ABSTRACT A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some... more
ABSTRACT A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some non-Ashkenazi individuals led us to hypothesize that within the Jewish people, the I1307K polymorphism may reflect a founder mutation, and that the mutation is not restricted to ethnic Ashkenazis. To test that notion, and to establish the occurrence rate of the I1307K polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and Moroccan Jews and consecutive Jewish CRC patients and performed haplotype analysis with APC-linked markers in two I1307K carrier families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148 Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi). The mutation detection scheme included PCR followed by denaturing gradient gel electrophoresis (DGGE) or modified restriction analysis (MRA). Haplotypes were assessed using three intragenic and three flanking markers. The I1307K polymorphism was detected in 29/227 Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2 individuals each (approximately 1%) within the Moroccan and Iraqi populations. Allelic pattern analysis in all our I1307K carriers, revealed a common haplotype for the three intragenic markers tested, in all mutation carriers, regardless of ethnic origin. The I1307K polymorphism, therefore, exists in all ethnic Jewish populations: Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K mutation carriers share a common allelic pattern with APC-linked markers. This strongly supports the notion of a founder mutation for I1307K.
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ABSTRACT Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie... more
ABSTRACT Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two inherited syndromes: Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The known association of CD with breast cancer risk made it plausible that germline mutations within PTEN may play a role in inherited predisposition to breast cancer. The nine coding exons of the PTEN gene were screened for harboring germline mutations using denaturing gradient gel electrophoresis (DGGE) complemented by sequencing, in two subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparent inherited predisposition to breast cancer, some with salient features of CD. Two of three familial BRRS patients exhibited novel germline mutations in PTEN: a missense mutation changing methionine to arginine at codon 134, and insertion of two nucleotides (CA) at cDNA position 1215 resulting in a frameshift at codon 61 and a premature stop at codon 99. Among 89 high-risk women, two missense mutations were detected in exon 4: A to C change at cDNA position 1279 resulting in a change of aspargine to threonine at codon 82 (N82T), and a G to an A alteration in 1269 which alters threonine to alanine at codon 78 (T78A), a non-conservative missense mutation. This study suggests that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.
Research Interests: Genetics, Breast Cancer, Biology, Medicine, Israel, and 10 moreHumans, Genetic Testing, Female, Clinical, Clinical Genetics, Phenotype, Clinical Sciences, PTEN, Germline, and Exon
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The current standard of adjuvant treatment for gastric cancer after curative resection is concurrent administration of radiotherapy and 5-fluorouracil-based chemotherapy. The radiation fields are often arranged as... more
The current standard of adjuvant treatment for gastric cancer after curative resection is concurrent administration of radiotherapy and 5-fluorouracil-based chemotherapy. The radiation fields are often arranged as anterioposterior-posteroanterior opposed parallel fields with general recommendations for sparing at least two-thirds of one kidney. We investigated whether a better radiation distribution would be achievable with three-dimensional conformal approaches compared with the classic anterioposterior-posteroanterior fields. A total of 19 patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a non-coplanar four-field arrangement. In each case, parallel planning using an anterioposterior-posteroanterior arrangement and a four-field "box" was performed, and the generated plans were subsequently compared for coverage of target volumes and doses to irradiated organs next to the tumor bed. A separate analysis was performed for kidneys exposed to greater and lower doses in each patient. The mean radiation dose and percentage of kidney volume receiving a dose >20 Gy were registered. Statistical analysis was performed using the two-tailed t test. The clinical target volume was adequately covered in all three plans. In the greater-dose kidney group, all the differences were statistically significant with a benefit for the three-dimensional plan. In the lower-dose kidney group, the differences in the mean radiation dose did not reach the level of statistical significance, and the differences in the kidney volume receiving a dose >20 Gy showed a statistically significant benefit for the three-dimensional plan. Non-coplanar three-dimensional-based conformal planning for postoperative radiotherapy for gastric cancer provided the best results regarding kidney and spinal cord exposure with adequate clinical target volume coverage. This technique was readily implemented in clinical practice.
Research Interests: Statistical Analysis, Radiation Therapy, Nuclear medicine, Medicine, Clinical Practice, and 13 moreHumans, Kidney, Spinal Cord, Gastric Cancer, Statistical Significance, Clinical Sciences, Radiation Dose, Radiation Injuries, Three Dimensional, Adjuvant Chemotherapy, Adenocarcinoma, Gastrectomy, and Stomach neoplasms
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15145 Background: The Current standard of adjuvant treatment for gastric cancer following curative resection is concurrent administration of radiation and 5FU-based chemotherapy (INT0116). Radiation fields are often arranged as AP-PA... more
15145 Background: The Current standard of adjuvant treatment for gastric cancer following curative resection is concurrent administration of radiation and 5FU-based chemotherapy (INT0116). Radiation fields are often arranged as AP-PA opposed parallel fields with general recommendations for sparing at least two thirds of one kidney. In the current trial we investigated whether a better radiation distribution is achievable with 3-D conformal approaches as opposed to classical AP-PA fields. Methods: Nineteen patients with adenocarcinoma of stomach were treated by adjuvant chemoradiotherapy using a non-coplanar four field arrangement. In each case parallel planning by AP-PA arrangement and four fields “box was carried out and the generated plans were subsequently compared with dose volume histograms (DVH). Adequate coverage of the CTV was the basis for a comparison between other planning parameters. Separate analysis was performed not for right and left kidney but rather for kidneys exp...
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8197 Background: The term ‘World assumptions’ (WA) refers to beliefs by which one defines his/her own identity and coping strategies. Psychologists have been interested in the association between depression, anxiety and WA. It was even... more
8197 Background: The term ‘World assumptions’ (WA) refers to beliefs by which one defines his/her own identity and coping strategies. Psychologists have been interested in the association between depression, anxiety and WA. It was even suggested that anxiety and depression can be treated by mainly focusing on altering dysfunctional beliefs. The aim of the current study was to investigate which beliefs are associated with anxiety and depression amongst cancer patients. Methods: We conducted a convenience sampling with 69 female breast cancer patients, and 68 colorectal cancer patients (33 males, 35 females), aged 35–85, treated in 3 urban medical centers in Israel. Measurements were made using the world assumptions scale and the brief symptoms index. Results: In our sample, anxiety and depression were both found to be significantly more severe among breast cancer patients than in colorectal patients. Breast cancer patients also reported more dysfunctional world assumptions. A Pearson correlation procedure ...
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Research Interests: Genetics, Biology, Family history, Israel, Colorectal cancer, and 15 moreBiological Sciences, Endometrial Cancer, Humans, Haplotypes, Female, Male, Jews, Lynch syndrome, Hereditary nonpolyposis colorectal cancer, Alanine, DNA binding proteins, Founder Effect, Case Control Studies, Gene frequency, and Genetic predisposition to disease
Purpose In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the... more
Purpose In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups. Patients and Methods A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the numb...
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To assess diagnostic accuracy of combined positron emission tomography (PET) and computed tomography (CT) in detection of pelvic recurrence in patients with rectal cancer who underwent abdominoperineal or anterior resection. Sixty-two... more
To assess diagnostic accuracy of combined positron emission tomography (PET) and computed tomography (CT) in detection of pelvic recurrence in patients with rectal cancer who underwent abdominoperineal or anterior resection. Sixty-two patients were enrolled; 37 were men, and 25 were women. Seventeen patients underwent abdominoperineal resection and 45 underwent anterior resection with an anastomosis in the pelvic region before referral for PET/CT. Pelvic sites of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake were rated separately on PET and PET/CT images as benign or malignant on the basis of shape, location, and intensity of (18)F FDG uptake (1-2 = benign and/or physiologic, 3 = equivocal, 4-5 = malignant). Two readers interpreted images in consensus. Altered pelvic anatomy and presence of presacral abnormalities were assessed with CT. Pelvic recurrence was confirmed with histologic analysis or clinical and imaging follow-up. Sensitivity, specificity, positive and negative predictive values, and accuracy of PET and PET/CT in the detection of pelvic recurrence were compared with lesion- and patient-based analyses by using the chi(2) test. Clinical relevance of PET/CT assessment was determined. Of 81 pelvic sites with increased (18)F FDG uptake, 44 were malignant. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for differentiating malignant from benign (18)F FDG uptake in the pelvis were 98%, 96%, 90%, 97%, and 93% for PET/CT and 82%, 65%, 73%, 75%, and 74% for PET, respectively. The most common cause for false-positive interpretation of PET findings was physiologic (18)F FDG uptake in displaced pelvic organs. Presacral CT abnormalities were present in 30 (48%) of 62 patients, and seven (23%) abnormalities were malignant. PET/CT was used to distinguish benign and malignant presacral abnormalities with a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 96%, 88%, and 100%, respectively. PET/CT findings were clinically relevant in 29 (47%) of 62 patients. PET/CT is an accurate technique in the detection of pelvic recurrence after surgical removal of rectal cancer.
Research Interests: Radiology, Positron Emission Tomography, Medicine, Colorectal cancer, Humans, and 13 moreFemale, Male, Aged, Middle Aged, Pelvis, Single Photon Emission Computed Tomography, Adult, Retrospective Studies, X ray Computed Tomography, Rectal Cancer, Abdominoperineal resection, Medical and Health Sciences, and Rectal neoplasms
Research Interests: Genetics, Medicine, Israel, Colorectal cancer, Endometrial Cancer, and 15 moreHumans, Genetic Testing, Female, Male, Clinical Sciences, Aged, Lynch syndrome, Adult, DNA binding proteins, Genetic, Colorectal Neoplasms, DNA mutational analysis, Familial adenomatous polyposis, Endometrial neoplasms, and Genetic predisposition to disease
Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the... more
Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.
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Research Interests: Medicine, Colorectal cancer, Humans, Female, Male, and 15 moreAged, Middle Aged, Adult, Retrospective Studies, Prognosis, Postoperative Complication, Blood Transfusion, Hospital Mortality, Rectal Cancer, Postoperative Complications, Combined Modality Therapy, neoadjuvant therapy, Disease Free Survival, Neoplasm staging, and Rectal neoplasms
Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is... more
Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients. Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls. Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212 sporadic and 56 carriers of either a BRCA1 or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent autoradiography. Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only (3/536, 0.6%). Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.
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Patients with rectal cancer who have complete rectal wall tumor regression after neoadjuvant chemoradiation probably have eradication of tumor cells in the mesorectum as well, thus raising the possibility of transanal excision. All... more
Patients with rectal cancer who have complete rectal wall tumor regression after neoadjuvant chemoradiation probably have eradication of tumor cells in the mesorectum as well, thus raising the possibility of transanal excision. All pathology reports of all patients with locally advanced low and mid rectal cancer who underwent preoperative chemoradiation followed by radical resection from May 2000 to June 2004 were reviewed to evaluate the correlation between complete tumor response (ypT0) and nodal response. One hundred one consecutive patients had neoadjuvant chemoradiation followed by definitive operation. Four were excluded, leaving 64 men and 33 women (median age, 62 years). Fifty-three patients (55%) had mid rectal cancer, and 44 (45%) had low rectal cancer. Fifty-eight patients (60%) underwent low anterior resection, and 36 (37%) underwent abdominoperineal resection. In 17 patients (18%), no residual tumor cells were present within the rectal wall. One patient (6%) with ypT0 disease had positive lymph nodes. No residual tumor in the rectal wall correlates with the absence of viable cancer cells in the mesorectal tissue (94%). Approximately 10% of T1 tumors have involved lymph nodes, and local excision is an accepted option. Transanal excision could probably be considered in a highly selected group of patients with a mural pathologic complete response to neoadjuvant therapy. This approach should be prospectively investigated, and strict selection guidelines should be used.
Research Interests: Surgery, Medicine, Colorectal cancer, Humans, Female, and 15 moreMale, Aged, Middle Aged, Adult, Retrospective Studies, Lymph Node, Rectal Cancer, Combined Modality Therapy, neoadjuvant therapy, Patient selection, Disease Free Survival, Anal Canal, Abdominoperineal resection, Rectum, and Rectal neoplasms
Research Interests: Decision Making, Chemotherapy, Medicine, Colorectal cancer, Humans, and 15 moreFemale, Male, Clinical Sciences, Aged, Middle Aged, Group, Computerized tomography, Bevacizumab, Neoadjuvant Chemotherapy, Colorectal Neoplasms, neoadjuvant therapy, liver metastases, Hepatectomy, Gastrointestinal surgery, and Liver neoplasms
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While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli... more
While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.
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(18)F-FDG PET has been shown to be of high diagnostic accuracy for the evaluation of recurrent colorectal cancer. However, the limited availability of PET scanners precludes (18)F-FDG assessment of many patients for whom the study is... more
(18)F-FDG PET has been shown to be of high diagnostic accuracy for the evaluation of recurrent colorectal cancer. However, the limited availability of PET scanners precludes (18)F-FDG assessment of many patients for whom the study is indicated. An alternative is the SPECT system in coincidence mode. The aim of this study was to determine the role of dual-head camera (18)F-FDG coincidence imaging (DHC (18)F-FDG) in patients with recurrent colorectal cancer. Methods: Sixty-seven DHC (18)F-FDG studies were performed on 62 patients with suspected recurrent colorectal cancer. Reports of contemporary CT were available for the purpose of correlation for 61 of the studies. The final diagnosis of the imaging findings was based on histology or clinical and imaging follow-up of at least 6 mo. Results: In lesion-based analysis, 103 tumor sites were suspected on DHC (18)F-FDG, CT, or colonoscopy. Ninety-three of them were found to be true tumor sites. For DHC (18)F-FDG, the sensitivity was 88%, specificity was 80%, positive predictive value (PPV) was 98%, negative predictive value (NPV) was 42%, and accuracy was 87%. For CT, the sensitivity was 63%, specificity was 10%, PPV was 85%, NPV was 3%, and accuracy was 57%. In patient-based analysis, DHC (18)F-FDG differentiated patients with recurrent cancer from disease-free patients with a sensitivity of 91%, specificity of 73%, PPV of 94%, NPV of 62%, and accuracy of 88%. DHC (18)F-FDG detected tumor sites in 12 (67%) of 18 patients with elevated carcinoembryonic antigen and negative CT findings. Conclusion: DHC (18)F-FDG is an adequate readily available technique for assessment of recurrent colorectal cancer and has a diagnostic accuracy better than that of CT.
Research Interests: Image Processing, Evaluation, Nuclear medicine, Medicine, Colorectal cancer, and 15 moreNuclear, Humans, Female, Male, Colonoscopy, Clinical Sciences, Aged, Middle Aged, Adult, Gamma Camera, Diagnostic Accuracy, Carcinoembryonic Antigen, Colorectal Neoplasms, Negative predictive value, and Neoplasm metastasis
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Research Interests: Image Processing, Evaluation, Nuclear medicine, Medicine, Colorectal cancer, and 15 moreNuclear, Humans, Female, Male, Colonoscopy, Clinical Sciences, Aged, Middle Aged, Adult, Gamma Camera, Diagnostic Accuracy, Carcinoembryonic Antigen, Colorectal Neoplasms, Negative predictive value, and Neoplasm metastasis
The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into... more
The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P < 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P < 0.01). Mutation carriers had a more advanced disease stage (14/28 - 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P = 0.02). The mean age at diagnosis was similar: 65 (+/- 9.7) years and 66.3 (+/- 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences wer...
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The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer... more
The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1-5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron...
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To assess diagnostic accuracy of combined positron emission tomography (PET) and computed tomography (CT) in detection of pelvic recurrence in patients with rectal cancer who underwent abdominoperineal or anterior resection. Sixty-two... more
To assess diagnostic accuracy of combined positron emission tomography (PET) and computed tomography (CT) in detection of pelvic recurrence in patients with rectal cancer who underwent abdominoperineal or anterior resection. Sixty-two patients were enrolled; 37 were men, and 25 were women. Seventeen patients underwent abdominoperineal resection and 45 underwent anterior resection with an anastomosis in the pelvic region before referral for PET/CT. Pelvic sites of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake were rated separately on PET and PET/CT images as benign or malignant on the basis of shape, location, and intensity of (18)F FDG uptake (1-2 = benign and/or physiologic, 3 = equivocal, 4-5 = malignant). Two readers interpreted images in consensus. Altered pelvic anatomy and presence of presacral abnormalities were assessed with CT. Pelvic recurrence was confirmed with histologic analysis or clinical and imaging follow-up. Sensitivity, specificity, positive and negative predictive values, and accuracy of PET and PET/CT in the detection of pelvic recurrence were compared with lesion- and patient-based analyses by using the chi(2) test. Clinical relevance of PET/CT assessment was determined. Of 81 pelvic sites with increased (18)F FDG uptake, 44 were malignant. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for differentiating malignant from benign (18)F FDG uptake in the pelvis were 98%, 96%, 90%, 97%, and 93% for PET/CT and 82%, 65%, 73%, 75%, and 74% for PET, respectively. The most common cause for false-positive interpretation of PET findings was physiologic (18)F FDG uptake in displaced pelvic organs. Presacral CT abnormalities were present in 30 (48%) of 62 patients, and seven (23%) abnormalities were malignant. PET/CT was used to distinguish benign and malignant presacral abnormalities with a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 96%, 88%, and 100%, respectively. PET/CT findings were clinically relevant in 29 (47%) of 62 patients. PET/CT is an accurate technique in the detection of pelvic recurrence after surgical removal of rectal cancer.
Research Interests: Radiology, Positron Emission Tomography, Medicine, Colorectal cancer, Humans, and 13 moreFemale, Male, Aged, Middle Aged, Pelvis, Single Photon Emission Computed Tomography, Adult, Retrospective Studies, X ray Computed Tomography, Rectal Cancer, Abdominoperineal resection, Medical and Health Sciences, and Rectal neoplasms
Purpose Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus... more
Purpose Capecitabine has demonstrated high efficacy as first-line treatment for metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil (FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin), established in a previous dose-finding study, should improve on infused oxaliplatin with FU and leucovorin (FOLFOX) regimens. The present studies further characterize efficacy and safety of the XELOX regimen. Patients and Methods The antitumor activity of XELOX was investigated in a colon cancer xenograft model. Patients with MCRC received first-line XELOX in 3-week treatment cycles: intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice daily (day 1, evening, to day 15, morning). Results A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study, 53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization ...
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While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli... more
While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.
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Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG,... more
Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.
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Research Interests: Genetics, Medicine, Israel, Colorectal cancer, Endometrial Cancer, and 15 moreHumans, Genetic Testing, Female, Male, Clinical Sciences, Aged, Lynch syndrome, Adult, DNA binding proteins, Genetic, Colorectal Neoplasms, DNA mutational analysis, Familial adenomatous polyposis, Endometrial neoplasms, and Genetic predisposition to disease
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Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the... more
Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.
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Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two... more
Germline mutations in BRCA1 or BRCA2 account for the majority of inherited breast cancer cases. Yet, in up to 40% of familial breast cancer cases, no mutations can be detected in either gene. Germline mutations in PTEN underlie two inherited syndromes: Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The known association of CD with breast cancer risk made it plausible that germline mutations within PTEN may play a role in inherited predisposition to breast cancer. The nine coding exons of the PTEN gene were screened for harboring germline mutations using denaturing gradient gel electrophoresis (DGGE) complemented by sequencing, in two subsets of Israeli patients: 12 patients clinically diagnosed with BRRS, and 89 women with an apparent inherited predisposition to breast cancer, some with salient features of CD. Two of three familial BRRS patients exhibited novel germline mutations in PTEN: a missense mutation changing methionine to arginine at codon 134, and insertion of two nucleotides (CA) at cDNA position 1215 resulting in a frameshift at codon 61 and a premature stop at codon 99. Among 89 high-risk women, two missense mutations were detected in exon 4: A to C change at cDNA position 1279 resulting in a change of aspargine to threonine at codon 82 (N82T), and a G to an A alteration in 1269 which alters threonine to alanine at codon 78 (T78A), a non-conservative missense mutation. This study suggests that PTEN does not play a major role in predisposing to hereditary breast cancer in Israeli women, and that detection of PTEN mutations in BRRS patients is more likely in familial cases.
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Patients with rectal cancer who have complete rectal wall tumor regression after neoadjuvant chemoradiation probably have eradication of tumor cells in the mesorectum as well, thus raising the possibility of transanal excision. All... more
Patients with rectal cancer who have complete rectal wall tumor regression after neoadjuvant chemoradiation probably have eradication of tumor cells in the mesorectum as well, thus raising the possibility of transanal excision. All pathology reports of all patients with locally advanced low and mid rectal cancer who underwent preoperative chemoradiation followed by radical resection from May 2000 to June 2004 were reviewed to evaluate the correlation between complete tumor response (ypT0) and nodal response. One hundred one consecutive patients had neoadjuvant chemoradiation followed by definitive operation. Four were excluded, leaving 64 men and 33 women (median age, 62 years). Fifty-three patients (55%) had mid rectal cancer, and 44 (45%) had low rectal cancer. Fifty-eight patients (60%) underwent low anterior resection, and 36 (37%) underwent abdominoperineal resection. In 17 patients (18%), no residual tumor cells were present within the rectal wall. One patient (6%) with ypT0 disease had positive lymph nodes. No residual tumor in the rectal wall correlates with the absence of viable cancer cells in the mesorectal tissue (94%). Approximately 10% of T1 tumors have involved lymph nodes, and local excision is an accepted option. Transanal excision could probably be considered in a highly selected group of patients with a mural pathologic complete response to neoadjuvant therapy. This approach should be prospectively investigated, and strict selection guidelines should be used.