200 Medical Plaza #B265
Los Angeles CA 90095
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Alternative cyclin D1 splice forms differentially regulate the DNA damage response. - Cancer research
The DNA damage response (DDR) activates downstream pathways including cell cycle checkpoints. The cyclin D1 gene is overexpressed or amplified in many human cancers and is required for gastrointestinal, breast, and skin tumors in murine models. A common polymorphism in the human cyclin D1 gene is alternatively spliced, resulting in cyclin D1a and D1b proteins that differ in their carboxyl terminus. Cyclin D1 overexpression enhances DNA damage-induced apoptosis. The role of cyclin D1 and the alternative splice form in regulating the DDR is not well understood. Herein cyclin D1a overexpression enhanced the DDR as characterized by induction of Î³H2AX phosphorylation, the assembly of DNA repair foci, specific recruitment of DNA repair factors to chromatin, and G(2)-M arrest. Cyclin D1 deletion in fibroblasts or small interfering RNA-mediated reduction of endogenous cyclin D1 in colon cancer cells reduced the 5-fluorouracil-mediated DDR. Mechanistic studies showed that cyclin D1a, like DNA repair factors, elicited the DDR when stably associated with chromatin.Â©2010 AACR.
Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. - Gastroenterology
The human equilibrative nucleoside transporter (hENT1) protein transports gemcitabine into cells. Small retrospective studies in pancreatic cancer suggest that levels of hENT1 protein or messenger RNA may have prognostic value. We studied the predictive value of hENT1 levels in a cohort of pancreatic adenocarcinoma patients from the large prospective randomized adjuvant treatment trial RTOG9704.In RTOG9704, 538 patients were assigned randomly, after surgical resection, to groups that were given either gemcitabine or 5-fluorouracil (5-FU). Immunohistochemistry for hENT1 was performed on a tissue microarray of 229 resected pancreatic tumors from RTOG9704 and scored as having no staining, low staining, or high staining. Associations between hENT1 protein and treatment outcome were analyzed by unconditional logistic regression analysis using the chi-square test and the Cox proportional hazards model.HENT1 expression was associated with overall and disease-free survival in a univariate (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.91; P= .02; and HR, 0.57; 95% CI, 0.32-1.00; P= .05) and multivariate model in the group given gemcitabine (HR, 0.40; 95% CI, 0.22-0.75; P= .004; and HR, 0.39; 95% CI, 0.21-0.73; P= .003). hENT1 expression was not associated with survival in the group given 5-FU.In this prospective randomized trial, hENT1 protein expression was associated with increased overall survival and disease-free survival in pancreatic cancer patients who received gemcitabine, but not in those who received 5-FU. These findings are supported by preclinical data; the gemcitabine transporter hENT1 is therefore a molecular and mechanistically relevant predictive marker of benefit from gemcitabine in patients with resected pancreatic cancer.
Early detection markers in Pancreas Cancer. - Cancer biomarkers : section A of Disease markers
The role of early detection in cancer has shown improved survival for certain cancers, including colon cancer, cervical cancer and breast cancer. The possibility for early detection of pancreatic cancer may be realized by an improved understanding of the histology and molecular genetics of precursor lesions and cancerous lesions in pancreatic cancer and the development of sensitive and specific screening tests (both invasive and non-invasive) to detect early pancreatic cancer. The NIH-NCI Early Detection Research Network (EDRN) in Pancreatic Cancer has been focussed on the development and validation of new biomarkers for the detection of early pancreatic cancer. This review will focus on our understanding of the histologic and molecular model of pancreatic carcinogenesis, current strategies and limitations of screening for pancreatic cancer and the development and validation of new biomarkers for the early detection of pancreatic cancer.
The efficacy of hyperbaric oxygen therapy in the treatment of radiation-induced late side effects. - International journal of radiation oncology, biology, physics
We investigated the efficacy of hyperbaric oxygen therapy (HBOT) in the management of patients with radiation-induced late side effects, the majority of whom had failed previous interventions.Of 105 eligible subjects, 30 had either died or were not contactable, leaving 75 who qualified for inclusion in this retrospective study. Patients answered a questionnaire documenting symptom severity before and after treatment (using Radiation Therapy Oncology Group criteria), duration of improvement, relapse incidence, and HBOT-related complications.The rate of participation was 60% (45/75). Improvement of principal presenting symptoms after HBOT was noted in 75% of head-and-neck, 100% of pelvic, and 57% of "other" subjects (median duration of response of 62, 72, and 68 weeks, respectively). Bone and bladder symptoms were most likely to benefit from HBOT (response rate, 81% and 83%, respectively). Fifty percent of subjects with soft tissue necrosis/mucous membrane side effects improved with HBOT. The low response rate of salivary (11%), neurologic (17%), laryngeal (17%), and upper gastrointestinal symptoms (22%) indicates that these were more resistant to HBOT. Relapse incidence was low (22%), and minor HBOT-related complications occurred in 31% of patients.Hyperbaric oxygen therapy is a safe and effective treatment modality offering durable relief in the management of radiation-induced osteoradionecrosis either alone or as an adjunctive treatment. Radiation soft tissue necrosis, cystitis, and proctitis also seemed to benefit from HBOT, but the present study did not have sufficient numbers to reliably predict long-term response.
CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
The CpG island methylator phenotype (CIMP) is observed in approximately 30% of colorectal cancer (CRC) cases and is characterized by the concurrent methylation of multiple CpG islands in tumor DNA. This phenotype (CIMP+) is more frequently observed in tumors with proximal location, microsatellite instability, and normal p53. Because it has previously been observed that each of these features is associated with a good survival benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy, we investigated in the present study whether CIMP+ has independent predictive value.CIMP+ status was evaluated in 103 stage III CRCs from patients treated with surgery alone and for an additional 103 cases from patients treated with surgery and adjuvant 5-FU-based chemotherapy. The two cohorts were randomly pair-matched for age, sex, and tumor site, and the median length of follow-up time was 39 months.CIMP+ status predicted survival benefit from 5-FU treatment independently of microsatellite instability and p53 mutation status (relative risk = 0.22; 95% confidence interval, 0.06-0.84; P = 0.027). Unmeasured, high-risk confounding factors could only account for this association if they were unequally distributed between the two patient cohorts by a factor of at least 2-fold.CIMP+ has independent predictive significance for the survival benefit from 5-FU chemotherapy in CRC. This molecular marker should be incorporated into prospective clinical trials of fluorouracil-based therapies to confirm its clinical value.
Extent of nodal involvement in Stage III colorectal carcinoma: relationship to clinicopathologic variables and genetic alterations. - Diseases of the colon and rectum
Recent evidence from our laboratory suggests that the factors of tumor site, patient gender, microsatellite instability, and mutations are important determinants in the survival benefit associated with adjuvant chemotherapy in Stage III colorectal carcinoma. In the present study we investigated whether these factors, as well as Ki- mutations, were also associated with the extent of nodal involvement in Stage III cancers.Nodal involvement was retrospectively evaluated in a series of 645 patients with Stage III colorectal cancer from Sir Charles Gairdner Hospital. The number of involved nodes was correlated with the clinicopathologic features of gender, age, tumor site, and histologic grade, as well as to the genetic alterations of mutation, Ki- mutation, and microsatellite instability.The median number of nodes examined per tumor was 11 (range, 1-53). Forty-nine percent of cases had one or two involved nodes and 51 percent had three or more involved nodes, the latter feature being associated with significantly reduced patient survival. No differences in the extent of nodal involvement were apparent with respect to tumor site, patient gender, or or Ki- mutation status. Tumors from younger patients (P = 0.025) or with poorly differentiated histology (P = 0.007), were associated with significantly higher nodal burden, whereas the microsatellite instability phenotype was associated with less extensive nodal involvement (P = 0.020). Survival benefits from the use of chemotherapy were apparent for both the low and high nodal involvement groups, although the latter seemed to obtain relatively more benefit. Multivariate analysis of patients treated with chemotherapy found that gender, grade, and microsatellite instability, but not nodal involvement, were independently prognostic for survival.The extent of nodal involvement in Stage III colorectal cancer is related to patient age, tumor grade, and microsatellite instability status, but not to tumor site, patient gender, or Ki- mutation. These results indicate that differences in metastatic nodal burden cannot explain previously observed site, gender, and mutation differences in the response to chemotherapy.
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200 Medical Plaza #B265 Los Angeles, CA 90095
Ucla Cardiothoracic Surgery 10833 Leconte Ave 62-182 Chs
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