Numerical aberration of chromosome 17 is correlated with multiple primary cancer in colorectal carcinoma

In order to test the hypothesis that attention deficit hyperactivity disorder (ADHD) is related to deficits in somatosensory processing, 49 ADHD male children and 49 matched controls were tested on a wide range of tactile tasks, and somatosensory evoked potentials (SEP) were also recorded. In addition, parents' and teachers' ratings on the children's typical responses to tactile stimuli were obtained. The results show that the ADHD children were less skilled on suprathreshold, but not on threshold tasks than were the controls. Further, a larger percentage of ADHD children were 'tactile defensive'. Finally, the ADHD children showed larger-than-normal amplitudes of late, but not early components of the SEP. These data suggest that some aspects of somatosensory processing by ADHD children are deficient.     

Allelic imbalance at NME1 in microdissected primary and metastatic human colorectal carcinomas is frequent but not associated with metastasis to lymph nodes or liver

Allelic imbalance at the NME locus on chromosome 17q21 was analyzed in colorectal cancer patients using a highly polymorphic microsatellite repeat sequence within NME1 itself. Duplicate samples of carcinoma and adjacent normal tissue was obtained by microdissection from 6 to 7-microns paraffin sections of 94 primary carcinomas (treatment years 1979-1993) and available lymph node and liver secondaries. In 55 patients informative (heterozygous) at this locus, allelic imbalance was examined in primary and secondary carcinomas. Microsatellite instability prevented assessment of allelic balance in two cases, and there was no evidence of homozygous loss at NME1 in any case analyzed. Allelic imbalance at the NME locus in carcinomas was frequent (27/53; 51%), and concordant results were obtained between primary carcinoma and secondary deposits in 30 of 33 (91%) cases. Three discordant cases showed allelic imbalance in secondary deposits but not the primary lesion. Although frequent, allelic imbalance at NME1 had no relationship to Dukes' stage at presentation or with subsequent hepatic metastasis, nor with the primary carcinoma site (proximal versus distal), tumor size, or mitotic or apoptotic index. Moreover, neither disease-free nor overall survival differed between patients with carcinomas showing NME1 allelic imbalance and patients with carcinomas that did not. Our results show that although allelic imbalance is frequent at the NME locus in primary and secondary colorectal carcinomas, there is no evidence to link this with clinical or pathological features or with metastatic potential. Microsatellite PCR and microdissection of enriched populations of carcinoma cells allowed uniformly successful analysis of samples from archival formalin-fixed paraffin-embedded tissue up to 15 years old and clear assessment of allelic imbalance in tumor specimens. Target sequences (e.g., microsatellites and minisatellites) up to approximately 200-250 bp may be reliably analyzed for allelic balance, suggesting that this method is of general utility in the genetic analysis of primary and metastatic neoplasia.     

Comparison of the pattern of integrin expression between primary tumors and liver metastasis of gastric and colorectal cancers

To investigate the interrelationship between integrin VLA3 overexpression and liver metastasis, immunohistochemical studies of VLA3 were made in 73 cases of gastric cancer (66 cases without liver metastasis, 7 cases with liver metastasis) and 15 cases of colorectal cancer (3 cases without liver metastasis, 12 cases with liver metastasis). The rate of integrin VLA3 expression in 69 primary gastric and colorectal cancers without liver metastasis was 41%, that was higher than that (0%) in the 19 primary tumors of gastric and colorectal cancers with liver metastasis. In contrast, the positive rate for integrin VLA3 staining in 19 cases involving liver metastasis of gastric and colorectal cancers was 58% (11/19), which was higher than that (0%) in primary tumors. These findings suggest that VLA3 may play an important role in the process of liver metastasis of gastric and colorectal cancers.     

淋巴管生成因子的定量表达与大肠癌转移研究

.Objective:The purpose of this paper was to study the expression levels of newly described lymphatic endothelial markers – LYVE-1,Prox-1,podoplanin and 5'-nucleotidase,and their correlation with metastasis of human colorectal cancers.Methods:Tumor and corresponding tumor-side normal tissue samples were obtained from resected specimens immediately after operation.Expression level of each factor was determined by quantitative real-time PCR (RT-PCR) and Western blot technique.Results:Expression levels of lymphatic endothelial markers LYVE-1,Prox-1,podoplanin and 5'-nucleotidase were significantly different in tumor and tumor-side normal groups.Expression levels of Prox-1 and podoplanin were higher in patients with positive lymph node metastasis than those without metastasis.LYVE-1,but not 5'-nucleotidase expression level was higher in both cancer and normal groups.Conclusion:These results indicate that combined quantitative analysis of lymphangiogenic markers LYVE-1,Prox-1 and podoplanin in colorectal cancer specimens may be useful in predicting metas-tasis of colorectal cancer to regional lymph nodes.However,the role of 5'-nucleotidase in predicting metastasis of colorectal cancer still remains to be further analyzed.     

Liver metastasis rare in colorectal cancer patients with fatty liver

BACKGROUND/AIMS: As no reports in terms of the relationship between fatty liver and liver metastasis of colorectal cancer clinicopathological analysis of colorectal cancer patients with fatty were found a liver was carried out. PATIENTS AND METHODS: Among 839 patients with single colorectal carcinoma who underwent operations at our department between 1985 and 1994, 121 patients were designated as fatty liver using ultrasonography (FL group). The remaining 718 non-fatty liver patients with colorectal cancer (NFL group) were compared to the FL group regarding clinicopathological aspects. RESULTS: (1) There were only two patients who had liver metastasis in the FL group (1.7%), while the NFL group included 115 patients with liver metastasis (16.0%) (p < 0.01). (2) The five-year survival rate of the FL group was 95.7%, which was significantly higher than that in the NFL group (9.8%) (p < 0.001). (3) In the multivariate analysis, the fatty liver was identified as an independent prognostic factor. CONCLUSIONS: The FL group had a much better prognosis compared to the NFL group. Especially, liver metastasis was extremely rare in the FL group. We believe that these results will lead to the clarification of the liver metastasis mechanism.     

Significance of angiogenic factors in liver metastatic tumors originating from colorectal cancers

We examined the expression of vascular endothelial growth factor (VEGF) and microvessel counts expressed by CD34 staining in 39 patients with primary and 44 patients with metastatic liver tumors of metastatic colorectal carcinoma, and 29 patients with nonmetastatic colorectal carcinoma as control in order to determine their value in the evaluation of prognosis and recurrence after hepatectomy. Microvessel counts in primary colorectal carcinomas of the metastatic group were significantly higher than those in control (P<0.05). Neither factor correlated with any clinicopathological feature of primary or metastatic liver carcinomas. Higher microvessel counts in metastatic liver tumors tended to be associated with a shorter disease-free interval to second recurrence in the remaining liver (P = 0.069) and were significantly associated with poor prognosis after hepatectomy (P<0.05). We conclude that microvessel count is an important marker of liver metastasis and prognosis in patients with colorectal carcinoma treated with hepatectomy.     

Significance of p53 and VEGF expression in liver metastasis from colorectal cancer

BACKGROUND: Children with large anterior mediastinal masses frequently present with severe respiratory compromise and often pose a difficult diagnostic dilemma. A biopsy is preferred for diagnosis before treatment can begin; however, many of these children are at risk of acute clinical deterioration and cardiovascular arrest with the induction of anesthesia. The authors noted a correlation between pleural effusions and lymphoblastic lymphoma and recently diagnosed three cases of lymphoblastic lymphoma in children with a large anterior mediastinal mass and pleural effusion through cytological and flow cytometric examination of the pleural fluid. METHODS: To focus on this problem, 101 pediatric patients presenting with an anterior mediastinal mass between January 1980 and September 1994 were reviewed to determine if pleural effusions occur more frequently at initial presentation with lymphoblastic lymphoma than with Hodgkin's disease, thus offering a means of diagnosis in children with severe respiratory compromise. The patients' chest radiographs and/or computed tomograms for the 88 cases in which they were available were reviewed retrospectively in a blinded fashion to identify those children with pleural effusions at the time of presentation. RESULTS: In this study, 71% of patients with lymphoblastic lymphoma (10 of 14) had a pleural effusion at presentation, whereas only 11.7% of patients with Hodgkin's disease (7 of 60) had a pleural effusion on initial presentation. (P < .002 Fisher's Exact test). CONCLUSION: This retrospective review suggests that there is a significantly greater association of pleural effusions in patients with lymphoblastic lymphoma than with Hodgkin's disease. Our experience supports the conclusion that thoracentesis may provide a means of diagnosis in children presenting in severe respiratory compromise obviating the need for anesthesia and open biopsy.     

A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers

Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.     

Reduction of radiation-induced chromosome aberration and apoptosis by dithiothreitol

We have examined in vitro and in vivo radioprotective effects of a well-known thiol-containing compound, dithiothreitol (DTT). The treatment of both 0.5 and 1 mM of DTT significantly increased clonogenic survival of gamma-ray irradiated Chinese hamster (V79-4) cells. In order to investigate the possible radioprotective mechanism of DTT, we measured gamma-ray induced chromosome aberration by micronucleus assay. In the presence of 0.5 mM or 1 mM DTT, the frequencies of micronuclei were greatly reduced in all dose range examined (1.5-8 Gy). Slightly higher reduction in micronucleus formation was observed in 1 mM DTT-treated cells than in 0.5 mM DTT-treated cells. In addition, incubation with both 0.5 and 1 mM of DTT prior to gamma-ray irradiation reduced nucleosomal DNA fragmentation at about same extent, this result suggests that treatment of DTT at concentrations of 0.5 and 1 mM reduced radiation-induced apoptosis. In vivo experiments, we also observed that DTT treatment reduced the incidence of apoptotic cells in mouse small intestine crypts. In irradiated control group 4.4 +/- 0.5 apoptotic cells per crypt were observed. In DTT-administered and irradiated mice, only 2.1 +/- 0.4 apoptotic cells per crypt was observed. In vitro and in vivo data obtained in this study showed that DTT reduced radiation-induced damages and it seems that the possible radioprotective mechanisms of action of DTT are prevention of chromosome aberration.     

Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer

DNA amplification at 20q13.2 is common in breast cancer, correlates with poor prognosis, and may reflect location of an important oncogene. Recently, other regions along 20q were also found to undergo amplification. Here, amplification levels and patterns of co-amplification were analyzed by interphase fluorescence in situ hybridization at 14 loci along 20q in 146 uncultured breast carcinomas and 14 cell lines. Three regions were independently amplified in uncultured tumors: RMC20C001 region at 20q13.2 (highly amplified in 9.6% of the cases), PTPN1 region 3 Mb proximal (6.2%), and AIB3 region at 20q11 (6.2%). Co-amplifications involving two or three of these regions were seen in 11 of the 19 highly amplified tumors. The results suggest that three distinct nonsyntenic regions along 20q may be important and that complex chromosomal rearrangements underlie their frequent co-amplification in breast cancer.     

Chemotherapy of colorectal cancers with metastases

The chemotherapy of metastatic colorectal cancer has demonstrated a symptomatic benefit and a prolongation in survival. The modulation of 5-fluorouracil (5-FU) by leucovorin is the current standard treatment. The best protocols include 5-FU 24 or 48 hour continuous infusion on a weekly or bimonthly schedule. The response rate is about 30%, the median progression-free survival is 6 to 8 months and the median survival 10 to 15 months. The toxicity is moderate. New drugs are available or under evaluation: 5-FU prodrugs, raltitrexed, CPT11, oxaliplatin, trimetrexate. Synergisms with 5-FU allow to consider more effective polychemotherapies.     

The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type

Primary extranodal malignant non-Hodgkin's lymphoma arising from the mucosa-associated lymphoid tissue (MALT-type lymphoma) represents a subtype of B-cell lymphoid malignancies with distinct clinicopathological features and is often associated with a favorable prognosis. Unlike the situation in nodal non-Hodgkin's lymphoma of B-cell lineage, few data are still available concerning the chromosomal constitution of MALT-type lymphomas. Until now, cytogenetic data from 29 low-grade MALT lymphomas with karyotypic alterations have been reported from different institutions, and virtually no data were available for high-grade MALT-type lymphomas. We have analyzed the cytogenetics of 44 MALT lymphomas arising in the stomach, parotid gland, thyroid gland, lung, breast, and conjunctiva. Clonal chromosome aberrations have been detected in 13 of 20 (65%) low-grade and 20 of 24 (83%) high-grade tumors. More than half of the low-grade lymphomas with abnormal karyotypes (7 of 13 cases, 53%) displayed clonal t(11;18)(q21;q21), thus specifically associating this translocation with MALT-type lymphomas for the first time in a larger series. In contrast, t(11;18) was not found in a single case of 20 high-grade MALT-type lymphomas with abnormal karyotypes, nor were translocations t(14;18) or t(3;14), characterizing about 10-35% of primary nodal large cell lymphomas. Instead, these lymphomas were associated with t(8;14)(q24;q32) in three cases, frequent deletions in the long arm of chromosome 6, and partial or whole gains of chromosomes 3, 7, 17, 18, and 21.     

Clinical implications of microsatellite instability in colorectal cancers

BACKGROUND: Microsatellite instability (MI) has been reported in some sporadic colon tumors and in cases of hereditary nonpolyposis colorectal cancer (HNPCC). The criteria for HNPCC have not been fully defined, and clinical criteria are used to identify as many HNPCC patients as possible. To clarify the conformity of these criteria with the identification of eligible HNPCC cases, we analyzed MI in HNPCC patients diagnosed using clinical criteria. METHODS: Genomic DNA was extracted from surgical specimens of 56 colorectal cancers, including 36 from patients diagnosed with HNPCC using the clinical criteria. We analyzed four microsatellite loci using 32P-labeled primers. RESULTS: Among HNPCC patients diagnosed using clinical criteria, patients who were positive for MI accounted for 62% of Group A (a confirmed group) and 35% of Group B (a high risk group); only 5% of randomly selected colorectal cancer patients (Group C), were positive for MI. Furthermore, MI-positive tumors were found in patients who had a tendency for tumors to involve the right side of the colon, an association with cancers in other organs, a lower incidence of p53 protein positivity, and a higher proportion of poorly differentiated cancers. CONCLUSIONS: The presence of MI, in concert with modified clinical criteria, may identify legitimate cases of HNPCC in patients who might otherwise be excluded by the minimum criteria.     

Intra-arterial preventive chemotherapy for residual liver after resection of hepatic metastasis from colorectal cancer

We treated 18 cases with intra-hepatic arterial infusion chemotherapy after resection of hepatic metastasis from colorectal cancer (June 1991-September 1997). Eight cases were H1, 7 were H2, and 3 were H3. Hepatic lobectomy was done in 3 cases, lobectomy + partial resection in 2 cases, and partial resection in 13 cases. All cases received high-dose intermittent 5-FU infusion (WHF = 5-FU 1,000 mg/m2/5 hrs/w) on an outpatient basis. The total frequency of WHF was 4-54 times (average 29), and total 5-FU doses ranged from 6.0 to 81.0 g (average 40 g). The 1- and 5-year cumulative survival rates were 100% and 77.5% in all patients 100% and 87.5% in H1 group and 100% and 64.3% in H2 + H3 group, respectively. There was no significant difference of survival between the H1 and H1 + H3 groups. The 1- and 5-year recurrence rates in residual liver were 5.9% and 14.4%, respectively. One of 2 cases with residual liver recurrence was resected for metastasis again, and the patient is now in a disease-free state. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect for their survival, not only in H1 group but also in H2 + H3 group.     

Metachronous liver metastasis of colorectal cancer: timing of occurrence and efficacy of adjuvant portal chemotherapy

We estimated the time of occurrence of metachronous liver metastasis in colorectal cancer patients from tumor diameter and doubling time. Micro-metastasis was present prior to operation in most patients and a few metastatic cases could have been initiated by the surgical procedure. Portal chemotherapy is more effective against liver metastasis than intravenous infusion because a higher drug concentration in the liver can be obtained. This efficacy of portal chemotherapy on survival was also observed in a rat model. Thus perioperative adjuvant treatment should be undertaken for metastasis which already existed before the operation and adjuvant chemotherapy via portal vein is the treatment of choice. The no touch isolation technique is also needed to avoid spreading of tumor cells during surgery.     

Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers

The systemic administration of thyrotropin-releasing hormone (TRH) to rats elicits locomotor activation, wet dog shakes, jaw movements, paw licking and tail rattle. Central dopamine (DA) and 5-hydroxytryptamine (5-HT) systems and peripheral vagal afferents have been implicated in these responses. To define this circuitry further, the effects of lesions of these pathways on the behavioral responses elicited by intraperitoneal (IP) injections of TRH were assessed in rats. Lesions of the DAergic innervation of the nucleus accumbens did not affect the locomotor activation, wet dog shakes, paw licking, jaw movements or tail rattle elicited by TRH. This is consistent with our in vivo microdialysis finding that TRH did not affect the release of DA in the nucleus accumbens at a dose that strongly increased locomotor activity. Depletion of spinal 5-HT significantly decreased the wet dog shakes induced by TRH, while depletion of forebrain 5-HT had no effect on any behavior. Bilateral vagotomy did not affect the locomotor response to TRH or any of the other behaviors measured. Taken together these results suggest that the DAergic mesolimbic, the 5-HTergic projections to the forebrain and vagal afferent systems are not mediators of the behavioral responses to systemic TRH. In contrast, the raphe-spinal 5-HTergic projection system may serve to modulate the wet dog shakes elicited by this peptide.     

Significant correlation of telomerase activity in lung adenocarcinomas with cell differentiation and chromosome aberration

OBJECTIVE: To assess the long-term safety of adjunctive corticosteroids in the treatment of Pneumocystis carinii pneumonia (PCP). DESIGN: Analysis of data from a large prospective observational database. SETTING: HIV clinic at a large urban teaching hospital. PATIENTS: One hundred seventy-four patients who developed PCP after being enrolled in the database. RESULTS: Fifty-three patients (30%) received adjunctive corticosteroids and 121 (70%) did not. Survival did not differ between groups after adjusting for CD4 count (relative risk for adjunctive corticosteroids = 0.74, p = 0.13). There were no differences in the incidence of cytomegalovirus disease (adjunctive corticosteroids: 18.5 cases per 100 person-years vs no adjunctive corticosteroids: 15.7, p = 0.22), Mycobacterium avium complex (23.4 vs 27.0, p = 0.73), cryptococcal meningitis (1.8 vs 4.1, p = 0.58), toxoplasmosis (3.6 vs 11.0, p = 0.28), Kaposi's sarcoma (1.8 vs 2.2, p = 0.92), herpes simplex (27.1 vs 42.7, p = 0.66), herpes zoster (3.8 vs 6.9, p = 0.71), oropharyngeal candidiasis (18.9 vs 10.9, p = 0.09), or non-Hodgkin's lymphoma (3.5 vs 4.2, p = 0.92). Esophageal candidiasis was more common among adjunctive corticosteroid recipients (45.1 vs 26.6, p = 0.01). Results were similar for time to development of opportunistic conditions. CONCLUSIONS: Adjunctive corticosteroids do not increase mortality or the risk of most common HIV-associated complications.     

SOX20, a new member of the SOX gene family, is located on chromosome 17p13

SOX genes share a high sequence identity with the HMG box present in the testis determining gene SRY. We have identified a HMG box-like sequence motif on six contiguous cosmids, which cross-hybridize to a SOX9 cDNA probe. A data base search revealed a high similarity of the deduced amino acid sequence to the human SOX12 and the murine Sox16 HMG domains. The cosmids were assigned to chromosome 17p13 by FISH analysis.     

Bone metastasis from colorectal cancer in autopsy cases

The incidence of bone metastasis from colorectal cancer is reported to be 10.7% in autopsy cases. However, the characteristics of the primary cancers, as well as the patterns of bone metastasis, remain unclear. We analyzed the clinical and autopsy records of 118 patients with primary colorectal cancer treated either surgically or conservatively and eventually autopsied between 1970 and 1987 at Toranomon Hospital in Tokyo. Bone metastasis was detected in 23.7% (28/118). The average age of patients with bone metastasis was lower than that in patients without bone metastasis (P < 0.02). Cancers to the rectum and cecum were accompanied by bone metastasis more frequently than cancers of other portions of the colon. Signet-ring cell carcinoma showed a high incidence of bone metastasis (P = 0.041). Bone metastasis from colorectal cancer was associated with liver or lung metastases (P < 0.0001). These results indicated that bone metastasis from colorectal cancer is not as infrequent as previously described.