Home About us Contact
|
Home About us Contact | ||
|
|
||
Tumors.
Kinds of Tumors. Selected AbstractsEndoscopic mucosal resection of colorectal tumorsDIGESTIVE ENDOSCOPY, Issue 1 2004Yuji Inoue It has been possible to resect early colorectal cancer by endoscopy due to the progress of colonoscopic diagnosis and technology. Therefore, most cases of colorectal mucosal cancer and benign tumor have been resected by endoscopy only. We report some techniques for endoscopic resection of colorectal tumors. The technique of endoscopic resection: (i) The B-Wave bipolar snare device: It is difficult to resect flat lesions that are not sufficiently elevated to be ligated by a usual snare. The snare of the B-Wave bipolar snare device is coated to prevent slipping on the colorectal mucosa. (ii) ,Sculpting down' polypectomy: It is difficult to resect large sessile lesions because the bases of these lesions cannot be well observed endoscopically. ,Sculpting down' polypectomy is a useful method for safe resection of such tumors. (iii) Endoscopic resection through a retroflexed scope: Under retroverted colonoscopic observation, submucosal injection and partial resection is performed. Then, under ordinary observation, complete resection of the residual tumor is performed. (iv) Endoscopic mucosal resection using a cap-fitted panendoscope (EMRC): EMRC is useful for lesions located in the lower rectum because there is no risk of free perforation. At first, submucosal injection is performed. The snare is set in the transparent cap and the lesion is aspirated into the cap. Then, it is snared and resected. [source] Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: An approach to identify candidate genes involved in tumor developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2009Edoardo Missiaglia Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3 - and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors. © 2009 Wiley-Liss, Inc. [source] Papillary and muscle invasive bladder tumors with distinct genomic stability profiles have different DNA repair fidelity and KU DNA-binding activitiesGENES, CHROMOSOMES AND CANCER, Issue 4 2009Johanne Bentley Low-grade noninvasive papillary bladder tumors are genetically stable whereas muscle invasive bladder tumors display high levels of chromosomal aberrations. As cells deficient for nonhomologous end-joining (NHEJ) pathway components display increased genomic instability, we sought to determine the NHEJ repair characteristics of bladder tumors and correlate this with tumor stage and grade. A panel of 13 human bladder tumors of defined stage and grade were investigated for chromosomal aberrations by comparative genomic hybridization and for NHEJ repair fidelity and function. Repair assays were conducted with extracts made directly from bladder tumor specimens to avoid culture-induced phenotypic alterations and selection bias as only a minority of bladder tumors grow in culture. Four noninvasive bladder tumors (pTaG2), which were genetically stable, repaired a partially incompatible double-strand break (DSB) by NHEJ-dependent annealing of termini and fill-in of overhangs with minimal loss of nucleotides. In contrast, four muscle invasive bladder cancers (pT2-3G3), which displayed gross chromosomal rearrangements, repaired DSBs in an error-prone manner involving extensive resection and microhomology association. Four minimally invasive bladder cancers (pT1G3) had characteristics of both repair types. Error-prone repair in bladder tumors correlated with reduced KU DNA-binding and loss of TP53 function. In conclusion, there were distinct differences in DSB repair between noninvasive papillary tumors and higher stage/grade invasive cancers. End-joining fidelity correlated with stage and was increasingly error-prone as tumors became more invasive and KU binding activity reduced; these changes may underlie the different genomic profiles of these tumors. © 2008 Wiley-Liss, Inc. [source] Wilms tumor genetics: Mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumorsGENES, CHROMOSOMES AND CANCER, Issue 6 2008E. Cristy Ruteshouser Wilms tumor is genetically heterogeneous, and until recently only one Wilms tumor gene was known, WT1 at 11p13. However, WT1 is altered in only ,20% of Wilms tumors. Recently a novel gene, WTX at Xq11.1, was reported to be mutated in Wilms tumors. No overlap between tumors with mutations in WTX and WT1 was noted, suggesting that WT1 and WTX mutations could account for the genetic basis of roughly half of Wilms tumors. To assess the frequency of WTX mutations and their relationship to WT1 mutations in a larger (n = 125) panel of Wilms tumors which had been thoroughly assessed for mutations in WT1, we conducted a complete mutational analysis of WTX that included sequencing of the entire coding region and quantitative PCR to identify deletions of the WTX gene. Twenty-three (18.4%) tumors carried a total of 24 WTX mutations, a lower WTX mutation frequency than that previously observed. Surprisingly, we observed an equivalent frequency of WTX mutations in tumors with mutations in either or both WT1 and CTNNB1 (20.0%) and tumors with no mutation in either WT1 or CTNNB1 (17.5%). WTX has been reported to play a role in the WNT/,-catenin signaling pathway, and, interestingly, WTX deletion/truncation mutations appeared to be rare in tumors carrying exon 3 mutations of CTNNB1, encoding ,-catenin. Our findings indicate that WT1 and WTX mutations occur with similar frequency, that they partially overlap in Wilms tumors, and that mutations in WT1, WTX, and CTNNB1 underlie the genetic basis of about one-third of Wilms tumors. © 2008 Wiley-Liss, Inc. [source] Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non-microdeletion patientsGENES, CHROMOSOMES AND CANCER, Issue 10 2006Thomas De Raedt Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome characterized by the presence of multiple benign neurofibromas. In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes. We studied the frequency of loss of heterozygosity (LOH) in the NF1 region as a mechanism of somatic NF1 inactivation in neurofibromas from NF1 patients with and without a microdeletion. There was a statistically significant difference between these two patient groups in the proportion of neurofibromas with LOH. None of the 40 neurofibromas from six different NF1 microdeletion patients showed LOH, whereas LOH was observed in 6/28 neurofibromas from five patients with an intragenic NF1 mutation (P = 0.0034, Fisher's exact). LOH of the NF1 microdeletion region in NF1 microdeletion patients would de facto lead to a nullizygous state of the genes located in the deletion region and might be lethal. The mechanisms leading to LOH were further analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal microdeletion was found; in three, a mitotic recombination was responsible for the observed LOH; and in one, a chromosome loss with reduplication was present. These data show an important difference in the mechanisms of second hit formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor syndrome in which the type of germline mutation influences the type of second hit in the tumors. © 2006 Wiley-Liss, Inc. [source] ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: Toward a molecular definition of an inflammatory myofibroblastic tumor family?GENES, CHROMOSOMES AND CANCER, Issue 1 2001Nicolas Sirvent A prenatal tumor located in the lumbar paravertebral area was discovered during a routine ultrasound examination at 32 weeks of pregnancy and surgically removed at 4 months of life. The histopathological diagnosis was first suggested to be an infantile desmoid fibromatosis. The tumor karyotype showed a three-way translocation involving both chromosomes 2 and a chromosome 11, t(2;11;2)(p23;p15;q31). Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated a rearrangement, as previously described in inflammatory myofibroblastic tumors (IMTs). In light of the genetic analysis, the histopathological diagnosis was revised to IMT, although inflammatory cells were scarce. IMTs are pseudosarcomatous inflammatory lesions that primarily occur in the soft tissue and viscera of children and young adults. Our report describes for the first time the occurrence of IMT during prenatal life. The ALK rearrangement may represent the molecular definition of a subgroup of mesenchymal tumors, not always with complete morphological features of IMT, similar to the model of EWS rearrangement in the Ewing sarcoma family of tumors. © 2001 Wiley-Liss, Inc. [source] Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosisGLIA, Issue 13 2009Mar Lorente Abstract Gliomas, one of the most malignant forms of cancer, exhibit high resistance to conventional therapies. Identification of the molecular mechanisms responsible for this resistance is therefore of great interest to improve the efficacy of the treatments against these tumors. ,9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tumor cells. By analyzing the gene expression profile of two sub-clones of C6 glioma cells with different sensitivity to cannabinoid-induced apoptosis, we found a subset of genes with a marked differential expression in the two sub-clones. Furthermore, we identified the epidermal growth factor receptor ligand amphiregulin as a candidate factor to mediate the resistance of glioma cells to cannabinoid treatment. Amphiregulin was highly overexpressed in the cannabinoid-resistant cell line, both in culture and in tumor xenografts. Moreover, in vivo silencing of amphiregulin rendered the resistant tumors xenografts sensitive to cannabinoid antitumoral action. Amphiregulin expression was associated with increased extracellular signal-regulated kinase (ERK) activation, which mediated the resistance to THC by blunting the expression of p8 and TRB3,two genes involved in cannabinoid-induced apoptosis of glioma cells. Our findings therefore identify Amphirregulin as a factor for resistance of glioma cells to THC-induced apoptosis and contribute to unraveling the molecular bases underlying the emerging notion that targeted inhibition of the EGFR pathway can improve the efficacy of antitumoral therapies. © 2009 Wiley-Liss, Inc. [source] Endoscopic laser surgery of early glottic cancer: Involvement of the anterior commissure,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 5 2009Ralph M. W. Rödel MD Abstract Background Early glottic cancer can be cured with transoral laser resection, but in cases with anterior commissure involvement, there is still controversy concerning the best treatment modality. Methods The impact of anterior commissure involvement on local control was analyzed in a retrospective review of 444 patients with early glottic cancer (pT1a,pT2a) treated between 1986 and 2004 with transoral laser microsurgical resection. Results The anterior commissure was involved in 153 cases; the 5-year local control rate with and without anterior commissure involvement was 73% versus 89% for T1a and 68% versus 86% for T1b tumors. For T2a lesions, the 5-year local control rate was 76%, irrespective of anterior commissure involvement. Conclusion In early glottic cancer treated by transoral laser microsurgery, a decrease in local control is evident in case of anterior commissure involvement for T1a and T1b but not for T2a tumors. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [source] Predictive values for aspiration after endoscopic laser resections of malignant tumors of the hypopharynx and larynxHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 2 2004Manuel Bernal-Sprekelsen MD Abstract Background. CO2 -laser surgery is a relatively new treatment for selected carcinomas of the upper aerodigestive tract. The purpose of our study was to evaluate prospectively the functional results for swallowing after C02 -laser resections. Methods. The sample was composed of 210 consecutive patients with malignancies of the larynx and hypopharynx treated with CO2 laser between February 1998 and January 2002. Endoscopic resections included all T1 and T2 tumors and selected T3 and T4 tumors. T1 glottic tumors were not included in the analysis. We assessed the need for a feeding tube and the period the tube remained in place, aspiration pneumonia, tracheotomy secondary to aspiration, the need for a permanent or temporary gastrostomy, and total laryngectomy secondary to aspiration. Results. The nasogastric feeding tube was used in 23.2% of small tumors (2.5 ± 8.04 days) and in 63% of locally advanced tumors (13.95 ± 22.55 days). Frequency and period of storage of the feeding tube were higher in locally advanced tumors (p = .0001). Twelve patients (5.7%) had postoperative pneumonia and 59 (28.1%) had temporary postoperative cough during oral intake. Aspiration symptoms correlated with location (p = .001) and locally advanced tumors (p = .016). Eight patients (3.8%) needed a postoperative tracheotomy for severe swallowing difficulties; six (2.9%) of them were definitive and two (0.95%) temporary. Thirteen gastrostomies (6.2%) were performed to avoid severe aspirations; five of them were definitive. The need for gastrostomy correlated significantly with location (p = .002), pT3 and pT4 tumors (p = .002), age (p = .02), and postoperative radiotherapy (p = .04). No correlation was found with the period of feeding tube (p = .38), or aspiration pneumonia (p = .24). Conclusions. Endoscopic resection of laryngeal and hypopharyngeal tumors is associated with good recovery of deglutition. Many tracheotomies are avoided, the need for a feeding tube is usually reduced, and organ preservation is often feasible even in locally advanced tumors. © 2003 Wiley Periodicals, Inc. Head Neck26: 103,110, 2004 [source] The expression of key cell cycle markers and presence of human papillomavirus in squamous cell carcinoma of the tonsilHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2004Wei Li MMed Abstract Background. Chemical carcinogens induce squamous cell carcinoma (SCC) of the head and neck by targeting the p53 and the retinoblastoma (pRb) pathways. Human papillomavirus (HPV) might have an etiologic role in these cancers at particular sites. Few studies have compared cell cycle protein expression in HPV-positive and HPV-negative tumors in this region. Methods. Fifty tonsil SCCs were analyzed for HPV by PCR and for expression of cell cycle proteins (p53, pRb, p16INK4A, p21CIP1/WAF1, p27KIP1, and cyclinD1) by immunohistochemistry. Results. HPV was present in 42%; almost all were type 16. There were statistical associations between HPV positivity and reduced expression of pRb and cyclinD1, overexpression of p16, and younger patient age. Tumor with down-regulated p27 tended to have down-regulated pRb and p21. Conclusions. HPV-positive tonsil SCCs have distinct molecular pathways. Their association with younger patient age suggests that they are biologically distinct from HPV-negative tumors. © 2004 Wiley Periodicals, Inc. Head and Neck 26: 1,9, 2004 [source] Rim versus sagittal mandibulectomy for the treatment of squamous cell carcinoma: Two types of mandibular preservationHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 12 2003Mario Fernando Muńoz Guerra MD Abstract Background. The role of conservative mandibulectomy for patients with bone invasion from squamous cell carcinoma remains poorly defined. However, marginal mandibular resection is biomechanically secure in its design while maintaining the mandibular continuity. This procedure has proven to be a successful method of treating squamous cell carcinoma with limited mandibular involvement. Purpose. The purpose of this study was to analyze our results after the use of a marginal technique for the treatment of oral and oropharyngeal cancer and to compare two types of mandibular conservative procedures: rim resection versus sagittal inner mandibulectomy. Methods. A retrospective review of a cohort of 50 patients (global group) who underwent mandibular conservative resection for previously untreated squamous cell carcinoma was performed. Two subgroups were considered: rim group (n = 37) and sagittal group (n = 13). Clinical evaluation and preoperative radiologic studies were the means used to evaluate bony invasion and to decide on the extent of mandibulectomy. The treatment outcome after these two types of mandibular resection was calculated and compared using analysis by the Pearson ,2 test, logistic regression model for multivariate analysis, and the Kaplan-Meier method to determine survival. Results. In the sagittal group, specimens from 2 patients (11.7%) demonstrated tumor invasion on decalcified histologic examination, whereas the rim group showed 11 cases (29.7%) with bone invasion. Local recurrence was observed in the follow-up of 10 patients. No statistical relationship was found between the presence of histologic bone invasion and the risk of local recurrence. The size of bone resection >4 cm (p = .002) and tumor invasion of surgical margins (p = .039) were found to be associated with increased local recurrence rates. In multivariate analysis, lymph node affectation significantly correlated with histologic mandibular involvement (p = .02). In the global group, the 5-year observed survival rate was 56.97%. Overall survival and rate of recurrence were comparable in both groups. In the global group, tumor infiltration beyond the surgical margin was statistically related with poor survival (p = .01). Conclusions. Analysis of this series disclosed that marginal mandibulectomy is effective in the control of squamous cell carcinomas that are close to or involving the mandible. In carefully selected patients, sagittal bone resection seems to be as appropriate as rim resection in the local control of these tumors. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 000,000, 2003 [source] Benign metastasizing pleomorphic adenoma of the parotid gland: A clinicopathologic puzzleHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 12 2003Gino Marioni MD Abstract Background. Pleomorphic adenoma constitutes the most common benign parotid gland tumor. Local recurrence after surgical treatment (lateral or total parotidectomy) has been described in 1% to 5% of cases. Malignant degeneration has been reported in 2% to 9% of cases of pleomorphic adenoma of salivary gland origin. Metastasizing pleomorphic adenomas without histologic evidence of malignancy have rarely been reported. Metastatic lesions have been discovered in bone, lymph nodes, the lung, oral cavity, pharynx, skin, liver, retroperitoneum, kidney, calvarium, and central nervous system. To the best of our knowledge, we hereby report the first case of pleomorphic adenoma of the parotid gland metastasizing to the ipsilateral maxilla. Methods. We simultaneously examined apoptosis-related protein expression and markers of cell-proliferation activity in our case of benign pleomorphic adenoma metastasis and compared outcome with a control group of primary parotid pleomorphic adenomas. Results. Analysis of p53, Bcl-2, MIB1, CD 105, p27, and p21 expression did not reveal significant differences between metastasizing pleomorphic adenoma of the salivary gland and the control group of primary parotid pleomorphic adenomas. Conclusions. Clinical rather than pathologic evidence seems to justify inclusion of metastasizing salivary pleomorphic adenoma in the group of low-grade malignant salivary tumors. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 000,000, 2003 [source] Intratumoral cisplatin/epinephrine gel in advanced head and neck cancer: A multicenter, randomized, double-blind, phase III study in North America,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2003Dan J. Castro MD Abstract Background. The objective was to evaluate the efficacy and safety of a novel intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) for local control and palliation of tumor-related symptoms in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods. Eighty-seven patients were randomly assigned to either CDDP/epi or placebo gel in this phase III, double-blind study. Tumors were ,20 cm3; most recurrences (88%) were in a previously irradiated field. The most symptomatic or threatening tumor was designated as the target tumor. Dose: 0.25 mL CDDP/epi gel/cm3 tumor volume. Treatments: ,6 weekly intratumoral injections in an 8-week period. Primary outcomes: target tumor response and symptom relief. Results. During the blinded phase, 34% (21 of 62) of patients achieved an objective response (CR or PR) in the target tumor treated with CDDP/epi gel vs 0% (0 of 24) treated with placebo gel (p < .001). Responses occurred within a median of four treatments (range, 2,6) and were durable (median, 95 days; range, 34,168+ days). More patients treated with CDDP/epi gel achieved palliative benefit than did those treated with placebo gel (37% vs 12%, p = .036). Most frequent side effects were local pain and local cutaneous reactions, which resolved over 3,12 weeks. Renal and hematologic toxicities were rare. Conclusions. This phase III trial showed that CDDP/epi gel significantly reduces tumor burden, palliates tumor-related symptoms, and is an effective local treatment for recurrent tumors. © 2003 Wiley Periodicals, Inc. Head Neck 25: 717,731, 2003 [source] Pleiotropic function of ezrin in human metastatic melanomasINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Cristina Federici Abstract The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. © 2009 UICC [source] Cancer patterns in nasopharyngeal carcinoma multiplex families in TaiwanINTERNATIONAL JOURNAL OF CANCER, Issue 7 2009Kelly J. Yu Abstract Genetic and environmental factors have been implicated in the etiology of nasopharyngeal carcinoma (NPC), a tumor known to be closely associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC and have suggested the possible aggregation of NPC and other cancers. We evaluated familial aggregation of cancer in 358 high-risk families with two or more NPC cases enrolled in a NPC genetics study in Taiwan. Participants were linked to the Taiwan National Cancer Registry to identify incident cancers diagnosed after study enrollment (started in 1996) and before December 31, 2005, or death. In total, 2,870 individuals from the NPC Multiplex Family Study contributed 15,151 person-years over an average of 5.3 years of follow-up. One hundred ten incident cancers were identified. Multiple-primary standardized incidence ratios (MP-SIRs) were computed to evaluate overall cancer risk associated with infectious agents and with other tumors. The overall MP-SIR was 1.3 (95% CI: 1.1,1.6), which was largely explained by an excess in NPC (MP-SIR = 15; 95% CI: 10,23). Exclusion of incident NPC diagnoses led to an overall MP-SIR of 1.0 (95% CI: 0.83,1.3). Similarly, the observed excess risk of cancers associated with infectious agents (MP-SIR = 2.0; 95% CI: 1.5,2.6) was driven by the excess in NPC; exclusion of NPC cases led to a reduced MP-SIR that did not differ from 1.0. Analysis of the largest NPC multiplex family study to date confirms the presence of coaggregation of NPC within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. © 2008 Wiley-Liss, Inc. [source] K-ras mutations and mucin profile in preneoplastic lesions and colon tumors induced in rats by 1,2-dimethylhydrazineINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Angelo Pietro Femia Abstract K-ras and mucin profile variations, associated with intestinal carcinogenesis, were studied in the preneoplastic lesions, mucin-depleted foci (MDF) and aberrant crypt foci (ACF), and in colonic tumors induced in rats by 1,2-dimethylhydrazine (DMH). The frequency of lesions with K-ras mutations was 23% (3/13), 5.5% (1/18) and 100% (14/14) in MDF, tumors and ACF, respectively. Two of three MDF mutated in K-ras also carried a missense mutation in Apc. We also tested the expression of MUC2, a mucin abundantly expressed in normal colon and M1/MUCA5C, up-regulated in colon carcinogenesis, using immunohistochemistry. MDF and tumors showed a dramatic reduction in the expression of MUC2, whereas ACF showed only a slight reduction. The expression of M1/MUC5AC was almost absent in normal mucosa, but was increased in all the lesions (MDF, tumors and ACF). The expression of the intestinal trefoil factor (ITF), a marker of goblet cell lineage, was reduced in MDF and tumors compared to normal mucosa but not in ACF. In conclusion, although K-ras mutations are present in all ACF, they are less frequent in MDF and tumors; M1/MUC5AC is a marker associated with all preneoplastic events while the reduction of MUC2 and ITF expression is selectively associated with more advanced lesions such as MDF and tumors. © 2007 Wiley-Liss, Inc. [source] 99mTc-MIBI imaging for prediction of therapeutic effects of second-generation MDR1 inhibitors in malignant brain tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Toshio Sasajima Abstract The aim of this study was to explore whether 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS-209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (Vd) of 99mTc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased Vd of 99mTc-MIBI significantly in VCR-resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that 99mTc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of 99mTc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased 99mTc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using 14C-methyl- L -methionine (14C-Met) and MIB-5 index. 14C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of 99mTc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors. © 2007 Wiley-Liss, Inc. [source] Nonsteroidal anti-inflammatory drugs and the risk of developing breast cancer in a population-based prospective cohort study in Washington County, MDINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Lisa Gallicchio Abstract The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors. © 2007 Wiley-Liss, Inc. [source] Analysis of chromosome 10 aberrations in rat endometrial cancer,evidence for a tumor suppressor locus distal to Tp53INTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Carola Nordlander Abstract We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors. © 2006 Wiley-Liss, Inc. [source] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFN, gene to miceINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Tetsuo Takehara Abstract Interferon (IFN) , is a pleiotropic cytokine acting as an antiviral substance, cell growth inhibitor and immunomodulator. To evaluate the therapeutic efficacy and mechanisms of IFN, on hepatic metastasis of tumor cells, we hydrodynamically injected naked plasmid DNA encoding IFN,1 (pCMV-IFNa1) into Balb/cA mice having 2 days hepatic metastasis of CT-26 cells. Single injection of pCMV-IFNa1 efficiently enhanced the natural killer (NK) activity of hepatic mononuclear cells, induced production of IFN, in serum and led to complete rejection of tumors in the liver. Mice protected from hepatic metastasis by IFN, therapy displayed a tumor-specific cytotoxic T cell response and were resistant to subcutaneous challenge of CT-26 cells. NK cells were critically required for IFN,-mediated rejection of hepatic metastasis, because their depletion by injecting anti-asialo GM1 antibody completely abolished the antimetastatic effect. To find whether NK cells are directly activated by IFN, and are sufficient for the antimetastatic effect, the responses to IFN, were examined in SCID mice lacking T cells, B cells and NKT cells. IFN, completely rejected hepatic metastasis in SCID mice and efficiently activated SCID mononuclear cells, as evidenced by activation of STAT1 and a variety of genes, such as MHC class I, granzyme B, tumor necrosis factor-related apoptosis-inducing ligand and IFN,, and also enhanced Yac1 lytic ability. Study of IFN, knockout mice revealed that IFN, was not necessary for IFN,-mediated NK cell activation and metastasis protection. In conclusion, IFN, efficiently activates both innate and adaptive immune responses, but NK cells are critically required and sufficient for IFN,-mediated initial rejection of hepatic metastasis of microdisseminated tumors. © 2006 Wiley-Liss, Inc. [source] Human papillomavirus seropositivity and risks of head and neck cancerINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Elaine M. Smith Abstract We examined antibody response to VLP HPV-16, HPV-16 E6 and E7 antibodies as potential seromarkers of HPV-related head and neck cancer (HNC). The study included 204 HNC cases and 326 controls evaluated for HPV presence in sera using ELISAs for anti-HPV VLP antibodies and HPV-16 E6 and/or E7 antibodies, and in tumor tissue using PCR and DNA sequencing. Anti-HPV-16 VLP was detected in 33.8% of cases and 22.4% of controls, anti-E6 in 20.6% of cases and 0.9% of controls and anti-E7 in 18.6% of cases and 0.6% of controls. HPV-16 DNA was detected in 26.1% of tumors. The adjusted risk of HNC was elevated among those seropositive for HPV-16 VLP (odds ratio (OR) = 1.7, 1.1,2.5), E6 (OR = 32.8, 9.7,110.8) or E7 (OR = 37.5, 8.7,161.2). Compared to HPV DNA-negative/seronegative cases, tumor HPV-16 cases had increased risk of detection with anti-VLP antibodies (OR = 6.8, 3.1,14.9). The odds were more pronounced among cases seropositive for E6 (OR = 69.0, 19.3,247) or E7 (OR = 50.1, 14.7,171). Antibodies against E6 or E7 were associated with risk of cancer in the oral cavity (OR = 5.1, 1.2,22.4) and oropharynx (OR = 72.8, 16.0,330), and with disease characteristics: stage, grade and nodal status. Anti-E6 and/or E7 antibodies were found in 74% of tumor HPV-16 positive cases but in only 5% of tumor HPV-negative cases (K =0.7, 0.6,0.8) suggesting good correlation between the serologic marker and HPV tumor status. Antibodies to HPV-16 E6 and/or E7 represent a more specific biomarker than anti-HPV-16 VLP of an HPV-related HNC. Because of the survival advantage of HPV-related HNC, HPV-16 E6/E7 detection may be useful in therapy targeted for HPV-related tumors. © 2006 Wiley-Liss, Inc. [source] Survivin in esophageal cancer: An accurate prognostic marker for squamous cell carcinoma but not adenocarcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Antonio Rosato Abstract We quantified the expression of survivin, both as mRNA in real-time PCR and protein in immunohistochemistry, in tumor samples of 112 patients with esophageal cancer (56 squamous cell carcinomas and 56 adenocarcinomas). Overall survival of squamous cell carcinoma patients with high survivin mRNA levels was significantly less than that of patients with low survivin mRNA levels (p = 0.0033). Distribution pattern of survivin (nuclear vs. cytoplasmic or mixed) was not correlated to survival, while the extent of immunostaining was significantly correlated to survivin mRNA values (p = 0.016) and had prognostic relevance in univariate analysis (p = 0.0012). Cox's proportional-hazard regression model showed that tumor survivin expression in esophageal squamous cell carcinoma was the most important prognostic factor, independent of tumor stage and other histopathological factors, both as mRNA relative value (p = 0.0259) and protein immunostaining (p = 0.0147). In esophageal adenocarcinoma, survivin expression and pattern of distribution had no prognostic relevance. Thus, quantifying survivin expression provides a prognostic marker only for esophageal squamous tumors. © 2006 Wiley-Liss, Inc. [source] Identification of a novel human tissue factor splice variant that is upregulated in tumor cells,INTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Hitendra S. Chand Abstract Tissue factor (TF) is a transmembrane glycoprotein that serves as the prime initiator of blood coagulation and plays a critical role in thrombosis and hemostasis. In addition, a variety of tumor cells overexpress cell-surface TF, which appears to be important for tumor angiogenesis and metastasis. To elucidate the mechanism involved in the upregulation of TF in human tumor cells, a comprehensive analysis of TF mRNA from various normal and tumor cells was performed. The results of these studies indicate that, in addition to possessing a normal full-length TF transcript and minor levels of an alternatively spliced transcript known as alternatively-spliced tissue factor (asTF) (Bogdanov et al., Nat Med 2003;9:458,62), human tumor cells express additional full-length TF transcripts that are also generated by alternative splicing. Reverse transcriptase-polymerase chain reaction (RT-PCR) and 5,-rapid amplification of cDNA ends- (5,-RACE) based analyses of cytoplasmic RNA from normal and tumor cells revealed that there is alternative splicing of the first intron between exon I and exon II resulting in 2 additional TF transcripts. One of the transcripts has an extended exon I with inclusion of most of the first TF intron (955 bp), while the second transcript is formed by the insertion of a 495 bp sequence, referred to as exon IA, derived from an internal sequence of the first intron. The full length TF transcript with alternatively spliced novel exon IA, referred to as alternative exon 1A-tissue factor (TF-A), represented ,1% of the total TF transcripts in normal cells, but constituted 7,10% of the total TF transcript in tumor cells. Quantitative real-time RT-PCR analysis indicated that cultured human tumor cells contain 10,25-fold more copy numbers of TF-A in comparison to normal, untransformed cells. We propose that high-level expression of the novel TF-A transcript, preferentially in tumor cells, may have utility in the diagnosis and staging of a variety of solid tumors. © 2005 Wiley-Liss, Inc. [source] Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell lymphomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Emma Camacho Abstract Aurora-A and hMPS1 are kinases involved in spindle checkpoint and centrosome duplication regulation and whose alterations have been associated with cell transformation and chromosome instability in different tumor models. In this study, we have examined the possible alterations of these genes in 58 mantle cell lymphomas (MCLs) and 4 MCL-related cell lines. Aurora-A was also examined in 46 diffuse large B-cell lymphomas (DLBCLs). Aurora-A and hMPS1 mRNA expression levels were related to tumor proliferative activity. Interestingly, a MCL case with the highest number or chromosomal imbalances also showed an extremely high value of Aurora-A mRNA expression. No Aurora-A gene amplifications were detected in any tumor or cell line, whereas hemizygous hMPS1 gene deletions were observed in 23% of MCLs and 3 of the 4 cell lines. However, no expression alterations or gene mutations were detected in these cases. The Aurora-A proposed cancer susceptibility polymorphic variant (P31I) was observed with a similar frequency in MCL, DLBCL, chronic lymphocytic leukemia and in the 431 healthy controls. However, the 3 MCLs and 4 DLBCLs with the homozygous variant of this polymorphism had particular clinical characteristics with an unusual early-age presentation and second epithelial malignancies in MCL and extranodal origin in DLBCL. These findings indicate that Aurora-A and hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A overexpression may contribute to numerical chromosomal alterations in occasional MCL. Although the Aurora-A P31I polymorphic variant is not directly involved in a genetic predisposition to these lymphomas, it may modulate the clinical presentation of these tumors. © 2005 Wiley-Liss, Inc. [source] Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous systemINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Bernd U. Koelsch Abstract The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N -ethyl- N -nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX × BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX × BDIV) F2 rats exhibit a 2-fold higher incidence of EtNU-induced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors. © 2005 Wiley-Liss, Inc. [source] Molecular classification of borderline ovarian tumors using hierarchical cluster analysis of protein expression profilesINTERNATIONAL JOURNAL OF CANCER, Issue 6 2002Ayodele A. Alaiya Abstract Ovarian tumors range from benign to aggressive malignant tumors, including an intermediate class referred to as borderline carcinoma. The prognosis of the disease is strongly dependent on tumor classification, where patients with borderline tumors have much better prognosis than patients with carcinomas. We here describe the use of hierarchical clustering analysis of quantitative protein expression data for classification of this type of tumor. An accurate classification was not achieved using an unselected set of 1,584 protein spots for clustering analysis. Different approaches were used to select spots that were differentially expressed between tumors of different malignant potential and to use these sets of spots for classification. When sets of proteins were selected that differentiated benign and malignant tumors, borderline tumors clustered in the benign group. This is consistent with the biologic properties of these tumors. Our results indicate that hierarchical clustering analysis is a useful approach for analysis of protein profiles and show that this approach can be used for differential diagnosis of ovarian carcinomas and borderline tumors. © 2002 Wiley-Liss, Inc. [source] Neuroendocrine tumor targeting: Study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor modelINTERNATIONAL JOURNAL OF CANCER, Issue 6 2002Sylvie Froidevaux Abstract Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes 67Ga and 68Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals 111In, 90Y and 67Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to 111In or 90Y, labeling with 67Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. 67Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [67Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors. © 2002 Wiley-Liss, Inc. [source] ,v -Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascinINTERNATIONAL JOURNAL OF CANCER, Issue 5 2002Takashi Taga Abstract Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the ,v -integrin antagonist EMD 121974. This compound, a cyclic RGD-penta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their ,v -integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the ,v -integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Furthermore, only tumor cells expressing ,v -integrins responded to the treatment with EMD 121974, after xenotransplantation into the forebrain of nude mice, supporting the importance of tumor cell-matrix interactions in tumor cell survival in the brain. Thus, the ,v -antagonist EMD 121974 suppresses brain tumor growth through induction of apoptosis in both brain capillary and brain tumor cells by preventing their interaction with the matrix proteins vitronectin and tenascin. The dual action of this peptide explains its potent growth suppression of orthotopically transplanted brain tumors. © 2002 Wiley-Liss, Inc. [source] Effect of N-cadherin misexpression by the mammary epithelium in miceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Karen A. Knudsen Abstract N-cadherin is not typically expressed by epithelial cells. However, it is detected in breast cancers and increases tumor cell migration and invasion in vitro. To explore its misexpression, we generated transgenic mice with N-cadherin in the mammary epithelium. Mammary glands appeared normal and no tumors arose spontaneously. To investigate N-cadherin misexpression in mammary tumors, neu was overexpressed through breeding. Tumors developed in +/neu and N-cadherin/neu mice, although few tumors in bitransgenic mice expressed N-cadherin, and they did not differ from N-cadherin-negative tumors. © 2005 Wiley-Liss, Inc. [source] Impact of intraoperative sonography on resection and cryoablation of liver tumorsJOURNAL OF CLINICAL ULTRASOUND, Issue 5 2001Diana Gaitini MD Abstract Purpose We retrospectively analyzed the impact of intraoperative sonography (IOUS) on the management of patients referred for resection of liver tumors. Methods Forty patients underwent IOUS with a 7-MHz curved-array sector transducer; in selected cases, a 5-MHz linear-array transducer attached to a color Doppler unit was also used. The number, size, and location of tumors on IOUS, including tumor proximity to or invasion of major vessels or invasion of the diaphragm, were compared to findings on preoperative imaging studies. The effect of these findings on surgical management was assessed. Unresectable lesions were treated by cryoablation under ultrasound guidance. Results IOUS detected preoperatively unsuspected lesions in 7 patients (18%). Metastases suspected on CT arterial portography were ruled out in 2 patients (5%), and indeterminate lesions were diagnosed as cysts by IOUS in 2 other patients (5%). Vascular proximity or vascular or diaphragmatic invasion detected by IOUS rendered lesions unresectable in 4 patients (10%). Cryoablation under IOUS guidance and monitoring was attempted in 11 patients (28%) and performed successfully in 10. Conclusions IOUS changed the management in 38% of patients and guided cryoablation in 28% of patients. IOUS performed by an experienced sonologist is invaluable for the accurate assessment of liver tumor resectability; the detection of additional, preoperatively unknown lesions; and the guidance of cryoablation of unresectable tumors. © 2001 John Wiley & Sons, Inc. J Clin Ultrasound 29:265,272, 2001. [source] | ||||||||||||||||