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ABSTRACT: Cancer/testis (CT) genes are encoded by genes that are normally expressed only in the human germ line but which are activated in various malignancies. CT proteins are frequently immunogenic in cancer patients and their expression is highly restricted to tumors. They are thus important targets for anticancer immunotherapy. In several different tumor types, the expression of CT-X genes is associated with advanced disease and poor outcome, indicating that their expression might contribute to tumorigenesis. CT-X genes encoding members of the MAGE protein family on Xq28 have been shown to potentially influence the tumorigenic phenotype. We used small interfering RNA (siRNA) to investigate whether CT-X mapping to the short arm of the X-chromosome might also have tumorigenic properties and therefore be potentially targeted by functional inhibitors in a therapeutic setting. siRNAs specific to GAGE, SSX and XAGE1 were used in cell proliferation, migration and cell survival assays using cell lines derived from melanoma, a tumor type known to present high frequencies of expression of CT antigens. We found that of these, those specific to GAGE and XAGE1 most significantly impeded melanoma cell migration and invasion and those specific to SSX4 and XAGE1 decreased the clonogenic survival of melanoma cells. Our results suggest that GAGE, XAGE1 and SSX4 might each have a role in tumor progression and are possible therapeutic targets for the treatment of melanoma and other malignancies.
Oncotarget 04/2013; 4(4):531-41. · 4.78 Impact Factor
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ABSTRACT: Uniform and accurate reporting of surgical complications is the basis for quality control. We developed a computerized system for reporting and grading surgical complications in colorectal surgery. This study was conducted to evaluate this computerized reporting system.
A retrospective chart review was conducted of all surgical complications in patients who underwent resection of the colon or rectum at our institution between the years 1999 and 2004 (n = 408). All complications were recorded using the computerized reporting system and compared with complications reported in the literature.
Elective operations were performed in 75.7% of patients, and 24.3% required emergency operations. Of the 408 patients in the study, 239 (58.6%) had an uneventful recovery without complications. At least 1 complication was recorded in 169 (41.4%) patients. Grades 1 and 2 complications were recorded in 83 (20.3%) and 105 (25.7%) patients, respectively, requiring observation or medical treatment only, and 59 patients (14.5%) had grades 3 to 5 complications. The three leading complications were surgical site infection, intraabdominal abscess, and hemorrhage requiring blood transfusion. The grades 3 to 5 complication rate was within the range described in the literature, and the rate of grades 1 and 2 complications was substantially higher. These grades 1 and 2 complications were associated with a substantially longer hospital stay.
This novel complication reporting system was found feasible and proved to have a higher sensitivity for recording minor but meaningful complications that tend to prolong hospital stay.
Journal of the American College of Surgeons 04/2009; 208(3):355-61. · 4.55 Impact Factor
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Oliver Hofmann,
Otavia L Caballero,
Brian J Stevenson,
Yao-Tseng Chen, Tzeela Cohen,
Ramon Chua,
Christopher A Maher,
Sumir Panji,
Ulf Schaefer,
Adele Kruger,
Minna Lehvaslaiho,
Piero Carninci,
Yoshihide Hayashizaki,
C Victor Jongeneel,
Andrew J G Simpson,
Lloyd J Old,
Winston Hide
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ABSTRACT: Cancer/Testis (CT) genes, normally expressed in germ line cells but also activated in a wide range of cancer types, often encode antigens that are immunogenic in cancer patients, and present potential for use as biomarkers and targets for immunotherapy. Using multiple in silico gene expression analysis technologies, including twice the number of expressed sequence tags used in previous studies, we have performed a comprehensive genome-wide survey of expression for a set of 153 previously described CT genes in normal and cancer expression libraries. We find that although they are generally highly expressed in testis, these genes exhibit heterogeneous gene expression profiles, allowing their classification into testis-restricted (39), testis/brain-restricted (14), and a testis-selective (85) group of genes that show additional expression in somatic tissues. The chromosomal distribution of these genes confirmed the previously observed dominance of X chromosome location, with CT-X genes being significantly more testis-restricted than non-X CT. Applying this core classification in a genome-wide survey we identified >30 CT candidate genes; 3 of them, PEPP-2, OTOA, and AKAP4, were confirmed as testis-restricted or testis-selective using RT-PCR, with variable expression frequencies observed in a panel of cancer cell lines. Our classification provides an objective ranking for potential CT genes, which is useful in guiding further identification and characterization of these potentially important diagnostic and therapeutic targets.
Proceedings of the National Academy of Sciences 12/2008; 105(51):20422-7. · 9.68 Impact Factor
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Luiz Gonzaga Almeida,
Noboru J Sakabe,
Alice R deOliveira,
Maria Cristina C Silva,
Alex S Mundstein, Tzeela Cohen,
Yao-Tseng Chen,
Ramon Chua,
Sita Gurung,
Sacha Gnjatic,
Achim A Jungbluth,
Otávia L Caballero,
Amos Bairoch,
Eva Kiesler,
Sarah L White,
Andrew J G Simpson,
Lloyd J Old,
Anamaria A Camargo,
Ana Tereza R Vasconcelos
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ABSTRACT: The potency of the immune response has still to be harnessed effectively to combat human cancers. However, the discovery of T-cell targets in melanomas and other tumors has raised the possibility that cancer vaccines can be used to induce a therapeutically effective immune response against cancer. The targets, cancer-testis (CT) antigens, are immunogenic proteins preferentially expressed in normal gametogenic tissues and different histological types of tumors. Therapeutic cancer vaccines directed against CT antigens are currently in late-stage clinical trials testing whether they can delay or prevent recurrence of lung cancer and melanoma following surgical removal of primary tumors. CT antigens constitute a large, but ill-defined, family of proteins that exhibit a remarkably restricted expression. Currently, there is a considerable amount of information about these proteins, but the data are scattered through the literature and in several bioinformatic databases. The database presented here, CTdatabase (http://www.cta.lncc.br), unifies this knowledge to facilitate both the mining of the existing deluge of data, and the identification of proteins alleged to be CT antigens, but that do not have their characteristic restricted expression pattern. CTdatabase is more than a repository of CT antigen data, since all the available information was carefully curated and annotated with most data being specifically processed for CT antigens and stored locally. Starting from a compilation of known CT antigens, CTdatabase provides basic information including gene names and aliases, RefSeq accession numbers, genomic location, known splicing variants, gene duplications and additional family members. Gene expression at the mRNA level in normal and tumor tissues has been collated from publicly available data obtained by several different technologies. Manually curated data related to mRNA and protein expression, and antigen-specific immune responses in cancer patients are also available, together with links to PubMed for relevant CT antigen articles.
Nucleic Acids Research 11/2008; 37(Database issue):D816-9. · 8.03 Impact Factor
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ABSTRACT: This study was conducted to determine survival according to the expression of molecular markers in colorectal cancer (CRC) patients of various ethnic origins.
Resection of primary tumor was conducted on 171 patients with CRC. Corresponding archived paraffin-embedded blocks were retrieved and tissue microarray (TMA) constructed. Immunohistochemical staining of the TMA for p53, p27 and Ki-67 was quantified by two independent pathologists. Survival was analyzed using the Kaplan-Meier product limit method.
With a median follow-up of 65 months, 56 patients (32.7%) died of disease. AJCC stage correlated with disease-free (DFS, P < 0.0001) and overall survival (OS, P < 0.0001). IHC staining was positive for Ki-67 in 77.4%, p53 in 55.8% and p27 in 54.2% of patients. Primary tumor marker expression did not correlate with DFS or OS. The 5-year DFS for Ashkenazi Jews was 75%, significantly higher than Sephardic Jews (SJ) 64% and Palestinian Arabs (PA) 38%, P = 0.001.
Ethnicity among Ashkenazi and SJ and PA appears to have a significant impact on disease outcome in patients with CRC patients, while primary tumor expression of p53, p27 and Ki-67 was unrelated to disease outcome.
Journal of Surgical Oncology 05/2008; 97(5):416-22. · 2.10 Impact Factor
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ABSTRACT: Patients with subungual melanoma (SM) often experience delayed diagnosis and present with deep primary lesions. Breslow depth of the primary lesion is often unknown before definitive resection, thus complicating treatment planning.
Patients with SM treated at our institution from 1992 to 2004 were identified from our prospective melanoma database. Clinical and pathologic factors were reviewed; Student t test and Kaplan-Meier method were used for statistical analysis.
Forty-nine patients were identified; most were female (63%). The median age was 66 years (range 24 to 83). The most common site was the great toe (n = 21), followed by the thumb (n = 15). Eight patients had in situ disease; 6 were treated initially with wide local excision, and 4 of these eventually required amputation. The median Breslow depth of invasive lesions was 2.1 mm (range .2 to 11). Toe lesions were thicker than finger lesions (mean 3.5 vs 2.5 mm, P = .005). Patients with invasive SM of the toe had a less favorable outcome than those with finger lesions (5-year overall survival 40% vs 72%, respectively; P = .05). Sentinel lymph node (SLN) biopsy was performed in 30 patients and was positive in 5 (17%); all underwent completion lymphadenectomy. Median Breslow depth in patients with positive SLN was 4 mm (range 1.2 to 11). Four of 5 patients with positive SLN developed recurrence (median 16 months); 3 patients died of disease within 40 months.
Patients with SM present distinct therapeutic challenges. They continue to present with deep primary melanoma, particularly on the toe. Undertreatment of early disease is associated with local recurrence.
American journal of surgery 03/2008; 195(2):244-8. · 2.36 Impact Factor
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Suely K N Marie,
Oswaldo K Okamoto,
Miyuki Uno,
Ana Paula G Hasegawa,
Sueli M Oba-Shinjo, Tzeela Cohen,
Anamaria A Camargo,
Ana Kosoy,
Carlos G Carlotti,
Silvia Toledo,
Carlos A Moreira-Filho,
Marco A Zago,
Andrew J Simpson,
Otavia L Caballero
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ABSTRACT: We have performed cDNA microarray analyses to identify gene expression differences between highly invasive glioblastoma multiforme (GBM) and typically benign pilocytic astrocytomas (PA). Despite the significant clinical and pathological differences between the 2 tumor types, only 63 genes were found to exhibit 2-fold or greater overexpression in GBM as compared to PA. Forty percent of these genes are related to the regulation of the cell cycle and mitosis. QT-PCR validation of 6 overexpressed genes: MELK, AUKB, ASPM, PRC1, IL13RA2 and KIAA0101 confirmed at least a 5-fold increase in the average expression levels in GBM. Maternal embryonic leucine zipper kinase (MELK) exhibited the most statistically significant difference. A more detailed investigation of MELK expression was undertaken to study its oncogenic relevance. In the examination of more than 100 tumors of the central nervous system, we found progressively higher expression of MELK with astrocytoma grade and a noteworthy uniformity of high level expression in GBM. Similar level of overexpression was also observed in medulloblastoma. We found neither gene promoter hypomethylation nor amplification to be a factor in MELK expression, but were able to demonstrate that MELK knockdown in malignant astrocytoma cell lines caused a reduction in proliferation and anchorage-independent growth in in vitro assays. Our results indicate that GBM and PA differ by the expression of surprisingly few genes. Among them, MELK correlated with malignancy grade in astrocytomas and represents a therapeutic target for the management of the most frequent brain tumors in adult and children.
International Journal of Cancer 03/2008; 122(4):807-15. · 5.44 Impact Factor
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ABSTRACT: Soybeans have been shown to have numerous health benefits, but the underlying mechanisms are poorly understood. The aim of this study was to characterize some pharmacologic properties of active substances in aqueous soy extract.
The pharmacologic actions of the extract were tested by measuring mechanical activity of isolated guinea-pig ileum in an organ bath.
The ileum contracted in response to soy extract in a concentration-dependent manner. This response was unaffected by the nerve blocker tetrodotoxin (10(-6) M) but was completely inhibited by atropine (10(-9) M), indicating an action via muscarinic receptors on the muscle. In the presence of the M(3) muscarinic antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide and to a lesser extent in the presence of the M(2) muscarinic antagonist 11-([2-[(diethylamino)methyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, the response was decreased. When acetylcholine (ACh) esterase inhibitors were added to the medium before the addition of soy extract, the response to the extract was potentiated. Preincubation of the extract with exogenous ACh esterase reduced its activity. The response to choline, ACh, and phosphorylcholine was also tested, and none of these substances accurately replicated the response to soy extract. However, some qualitative similarities were observed between the effect of choline and ACh to that of the extract.
These results indicate the presence of an ACh-like substance in soy. Due to the abundance and importance of muscarinic receptors, the presence of a cholinergic substance in soy could have numerous implications. The role of this substance in the beneficial effect of soy on various body systems merits further investigation.
Nutrition 10/2007; 23(9):681-6. · 3.03 Impact Factor
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Wilson A Silva,
Sacha Gnjatic,
Erika Ritter,
Ramon Chua, Tzeela Cohen,
Melinda Hsu,
Achim A Jungbluth,
Nasser K Altorki,
Yao-Tseng Chen,
Lloyd J Old,
Andrew J G Simpson,
Otavia L Caballero
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ABSTRACT: Identification of genes that are upregulated in tumors, and whose normal expression excludes adult somatic tissues but includes germline and/or embryonic tissues, has resulted in a rich variety of cancer antigens that are attractive targets for cancer vaccine and other therapeutic approaches. In the present study, we extended this approach to include genes strongly and restrictively expressed in the placenta by mining publicly available SAGE and EST databases. We identified a number of genes with high expression in placenta and different cancer types but with relatively restricted expression in normal tissues. The gene with the most distinctive expression pattern was found to be PLAC1, which encodes a putative cell surface protein that is highly expressed in placenta, testis, cancer cell lines and lung tumors. Hence we have designated it CT92. We found by ELISA that PLAC1 is immunogenic in a subset of cancer patients and healthy women. Its physical and expression characteristics render it a potential target for both active and passive cancer immunotherapeutic strategies.
Cancer immunity: a journal of the Academy of Cancer Immunology 02/2007; 7:18.
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ABSTRACT: Carbohydrate antigen (CA) 19-9 is produced by adenocarcinomas of the pancreas, stomach, gall bladder, colon, ovary and lung. Serum CA 19-9 is considered the most sensitive marker for pancreatic cancer, being elevated in 75% or more of patients with pancreatic cancer. In all three cases of pancreatic cancer presented, patients died of their disease quite shortly after diagnosis. Preoperative imaging was unsuccessful in exposing the actual advanced state extent of the disease and even during surgery its real extent was underestimated. The only prognostic indicator of the observed rapid disease progression was a very significant elevation of preoperative serum CA 19-9.
Harefuah 12/2006; 145(11):793-4, 863.
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The Israel Medical Association journal: IMAJ 11/2006; 8(10):720-1. · 1.02 Impact Factor
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ABSTRACT: Sporadic late-onset medullary carcinoma of the thyroid is quite rare. Usually, the patient presents with a thyroid mass or neck node metastasis along with high levels of calcitonin and preoperative fine needle aspiration biopsy suggestive of medullary carcinoma of the thyroid. The role of genetic testing in such individuals, along with testing of other family members, remains somewhat unclear at this stage, especially in patients presenting with familial medullary thyroid carcinoma. Genetic testing with RET proto-oncogene mutational studies is very popular in familial medullary thyroid carcinoma, especially in children, with routine prophylactic thyroidectomy. However, its indications in adults remain unclear at this time.
Recently, a 69-year-old woman presented with a thyroid mass and underwent total thyroidectomy and central compartment dissection. She was found to have medullary carcinoma of the thyroid. The patient had four children, three of whom were found to have a RET mutation similar to their mother's, V804M. In view of the RET mutation, the three children were offered prophylactic thyroidectomy at ages 42, 45, and 47. The patient's son was noted to have extensive C-cell hyperplasia in both lobes of the thyroid. The other two individuals had benign pathology with no evidence of C-cell hyperplasia.
There is no definite consensus of opinion about the need for prophylactic total thyroidectomy in adults with RET mutation. The rarely reported 804 mutation is, however, a predictor of medullary carcinoma of the thyroid. One individual in this group had extensive C-cell hyperplasia, suggesting that he would have developed medullary carcinoma of the thyroid in the future. Prophylactic thyroidectomy should be recommended in patients with RET mutation and a family history of medullary carcinoma of the thyroid; however, its role in adult family members needs to be evaluated with larger registry of prophylactic thyroidectomy. Whether these adults with rare 804-mutation could be observed and followed with serial calcitonin, ultrasound, or calcitonin stimulation tests remains to be studied.
The Laryngoscope 10/2006; 116(9):1704-7. · 1.75 Impact Factor
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ABSTRACT: The clinical profile of breast cancer may vary among different ethnic groups living in the same country and therefore affect the yield of a breast cancer screening program. The present study attempts to better characterize the breast cancer clinical profile of Arab women compared with Jewish women in the greater Jerusalem area with a future aim of establishing a comprehensive and effective screening program for this population.
Retrospective chart review was conducted and the following covariates were correlated with survival: ethnicity, age at diagnosis, and American Joint Committee on Cancer (TNM) stage at diagnosis.
A total of 312 women were operated on for breast cancer between 1994 and 1999; 51% were Ashkenazi Jews (AJ), 26% were Sephardic Jews (SJ), 21% were Palestinian Arabs (PA), and 2% patients did not fit into those ethnic groups. The mean age at diagnosis was 51.5 years for the PA group, 53.4 +/- 1.5 for the SJ group, and 55.9 years for the AJ group (P <0.03 PA versus AJ). The tumor size (mean +/- SEM) was 38.8 +/- 3.7 mm, 31.1 +/- 2.4 mm, and 24.5 +/- 1.6 mm for the PA, SJ, and AJ groups, respectively (P = 0.03 for PA versus SJ and P <0.001 for PA versus AJ). Five-year overall survival was 77 %, 72%, and 58% for the AJ, SJ, and PA groups, respectively (P = 0.02); and 5-year disease-free survival was 72%, 51%, and 50% for the AJ, SJ, and PA groups, respectively (P = 0.03, AJ versus SJ).
Our data demonstrate younger age and larger primary tumor size for the Arab patients compared with the Jewish patients. These findings were associated with lower 5-year survival and disease-free survival of the Arab patients.
The American Journal of Surgery 07/2004; 188(1):62-7. · 2.78 Impact Factor
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ABSTRACT: The ultimate therapy for acute cholecystitis is cholecystectomy. However, in critically ill elderly patients the mortality of emergency cholecystectomy may reach up to 30%. Open cholecystostomy performed under local anesthesia was considered to be the procedure of choice for treatment of acute cholecystitis in high-risk patients. In recent years, ultrasound- or computed tomography (CT)-guided percutaneous transhepatic cholecystostomy (PTHC) replaced open cholecystostomy for the treatment of acute cholecystitis in critically ill patients.
The aim of the present study was to evaluate the results of a 5-year protocol using PTHC followed by delayed laparoscopic cholecystectomy for the treatment of acute cholecystitis in critically ill patients. We reviewed the charts of 55 patients who underwent PTHC at the Hadassah University Hospital Mount Scopus during the years 1994 to 1999.
The main indications for PTHC among this group of severely sick and high-risk patients was biliary sepsis and septic shock in 23 patients (42%); and severe comorbidities in 32 patients (58%). The median age was 74 (32 to 98) years, 33 were female and 22 male. Successful biliary drainage by PTHC was achieved in 54 of 55 (98%) of the patients. The majority of the patients (31 of 55) were drained transhepaticlly under CT guidance. The rest, (24 of 55) were drained using ultrasound guidance followed by cholecystography for verification. Complications included hepatic bleeding that required surgical intervention in 1 patient and dislodgment of the catheter in 9 patients that was reinserted in 2 patients. Three patients died of multisystem organ failure 12 to 50 days following the procedure. The remaining 52 patients recovered well with a mean hospital stay of 15.5 plus minus 11.4 days. Thirty-one patients were able to undergo delayed surgery: 28 underwent laparoscopic cholecystectomy of whom 4 (14%) were converted to open cholecystectomy. This was compared with a 1.9% conversion rate in 1,498 elective laparoscopic cholecystectomies performed at the same time period (P = 0.012). Another 3 patients underwent planned open cholecystectomy, 1 urgent and 2 combined with other abdominal procedures. There was no surgery associated mortality, severe morbidity, or bile duct injury.
The use of PTHC in critically ill patients with acute cholecystitis is both safe and effective.
The American Journal of Surgery 02/2002; 183(1):62-6. · 2.78 Impact Factor
