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Yuman Fong

Publications and source records attributed to Yuman Fong.

At least 19 recordsLinked to original sources
PubMed2007

Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity.

Oncolytic viruses based on herpes simplex virus type 1 (HSV-1) are able to infect and lyse a variety of malignant cell lines. However, there is variability in the degree of tumor susceptibility, and the cancer cell determinants of HSV sensitivity are poorly defined. Nectin-1 is a cell surface adhesion molecule that functions as a cellular receptor to HSV envelope glycoprotein D (gD). We assessed tumor nectin-1 expression as a predictor of oncolytic HSV sensitivity. A panel of human squamous carcinoma cell lines was evaluated for viral entry, replication, and cytotoxicity to an attenuated, replication-competent, oncolytic HSV (NV1023). Potential tumor determinants of HSV sensitivity were assessed, including nectin-1, herpes viral entry mediator, total gD receptor expression, S-phase fraction, and doubling time. Significant correlations between nectin-1 expression measured by quantitative fluorescence-activated cell sorting and viral sensitivity measures were identified using Pearson's coefficients. Cancer cell nectin-1 receptor blockade and nectin-1 transfection led to inhibition and enhancement of NV1023 viral entry, respectively. Cell lines with varying nectin-1 expression showed corresponding sensitivity to NV1023 therapy in vivo. Immunohistochemistry for nectin-1 was inversely related to E-cadherin staining, suggesting increased herpes sensitivity of E-cadherin-deficient tumors. These results suggest that nectin-1 may be used as a marker to predict the sensitivity of a tumor to herpes oncolytic therapy.

Animals↗
PubMed2006

Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy.

BACKGROUND: Hepatic resection is generally accepted as the only potential for long-term survival in patients with colorectal metastases confined to the liver. Despite an unknown benefit, hepatic resection is playing an increasing role in patients with extensive disease. METHODS: A retrospective review of a prospectively maintained hepatobiliary surgical database was carried out. Outcome after hepatectomy for four or more colorectal hepatic metastases was reviewed. RESULTS: Between 1998 and 2002, out of a total of 584 patients, 98 (17%) with four or more colorectal hepatic metastases were resected. Actuarial 5-year survival was 33% for the entire group, with seven actual 5-year survivors. There were no perioperative deaths, and the perioperative morbidity was 28%. Positive margins and extrahepatic disease resection were independently associated with poor outcome. The median disease-free survival was 12 months, with no actuarial disease-free survivors at 5 years. Recurrence pattern, response to neoadjuvant chemotherapy, time to recurrence, and resection of recurrent disease were also associated with outcome. CONCLUSIONS: Long-term survival can be achieved after resection of multiple colorectal metastases; however, because most patients will experience recurrence of disease, effective adjuvant therapy and close follow-up is necessary.

Adult↗
PubMed2006

Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study.

BACKGROUND: Bevacizumab (bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). Perioperative bev is now commonly used in patients undergoing hepatic resection. Little is known, however, about the safety of perioperative bev use in the setting of hepatic resection. METHODS: Computerized pharmacy records were used to identify all patients who received bev between January 2004 and June 2005. Patients who underwent hepatectomy for colorectal metastases and received bev within 12 weeks of surgery were identified and compared with a group of matched historical controls. RESULTS: Thirty-two patients underwent hepatic resection of colorectal cancer metastases and received bev within the specified perioperative period. Sixteen patients received bev before surgery and 24 received bev after surgery. A subset of eight patients received bev both before and after surgery. The median time between bev administration and surgery was 6.9 weeks before (range, 3-15 weeks) and 7.4 weeks after (range, 5-15 weeks). Perioperative complications occurred in 13 patients (40.6%), two of which were considered major complications. There was no statistically significant difference in perioperative morbidity and severity of complications when compared with a set of matched controls. CONCLUSIONS: Clinical experience thus far does not indicate a statistically significantly increased risk of perioperative complications with the incorporation of bev into pre- and/or postoperative treatment paradigms. Given the long half-life of bev and the potential for anti-VEGF therapy to impede wound healing and/or liver regeneration, we continue to favor a window of 6 to 8 weeks between bev administration and surgery.

Adult↗
PubMed2006

Radiation-induced cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) treated with radiotherapy (RT) has incomplete responses as a result of radiation-induced tumoral stress response that repairs DNA damage. Such stress response is beneficial for oncolytic viral therapy. We hypothesized that a combination of RT and NV1066, an oncolytic herpes virus, might exert an additive or synergistic effect in the treatment of MPM. METHODS: JMN, a MPM cell line, was infected with NV1066 at multiplicities of infection of .05 to .25 in vitro with and without radiation (1 to 5 Gy). Virus replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 (growth arrest and DNA damage repair 34, a DNA damage-repair protein) by real-time reverse transcriptase-polymerase chain reaction and Western blot test. Synergistic cytotoxicity dependence on GADD34 upregulation was confirmed by GADD34 small inhibitory RNA (siRNA). RESULTS: Synergism was demonstrated between RT and NV1066 across a wide range of doses. As a result of such synergism, a dose-reduction for each agent (up to 5500-fold) can be accomplished over a wide range of therapeutic-effect levels without sacrificing tumor cell kill. This effect is correlated with increased GADD34 expression and inhibited by transfection of siRNA directed against GADD34. CONCLUSIONS: RT can be combined with oncolytic herpes simplex virus therapy in the treatment of malignant pleural mesothelioma to achieve synergistic efficacy while minimizing dosage and toxicity.

Animals↗
PubMed2006

Differential diagnosis of proximal biliary obstruction.

BACKGROUND: Obstruction at the hepatic duct confluence is generally due to hilar cholangiocarcinoma (HCCA). However, in up to 15% of patients, hilar obstruction could be due to alternative diagnoses other than HCCA. The aim of this study was to determine preoperative criteria that could differentiate HCCA from the alternative diagnoses. METHODS: All patients with hilar obstruction presumed to represent HCCA were included (1997-2001). The extent of disease was assessed preoperatively with computed tomography, magnetic resonance cholangiopancreatography, and Duplex ultrasonography, and these findings were correlated to the final histopathology. RESULTS: A total of 171 patients were included in the study, with HCCA being the most common diagnosis (141 patients [82.4%], group I). Alternative diagnoses other than HCCA were encountered in 30 patients (17.5%, group II) and included benign stricture (9 patients [5.2%]) and other malignancy (21 patients [12%]). There was a higher incidence of involvement of the second-order bile ducts in group I (26% vs 3% in group II, P<.01). Vascular involvement and lobar atrophy were more common in group I (58% and 41%) when compared with group II (16% and 6%, P<.005 and P<.002). The combination of these 2 findings (vascular invasion+lobar atrophy) was reliable for discriminating patients with HCCA from the alternative diagnoses. (38% in group I and 3.3% in group II, P<.001). CONCLUSIONS: Involvement of second-order bile ducts, vascular invasion, and lobar atrophy are more likely in patients with HCCA. The combination of vascular invasion and lobar atrophy significantly increases the diagnostic likelihood of HCCA. The absence of these findings should raise awareness of the possibility of an alternative diagnosis.

Aged↗
PubMed2006

Particle embolization of recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND: Complete surgical resection is the mainstay of treatment for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients ultimately develop disease recurrence and the median survival from the time of recurrence is <1 year. The purpose of the current study was to review the authors' experience using bland hepatic arterial embolization to treat recurrent HCC after definitive surgical resection. METHODS: The authors reviewed their single-center hepatic embolization database from 1995 through 2004 to identify patients who underwent bland hepatic arterial embolization for disease recurrence. Data analyzed included patient demographics, Okuda stage and Child score, imaging findings, and embolization variables. Recurrence-free survival (from surgery to disease recurrence) and survival time (from recurrence to last follow-up) were calculated using the Kaplan-Meier method. RESULTS: The authors identified 45 patients treated with bland embolization for recurrent HCC after resection. Six patients also underwent ablative therapy after embolization. Of the 45 patients, 42 (93.3%) patients had Okuda Stage 1 disease. The median time to recurrence was 13 months. The median survival after embolization was 46 months, and actuarial survival rates at 1 year, 2 years, and 5 years after recurrence were 86%, 74%, and 47%, respectively, with a median follow-up of 31 months. Patients who developed disease recurrence with a solitary lesion had a significantly improved survival (P = .03) At the time of last follow-up, 3 patients (6.6%) were alive with no evidence of viable disease. CONCLUSIONS: Bland arterial embolization was found to be an effective method of salvage therapy for patients with good liver function with recurrent HCC after prior surgical resection. Patients whose disease recurred with a solitary lesion appear to have a significantly increased survival compared with patients who develop disease recurrence with multiple tumors. A small proportion of patients can be rendered without evidence of viable disease.

Adult↗
PubMed2006

Outcome of patients with fibrolamellar hepatocellular carcinoma.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma, has distinct pathologic features, and typically occurs in young patients without underlying hepatitis or cirrhosis. METHODS: Forty-one patients with the pathologic diagnosis of FL-HCC evaluated at our institution between 1986 and 2003 were identified from a prospective database. RESULTS: Median age of all patients was 27 years. None of these patients had underlying hepatitis or cirrhosis, and only 3 (7%) patients had an alpha-fetoprotein level > 200 ng/mL. Twenty-eight patients with primary disease underwent complete gross resection, and 13 patients were unresectable. In patients treated with resection, median tumor size was 9 cm (range, 3-17), 9 (36%) had vascular invasion, and 14 (50%) had lymph node metastases. There were no perioperative deaths. With a median follow-up of 34 months, 5-year overall survival for resected patients was 76%. However, 5-year recurrence-free survival was only 18%, and of the 9 resected patients with more than 5 years of follow-up, 7 had recurrences. Lymph node metastasis was the only significant negative prognostic factor. Seventeen (61%) patients underwent a second operation for recurrent disease. Median survival for unresected patients with FL-HCC was only 12 months, and no patient survived beyond 5 years. CONCLUSIONS: FL-HCC occurs in a distinctly different population of patients than common HCC, and patients with FL-HCC generally fare better after complete resection. These tumors have a relatively indolent tumor biology, and late recurrences are common. Repeat resections for recurrence should be considered given the lack of other effective treatment options.

Adolescent↗
PubMed2006

Differential cell cycle-regulatory protein expression in biliary tract adenocarcinoma: correlation with anatomic site, pathologic variables, and clinical outcome.

PURPOSE: Biliary tract adenocarcinomas (BTAs), although anatomically related, arise through ill-defined and possibly different location-related pathogenetic pathways. This clinicopathologic study characterizes differences in cell cycle-regulatory protein expression across the spectrum of BTA. METHODS: Tissue microarrays were prepared from paraffin-embedded surgical specimens with triplicate cores of BTA and benign tissue. Immunohistochemical expression of p53, cyclin D1, p21, Bcl2, p27, Mdm2, and Ki-67 was assessed, and the results were correlated with pathologic variables and survival. Hierarchical clustering was used to partition the data based on protein expression, and then the data were analyzed according to anatomic location. RESULTS: Tissue from 128 surgical patients (1992 to 2002) was obtained. Tumor sites of origin were intrahepatic cholangiocarcinoma (IH; n = 23), hilar cholangiocarcinoma (Hilar; n = 54), gallbladder (GB; n = 32), and distal bile duct (Distal; n = 19). p27 expression decreased progressively from proximal to distal in the biliary tree and correlated with location-related differences in outcome; cyclin D1 and Bcl2 overexpression also varied according to anatomic site. Aberrant p53 staining and cyclin D1 overexpression were lower in papillary tumors compared with the more common sclerosing tumors. The expression profiles of GB and Hilar were more similar to each other than either was to IH or Distal (86% clustering in the first partition). After an R0 resection, overexpression of Mdm2 (P = .0062) and absent p27 expression (P = .0165) independently predicted poor outcome. CONCLUSION: BTAs differentially express cell cycle-regulatory proteins based on tumor location and morphology. Prognostic roles were identified for Mdm2 and p27. Overlap in the pathogenesis of GB and Hilar tumors was suggested.

Aged↗
PubMed2006

Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery.

Current efforts on expanding minimally invasive techniques into the realm of oncological surgery are hindered by lack of accurate visualization of tumor margins and failure to detect micro metastases in real time. We used a systemic delivery of a herpes viral vector with cancer-selective infection and replication to precisely differentiate between normal and malignant tissue. NV1066 is a genetically modified, replication-competent herpes simplex virus carrying a transgene for enhanced green fluorescent protein (GFP). We tested the potential of NV1066 in delineating tumor tissue in vitro and in vivo in a wide range of cancers and whether NV1066-induced GFP expression can detect small foci of tumors and metastases in in vivo models using an operating endoscope with fluorescent filters. Our findings indicate that NV1066 can be used for real-time intraoperative imaging and enhanced detection of early cancers and metastases. We demonstrate that a single dose of NV1066, administered either locally (intratumoral or intracavitary) or systemically, will detect loco-regional and distant disease throughout the body. Such cancer selectivity is confirmed in 110 types of cancer cells from 16 different primary organs. Fluorescence-aided minimally invasive endoscopy revealed microscopic tumor deposits unrecognized by conventional laparoscopy/thoracoscopy. Furthermore, NV1066 ability to transit and infect tumor and metastases is proven in syngenic and transplanted tumors in different animal models, both immunocompetent and immunodeficient. Cancer-selective GFP expression is confirmed by histology, immunohistochemistry, and qRT-PCR. These studies form the basis for real-time, intraoperative diagnostic imaging of tumor and metastases by minimally invasive endoscopic technology.

Animals↗
PubMed2006

Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma.

BACKGROUND: NV1066, a replication-competent oncolytic herpes simplex virus type 1 (HSV-1) attenuated by a deletion in the gene gamma(1)34.5, preferentially replicates in and kills malignant cells. gamma(1)34.5 encodes ICP34.5, a viral protein essential for productive replication, which has homology with mammalian stress response induced GADD34 (growth arrest and DNA damage-inducible protein). We hypothesized that cisplatin upregulates GADD34 expression, which enhances NV1066 replication and oncolysis. METHODS: Ten human malignant pleural mesothelioma (MPM) cell lines were infected with NV1066 at multiplicities of infection (MOI; ratio of viral particles per tumor cell) 0.005 to 0.8 in vitro, with and without cisplatin (1 to 4 microM). In the MPM cell line VAMT, viral replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 induction by quantitative RT-PCR and Western blot. Synergistic efficacy was confirmed by the isobologram and combination index methods of Chou-Talalay. GADD34 upregulation by cisplatin was inhibited with GADD34 siRNA to further confirm the synergistic efficacy dependence with GADD34. RESULTS: Combination therapy with NV1066 and cisplatin showed strong synergism in epithelioid (H-2452, H-Meso), sarcomatoid (H-2373, H-28), and biphasic (JMN, Meso-9, MSTO-211H) MPM cell lines, and an additive effect in others. In VAMT cells combination therapy enhanced viral replication 4 to 11-fold (p < 0.01) and cell kill 2 to 3-fold (p < 0.01). Significant dose reductions for both agents (2 to 600-fold) were achieved over a wide range of therapeutic-effect levels (LD50-LD99) without compromising cell kill. Synergistic cytotoxicity correlated with GADD34 upregulation (2 to 4-fold, p < 0.01) and was eliminated following transfection with GADD34 siRNA. CONCLUSION: Cisplatin-induced GADD34 expression selectively enhanced the cytotoxicity of the gamma(1)34.5-deficient oncolytic virus, NV1066. This provides a cellular basis for combination therapy with cisplatin and NV1066 to treat MPM and achieve synergistic efficacy, while minimizing dosage and toxicity.

Antigens, Differentiation↗
PubMed2006

Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer that is refractory to current treatment modalities. Oncolytic herpes simplex viruses (HSV) used for gene therapy are genetically engineered, replication-competent viruses that selectively target tumor cells while sparing normal host tissue. The localized nature, the potential accessibility and the relative lack of distant metastasis make MPM a particularly suitable disease for oncolytic viral therapy. METHODS: The infectivity, selective replication, vector spread and cytotoxic ability of three oncolytic HSV: G207, NV1020 and NV1066, were tested against eleven pathological types of MPM cell lines including those that are resistant to radiation therapy, gemcitabine or cisplatin. The therapeutic efficacy and the effect on survival of NV1066 were confirmed in a murine MPM model. RESULTS: All three oncolytic HSV were highly effective against all the MPM cell lines tested. Even at very low concentrations of MOI 0.01 (MOI: multiplicity of viral infection, ratio of viral particles per cancer cell), HSV were highly effective against MPM cells that are resistant to radiation, gemcitabine and cisplatin. NV1066, an oncolytic HSV that expresses green fluorescent protein (GFP), was able to delineate the extent of the disease in a murine model of MPM due to selective infection and expression of GFP in tumor cells. Furthermore, NV1066 was able to reduce the tumor burden and prolong survival even when treatment was at an advanced stage of the disease. CONCLUSION: These findings support the continued investigation of oncolytic HSV as potential therapy for patients with therapy-resistant MPM.

Animals↗
PubMed2006

Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedes-type incisions compared to extended right subcostal incisions.

INTRODUCTION: The optimal abdominal incision for partial hepatectomy has not been established. METHODS: A prospective hepatobiliary surgery database was retrospective reviewed. Patients with Mercedes and extended right subcostal (ERSC) incisions were identified and compared. RESULTS: Between December 1991 and September 2001 a total of 1426 patients met the inclusion criteria. Among them, 856 (60%) had a Mercedes incision and 570 (40%) an ERSC incision. The two groups were well matched for demographics and operative variables. Perioperative morbidity and pulmonary complications were similar for the two groups as well. There was no difference in terms of early wound complications, although incisional hernias occurred in 9.8% of patients with a Mercedes incision compared to 4.8% of those with an ERSC incision (P = 0.0001). On multivariate analysis, the incision type, along with gender, body mass index, and age, were significant predictors of incisional hernia. CONCLUSIONS: An ERSC incision for partial hepatectomy provides adequate, safe access and is associated with fewer long-term wound complications.

Female↗
PubMed2006

Oncolytic herpes viral therapy is effective in the treatment of hepatocellular carcinoma cell lines.

The rising incidence of hepatocellular carcinoma (HCC) in western countries, along with the poor prognosis offered by present-day treatment modalities, makes novel therapies for this disease necessary. Oncolytic herpes simplex viruses (HSV) are replication-competent viruses that are highly effective in the treatment of a wide variety of experimental models of human malignancies. This study seeks to investigate the effectiveness of oncolytic herpes viruses in the treatment of primary HCC cell lines. Sixteen commercially available human HCC cell lines were studied. G207 is an attenuated, replication-competent, oncolytic HSV engineered to selectively replicate within cancer cells. Cell lines were tested for viral sensitivity to G207 and their ability to support viral replication using standard cytotoxicity and viral replication assays. Eleven of 16 cell lines were moderately to highly sensitive to G207 viral oncolysis. HCC cell lines additionally demonstrated the ability to support viral replication in vitro with as high as 800-fold amplification of the administered viral dose observed. G207 is cytotoxic to, and efficiently replicates within, HCC cell lines in vitro. From these data, we suggest that oncolytic HSV therapy may have a role in the treatment of HCC, and in vivo studies are warranted.

Animals↗
PubMed2006

The influence of positive peritoneal cytology on survival in patients with pancreatic adenocarcinoma.

The American Joint Committee on Cancer (AJCC) staging system for pancreatic adenocarcinoma classifies positive peritoneal cytology as stage IV disease. Data are limited with respect to the prevalence of positive peritoneal cytology and its influence on survival in patients with resectable, locally advanced, and metastatic disease. Four hundred sixty-two patients underwent staging laparoscopy for pancreatic adenocarcinoma between January 1995 and December 2005. Kaplan-Meier survival comparisons were performed to evaluate the significance of positive peritoneal cytology on overall survival (OS) in resected patients and patients with locally advanced and metastatic disease. Of the 462 patients, 47% (217/462) underwent a pancreatic resection. The 21% (95/462) with locally advanced disease and 32% (150/462) with metastatic disease did not undergo resection. Peritoneal cytology was positive in 17% (77/462), and was associated with stage of disease (metastatic, 37%; locally advanced, 11%; resected, 5%; P=0.01). Positive cytology was not associated with OS in patients with metastatic disease or locally advanced disease, but was in resected patients (median, 16 months vs. 8 months; P<0.001). Node-positive disease was present in 8 of 10 patients resected with positive cytology (2 years OS, 12% positive cytology vs. 23% negative; P=0.006). In this study, patients who underwent resection in the presence of positive peritoneal cytology and absence of other identifiable metastatic disease had a similar survival as other patients with stage IV disease.

Adenocarcinoma↗
PubMed2006

The utility of F-18 fluorodeoxyglucose whole body PET imaging for determining malignancy in cystic lesions of the pancreas.

Previous studies have suggested that whole body positron-emission tomography (PET) can distinguish between benign and malignant cysts of the pancreas. Patients were identified (n = 68) who had undergone whole body PET imaging for a cystic lesion of the pancreas between Jan. 1997 and May 2005. Cross-sectional imaging studies were reviewed by a single blinded radiologist, and positive PET studies were reviewed by a blinded nuclear medicine physician. Operative resection was performed in 21 patients (31%), and 47 patients were managed with radiographic follow-up. F-18 Fluorodeoxyglucose (FDG)-avid lesions were identified in eight of the 68 patients (12%). Within the resected group of patients (n=21), four of the seven patients (57%) with either in situ or invasive malignancy (adenocarcinoma: 3 of 5, papillary mucinous carcinoma: 1 of 2) had positive PET imaging (mean SUV, 5.9; range 2.5-8.0), and 2 of the 14 patients (14%) with benign lesions had positive PET imaging (serous cystadenoma, n=1, SUV=3.3; pseudocyst n=1, SUV=2.7). All lesions proven to be malignant with increased FDG uptake had highly suspicious findings on cross-sectional imaging. Within the group of resected patients, the sensitivity of PET for identifying malignant pathology was 57%, and the specificity was 85%. The sensitivity and specificity of PET for malignancy in this study was lower than previously reported, and PET findings did not identify otherwise occult malignant cysts. We do not believe whole body FDG-PET to be essential in the evaluation of cystic lesions of the pancreas.

Adenocarcinoma↗