity figures were assumed to be underestimated partly due to the newly proposed clinical entity of adult T-cell leukemia/lymphoma.

Two independent pathways mediated by cAMP and protein kinase A enhance spontaneous transmitter release at Drosophila neuromuscular junctions.

cAMP is thought to be involved in learning process and known to enhance transmitter release in various systems. Previously we reported that cAMP enhances spontaneous transmitter release in the absence of extracellular Ca(2+) and that the synaptic vesicle protein neuronal-synaptobrevin (n-syb), is required in this enhancement (n-syb-dependent; Yoshihara et al., 1999). In the present study, we examined the cAMP-induced enhancement of transmitter release in the presence of external Ca(2+). We raised the intracellular concentration of cAMP by application of either forskolin, an activator of adenylyl cyclase, or by 4-chlorophenylthio-(CPT)-cAMP, a membrane-permeable analog of cAMP, in the presence of external Ca(2+), while recording miniature synaptic currents (mSCs) at the neuromuscular junction in n-syb null mutant embryos. The frequency of mSCs increased in response to elevation of cAMP, and this effect of cAMP was completely blocked by Co(2+) (n-syb-independent pathway). In contrast, in wild-type embryos the cAMP-induced mSC frequency increase was partially blocked by Co(2+). In a mutant, DC0, defective in protein kinase A (PKA), nerve-evoked synaptic currents were indistinguishable from the control, but mSCs were less frequent. In this mutant the enhancement by cAMP of both nerve-evoked and spontaneous transmitter release was completely absent, even in the presence of external Ca(2+). Taken together, these results suggest that cAMP enhances spontaneous transmitter release by increasing Ca(2+) influx (n-syb-independent) as well as by modulating the release mechanism without Ca(2+) influx (n-syb-dependent) in wild-type embryos, and these two effects are mediated by PKA encoded by the DC0 gene.

Morphological changes in human gastric tumours after eradication therapy of Helicobacter pylori in a short-term follow-up.

BACKGROUND: It is controversial as to whether the development of gastric cancer is influenced by Helicobacter pylori eradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate. AIM: To investigate the morphological changes in the gastric neoplasm after H. pylori eradication. METHODS: We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication. RESULTS: Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels. CONCLUSIONS: The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate.

Enhanced expression of inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients.

Recent studies (K. Komoto et al., Am. J. Gastroenterol., 93: 1271-1276, 1998) have shown that Helicobacter pylori infection is associated with gastric cancer. However, the mechanism of H. pylori in carcinogenesis has not been clarified. H. pylori infection leads to a sustained production of reactive nitrogen species that may contribute to cause DNA damage. In this study, we examined the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine in gastric mucosa. The expression of iNOS and nitrotyrosine was examined by immunohistochemistry in 93 patients who initially underwent gastric biopsies between 1975 and 1992. Thirty-four individuals were later found to have gastric cancer at least 2 years after the initial biopsies (group A). The other 59 subjects have shown no evidence of gastric cancer during long-term follow-up. Fifty-one of these patients were positive for H. pylori (group B), and eight were negative for H. pylori (group C). The expression of iNOS and nitrotyrosine in the gastric mucosa was significantly higher in H. pylori-positive groups A and B than in H. pylori-negative group C. Among the H. pylori-positive patients, the expression of iNOS and nitrotyrosine was significantly higher in group A than in group B. These results suggest that high production of iNOS and nitrotyrosine in the gastric mucosa infected with H. pylori may contribute to the carcinogenesis of gastric cancer.

Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation.

The catalytic activities of Ret tyrosine kinases as the products of oncogene RET with multiple endocrine neoplasia type 2A (Ret-MEN2A) or 2B (Ret-MEN2B) mutations and the hybrid gene from c-RET and RFP (Rfp-Ret) were higher than those of c-Ret. We demonstrated that ultraviolet light (UV) irradiation induced activation of c-Ret and superactivation of genetically mutated, and thereby constitutively activated, Ret-MEN2A, Ret-MEN2B, and Rfp-Ret. We found that small proportions of c-Ret and Ret-MEN2B and a large proportion of MEN2A were dimerized due to disulfide bonds and that high kinase activity resided in these fractions. The UV-induced activation of c-Ret and superactivation of Ret-MEN2A and Ret-MEN2B were then shown to be closely associated with promotion of the disulfide bond-mediated dimerization of the Ret proteins. Furthermore, we showed that a large proportion of Rfp-Ret was dimerized or polymerized and that almost all kinase activities resided in the highly polymerized but not dimerized fraction. The UV-induced superactivation of Rfp-Ret was also found to be closely associated with promotion of polymerization but not with dimerization of Rfp-Ret. Further experiments revealed that UV induced intracellular dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Most importantly, the levels of basal kinase activity and dimerization of Ret-TPC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-TPC-1 was replaced with alanine, were low and were not increased by UV irradiation. These results suggest that the cysteine at this position works as the primary target of dimerization of Ret proteins inside the cell for both the maintenance of the basal kinase activity and its promotion by UV, possibly in co-operation with the cysteine(s) in the extracellular domain of Ret-MEN2A and Rfp-Ret, which is the target of dimerization and polymerization outside the cell. The potential biological significance of the UV-mediated superactivation of mutant Ret through the newly proposed mechanism in oncogenesis is discussed.

Cathepsin D expression as a possible predictor of lymph node metastasis in submucosal colorectal cancer.

The aim of this study was to clarify the usefulness of cathepsin D expression as a predictor of lymph node metastasis in submucosal colorectal cancer (CRC). Cathepsin D expression was examined immunohistochemically in cancer and stromal cells located at the deepest portion of 254 invasive tumours that had been resected from patients with submucosal CRC. In cancer cells, the expression was classified according to differences in intracellular localisation: polarity positive, apical type (PA); polarity positive, basal type (PB); polarity negative (PN); or no expression (NE). Lesions with PN or NE expression showed a significantly higher incidence of lymph node metastasis than those with PA or PB expression. Alternatively, lesions with positive expression in stromal cells showed a significantly higher incidence of lymph node metastasis than that of those with negative expression. None of the lesions with PA or PB expression and negative expression in stromal cells had metastasised to the lymph node. In conclusion, analysis combining cathepsin D expression in cancer and stromal cells may be a quite useful predictor for lymph node metastasis and may broaden the indications for curative endoscopic treatment of submucosal CRC.

Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa.

We examined the relationship between vascular endothelial growth factor (VEGF)-C expression and lymph node metastases in gastric carcinomas invading the submucosa. Of the six human gastric carcinoma cell lines, two constitutively expressed VEGF-C mRNA. In three of 12 gastric biopsy specimens (25%), VEGF-C mRNA was detected in tumour tissues, but not in corresponding normal mucosa by reverse transcriptase-polymerase chain reaction (RT-PCR). Of the 139 resected gastric carcinomas, 44 (32%) showed intense cytoplasmic VEGF-C immunoreactivity in many cancer cells at the invading edge. VEGF-C immunoreactivity was associated with greater depth of tumour invasion, lymphatic invasion and lymph node metastases. In addition, vessel count was also significantly higher in the VEGF-C immunoreactive tumours than in other tumours. These results suggest that VEGF-C may be involved in the progression of human gastric carcinoma, particularly via lymphangiogenesis. VEGF-C expression at the invading edge of a gastric carcinoma may be a sensitive marker for metastasis to the lymph nodes.

Interleukin 8 and vascular endothelial growth factor -- prognostic factors in human gastric carcinomas?

Gastric carcinoma cells express potent angiogenic factors including vascular endothelial growth factor (VEGF). We previously reported that interleukin-8 (IL-8) acts as an angiogenic factor for human gastric carcinomas. More recently, we found that IL-8 upregulates matrix metalloproteinase-9 (MMP-9) expression and increases invasive activity of gastric carcinoma cells. The purpose of this study was to determine whether the expression of IL-8 and VEGF correlates with clinicopathological parameters in human gastric carcinomas. IL-8 and VEGF expression levels were measured by an enzyme-linked immunosorbent assay (ELISA) in 56 gastric carcinomas and the surrounding normal mucosa. Macroscopic and histopathological tumour findings, presence of metastasis and prognosis were obtained from the patient records and endoscopic, surgical and pathological reports. IL-8 protein levels were higher in most neoplasms than in the corresponding normal mucosal tissue. In contrast, VEGF expression in the tumours was similar to that in normal mucosa. The IL-8 level in the neoplasms correlated significantly with the depth of invasion, venous invasion and lymphatic invasion. VEGF expression in the tumours correlated well with the depth of invasion and lymph node metastasis. No correlation between IL-8 and VEGF expression in the tumours was observed. The survival rates of patients with tumours displaying high IL-8 and VEGF expression levels were significantly lower (P<0.05) than those of patients with tumours displaying low IL-8 and VEGF expression. The results suggest that IL-8 and VEGF may be independent and important prognostic factors in human gastric carcinomas.

Pit pattern diagnosis of early colorectal carcinoma by magnifying colonoscopy: clinical and histological implications.

The relation between subclassification of V type pit pattern and histopathologic features, particularly, in regards to the invasion depth, was examined in 75 cases of early colorectal carcinoma. After we classified two grades (VA, VN) of V type pit pattern, we subclassified VN type pit pattern into three subtypes (Grade A, B, and C) according to the degree of appearance of VN pit pattern. V type pit pattern subclassification was diagnosed with use of a magnifying colonoscope. There were 37 VA type lesions, 8 VN.Grade A type, 16 VN.Grade B type, and 14 VN.Grade C type lesions. The incidence of submucosal massive invasion (sm2, sm3) rates was 5 (14%) of the 37 VA type lesions, 3 (38%) of the 8 VN.Grade A type, 15 (94%) of the 16 VN.Grade B type and 14 (100%) of the 14 VN.Grade C type lesions, respectively. The incidence of desmoplastic reaction (++) levels in VN.Grade B and C type lesions was significantly higher than that in VA type lesions (P<0.01), and that in VN.Grade C type lesions was significantly higher than that in VN.Grade A type lesions (P<0.05). The incidence of pit disorder or destruction (+) and (++) levels in VN.Grade B and C type lesions was significantly higher than that in VA type lesions (P<0.01), and that in VN.Grade C type lesions was significantly higher than that in VN.Grade A type lesions (P<0.01). The incidence of high grade carcinoma in VN.Grade B and C type lesions was significantly higher than that in VA type lesions (P<0.01), and that in VN.Grade C type lesions was significantly higher than that in VN.Grade A type lesions (P<0.05). These findings indicate that V type pit pattern subclassification, including our new subtype, is useful for predicting the detail invasion depth of early colorectal carcinoma. These V pit pattern subtypes are based on the degrees of desmoplastic reaction, pit disorder or destruction, and histologic grade of carcinoma.

Combined expression of urokinase-type plasminogen activator and proliferating cell nuclear antigen at the deepest invasive portion correlates with colorectal cancer prognosis.

To examine the relationship among the expression of urokinase-type plasminogen activator (u-PA), invasive/metastatic potential and prognosis of colorectal cancer (CRC), 58 patients with surgically resected advanced CRC were studied. u-PA expression and proliferating cell nuclear antigen labeling index (PCNA-LI) at the deepest invasive portion were examined immunohistochemically. u-PA expression was detected in 37 (63.8%) of 58 lesions. Lesions with liver metastasis showed a significantly (p < 0.01) higher incidence of u-PA expression than those without liver metastasis. Dukes staging also revealed a significant correlation with u-PA expression. The combination of u-PA expression and elevated PCNA-LI at the deepest invasive portion correlated significantly with prognosis. These results indicate that u-PA expression is an important predictor of CRC development and liver metastasis. Furthermore, combined analysis of u-PA expression and PCNA-LI at the deepest invasive portion is very useful in predicting CRC prognosis.

Single carcinoma cells at the deepest invasive portion correlate with metastatic potential of advanced colorectal carcinoma.

The clinical significance of detecting single carcinoma cells (SC) at the deepest invasive portion of a tumor in terms of metastatic potential and prognosis was examined in 57 patients with surgically resected advanced colorectal carcinoma. SC were detected using an immunohistochemical stain for cytokeratin in these sections. The deepest invasive portions of tumors were subclassified by histology into three grades as follows: well-differentiated (W), moderately-well differentiated (Mw; a type that more closely resembles the W tumor), and moderately-poorly differentiated (Mp; more closely resembling poorly differentiated tumor). SC detection was defined positive if more than three single cancer cells with clear cytoplasmic expression of cytokeratin was seen distinct from carcinoma glands and tumor sheets in mid-power (x100) field. SC were detected in 51 (89%) of the 57 carcinomas. There were 5 W or Mw (W/Mw) tumors without SC, 34 W/Mw tumors with SC, 1 Mp tumor without SC, and 17 Mp tumors with SC. W/Mw tumors with SC had a significantly higher (p<0.01) incidence of lymph node metastasis than W/Mw tumors without SC. There was no lesion with lymph node or liver metastasis of W/Mw tumors without SC. SC detection, when combined with histologic subclassification at the deepest invasive portion of a tumor, correlated with prognosis. These results indicate that a combination of the tumor histologic subclassification and SC detection at the deepest invasive portion is a useful predictor of metastatic potential and prognosis in advanced colorectal carcinoma.

MUC1 and cathepsin D expression in early colorectal carcinoma showing V type pit pattern.

The relation between MUC1, cathepsin D expression, and histologic features in early colorectal carcinomas (CRCs) with V type pit pattern was examined in 78 patients. We classified V type pit pattern into two grades (VA, VN) and we subclassified the VN type pit pattern into three subtypes (Grade A, B, and C) according to the degree of appearance of VN type pit pattern. At the tumor surface, the status of desmoplastic reaction and pit disorder or destruction were subclassified histologically into three grades (-, +, ++). MUC1 and cathepsin D expression were examined immunohistochemically at a superficial level and at the deepest part of the tumor invasion. MUC1 expression showed a significant correlation with high grade carcinoma, desmoplastic reaction (+) levels in VA type pit pattern (P<0.05), and high grade carcinoma, sm2 and sm3 lesions, desmoplastic reaction (+) and (++) levels, pit disorder or destruction (+) and (++) levels in VN type pit pattern (P<0.05). Cathepsin D expression had a significant correlation with m and sm1 lesions and desmoplastic reaction (-) levels in VN type pit pattern (P<0.05). In VA type pit pattern, a significant correlation between cathepsin D expression and histologic findings was absent. The incidence of MUC1 expression in VN.Grade B and C type pit pattern was significantly higher than that in VA and VN.Grade A type pit pattern (P<0.05). The incidence of cathepsin D expression in VA, VN.Grade A and B type pit pattern was significantly higher than that in VN.Grade C type pit pattern (P<0.05). MUC1 expression (+) or (++) levels at the deepest part of a tumor was identical to that (+) or (++) levels at the superficial part except for one case. Cathepsin D expression at the deepest part of a tumor differed from that at the superficial part. Desmoplastic reaction may be related to MUC1 and cathepsin D expression; however, pit disorder or destruction may be related to only MUC1 expression in V type pit pattern. MUC1 expression at the superficial part of a tumor may be related to expression at the deepest part; however, cathepsin D expression at the superficial part may not be related to expression at the deepest part in submucosal CRCs with V type lesions.