Biomedical subjects

Yuman Fong

Publications and source records attributed to Yuman Fong.

At least 73 records · Page 4Linked to original sources

PubMed2004

Overexpression of E2F-1 in lung and liver metastases of human colon cancer is associated with gene amplification.

We have shown previously that metastatic tumors of human colorectal cancer in lung as compared to liver have high levels of thymidylate synthase (TS) mRNA expression that correlated with high levels of E2F-1 mRNA expression. We now report that Comparative Genomic Hybridization (CGH) and DNA PCR analyses of lung and liver metastases of human colon cancer show frequent gains in the region of chromosome 20q and have an increase in gene copy number of E2F-1. In as much as TS is transcriptionally regulated by E2F-1, these results provide an explanation for the high levels of TS mRNA noted in some tumor samples.

Adenocarcinoma↗

PubMed2004

Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207).

Oncolytic viruses used for gene therapy have been genetically modified to selectively target tumor cells while sparing normal host tissue. The multimutant virus G207 has been attenuated by inactivation of viral ribonucleotide reductase and by deletion of both viral gamma134.5 genes. Deletion of gamma134.5 greatly decreases the neurovirulence of this mutant virus but also reduces its antitumor efficacy. The mammalian homologue to the gamma134.5 gene product is the GADD34 protein. This protein can functionally substitute for the gamma134.5 gene and is also up-regulated during DNA damage. We postulated that combining use of the chemotherapy agent mitomycin C (MMC) with G207 will selectively up-regulate GADD34 in tumor that may complement the gamma134.5 gene deletion and augment viral antitumor efficacy. This hypothesis was tested in human gastric cells in vitro and in vivo. Using both the isobologram method and combination-index method of Chou-Talalay, significant synergism was demonstrated between MMC and G207. As a result of such synergism, a dose-reduction for each agent can be accomplished over a wide range of drug-effect levels without sacrificing tumor cell kill. Northern blot analysis confirmed that expression of GADD34 mRNA was increased by MMC treatment. SiRNA directed at GADD34 decreased MMC-associated enhancement of viral proliferation and resulted in decreased viral synergy with MMC. These data indicate that induction of GADD34 selectively restores the virulent phenotype of the deleted gene in G207 and thus provides a cellular basis for the combined use of DNA-damaging agents and gamma134.5 HSV mutants in the treatment of cancer.

Animals↗

PubMed2004

Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12.

PURPOSE: There currently is no therapy that enhances the survival of patients with distantly metastatic squamous cell carcinoma (SCC). Engineered herpes oncolytic viruses are effective therapeutic agents when delivered directly to tumors in animal models, but their efficacy in treating disseminated disease is poorly defined. EXPERIMENTAL DESIGN: We treated disseminated pulmonary SCC in mice with an interleukin (IL)-12-expressing oncolytic herpes virus (NV1042) or with the parent oncolytic virus (NV1023, IL-12 deficient) by i.v. tail vein administration. RESULTS: Lung IL-12 was 16.1 pg/mg and IFN-gamma was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 x 10(7) plaque-forming units); levels of both were undetectable for NV1023. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry demonstrated viral infection of disseminated pulmonary tumor nodules by both vectors at day 1, with sparing of adjacent alveolar cells. NV1042-treated lungs showed no surface nodules at day 12, in contrast to NV1023-treated (92 +/- 27 surface nodules) and PBS-treated (225 +/- 9 surface nodules) lungs. Significantly enhanced survival was observed in NV1042-treated animals compared with NV1023- and PBS-treated animals (log rank < 0.05). In animals with a low tumor burden, 100% of NV1042-treated, 70% of NV1023-treated, and none of the control animals achieved long-term survival. NV1042 efficacy was similar to NV1023 efficacy in animals depleted of CD4/CD8 T lymphocytes, showing that IL-12 expression enhances oncolytic activity through immune effects. Histology showed no cytopathic effects in non-tumor-bearing lung, brain, spleen, liver, and pancreas after completion of viral therapy. No animals demonstrated any visible side effects attributable to viral therapy. CONCLUSIONS: The i.v. delivery of an oncolytic herpes virus may achieve effective infection, oncolysis, and transgene expression at distant tumor sites. This approach to systemic therapy combining oncolysis with IL-12 immune stimulation led to significantly improved survival in animals with disseminated SCC.

Animals↗

PubMed2004

Diagnostic laparoscopy prior to planned hepatic resection for colorectal metastases.

HYPOTHESES: (1) A clinical risk score (CRS) is useful in selecting patients for diagnostic laparoscopy prior to planned resection of colorectal metastasis. (2) Preventing unnecessary celiotomy in these patients undergoing laparoscopy is associated with shorter hospital stays and earlier administration of systemic chemotherapy. DESIGN: Retrospective analysis of data collected in a prospective database. SETTING: Tertiary cancer hospital. PATIENTS: Two hundred seventy-six patients who underwent laparoscopy prior to planned partial hepatic resection (n = 264) for colorectal metastases or prior to hepatic artery infusion pump placement for colorectal metastases (n = 12). MAIN OUTCOME MEASURES: The yield of laparoscopy for patients with potentially resectable tumors was analyzed in the context of a CRS, calculated by assigning 1 point for each of the following adverse, disease-related factors: lymph node-positive primary tumor, disease-free interval less than 12 months, more than 1 hepatic tumor, hepatic tumor greater than 5 cm, and cardio embryonic antigen level less than 200 ng/mL. The CRS represents the sum for each patient. Length of hospital stay and time to initiation of chemotherapy were compared in those patients determined to be unresectable. RESULTS: Staging laparoscopy prevented nontherapeutic celiotomy in 10% of patients submitted to operation for a potentially curative partial hepatectomy (26 of 264) and in 33% of patients scheduled for pump placement only (4/12). The CRS correlated closely with the likelihood of identifying radiographically occult unresectable disease: 0 or 1, 4%; 2 or 3, 21%; and 4 or 5, 38%. Likewise, the percentage of patients avoiding an unnecessary celiotomy increased progressively with increasing CRS: 0 or 1, 0%; 2 or 3, 11%; and 4 or 5, 24%. Preventing an unnecessary celiotomy with laparoscopy was associated with a decreased length of hospital stay (P<.01) and earlier initiation of chemotherapy (P = .045). CONCLUSIONS: Diagnostic laparoscopy does not need to be performed routinely in all patients prior to hepatic resection for colorectal cancer metastasis. Laparoscopy has a very low yield in patients with a CRS of 1 or less and is unnecessary. The yield of laparoscopy increases with increasing CRS. Preventing celiotomy with laparoscopy is associated with a decreased length of hospital stay and earlier initiation of postoperative chemotherapy.

Colorectal Neoplasms↗

PubMed2004

Effect of murine liver cell proliferation on herpes viral behavior: implications for oncolytic viral therapy.

Replication-competent herpes simplex oncolytic viruses are promising anticancer agents that partly target increased DNA synthesis in tumor cells. Investigators have proposed that these DNA viruses may be combined with liver resection to enhance killing of liver malignancies. Whether or not the cellular alterations associated with hepatic regeneration affect the efficacy and toxicity of these promising anticancer agents is unknown. This study examined the behavior of two oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered during the peak of liver regeneration, replication and appearance of both G207 and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical staining for the marker gene lac Z, immunohistochemical staining, and quantitative polymerase chain reaction. This increased appearance of virus in liver tissue correlates with increases in cellular ribonucleotide reductase activity and DNA synthesis and is also associated with increased viral binding. However, increased viral presence is transient, and viral detection declines to baseline within 7 days. When these viruses were delivered to animals even as early as 7 days after hepatectomy, there proved to be no measurable viral replication in any organ and no increased morbidity or mortality. In conclusion, the early stages of hepatic regeneration after resection provide an environment suitable for viral replication. Administration of replication-competent herpes simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits viral productivity in tissue that otherwise does not support viral growth. The increase in hepatotoxicity after hepatectomy is short-lived and can be predicted by peak hepatocyte DNA synthesis.

Animals↗

PubMed2004

Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma.

Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates tumor angiogenesis. The VEGF pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase-1 [sFlk-1]) that bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV)-derived amplicons are replication-incompetent viruses used for gene delivery. We attempt to attenuate angiogenesis and inhibit hepatoma growth through amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10xHRE) was cloned upstream of the sFlk-1 gene (10xHRE/sFlk-1). An amplicon expressing 10xHRE/sFlk-1 was genetically engineered (HSV10xHRE/sFlk-1). SK-HEP-1 human hepatoma cells were transduced with HSV10xHRE/sFlk-1 and incubated in normoxia (21% O2) or hypoxia (1% O2). Human umbilical vein endothelial cell assay evaluated capillary inhibition. Western blot assessed sFlk-1 expression. SK-HEP-1 flank tumors (n = 24) in athymic mice were treated with HSV10xHRE/sFlk-1. Media from hypoxic SK-HEP-1 transduced with HSV10xHRE/sFlk-1 yielded an 80% reduction in capillary formation (P < 0.005), whereas normoxic SK-HEP-1 yielded a 25% reduction (P < 0.05). Western blot of SK-HEP-1 transduced with HSV10xHRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia vs. normoxia. SK-HEP-1 tumors treated with HSV10xHRE/sFlk-1 yielded a 72% reduction in volume vs. the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma.

Angiogenesis Inhibitors↗

PubMed2004

Major hepatectomy with simultaneous pancreatectomy for advanced hepatobiliary cancer.

BACKGROUND: Combined major hepatectomy with pancreatectomy (MHP) is a rarely used operation for the treatment of hepatobiliary cancer. Few reports have discussed the utility of this procedure and its indications are poorly defined. The aim of this study was to review our experience with MHP. STUDY DESIGN: A review of our prospective hepatobiliary surgical database between January 1994 and July 2000 identified 17 patients who had undergone MHP. Preoperative radiographic and laboratory data, intraoperative findings, hospital outcomes, and longterm followup were obtained. RESULTS: A total of 3,579 patients with hepatobiliary malignancy were seen at our institution, of which 1,280 underwent resection and 17 (1.3%) had an MHP. The median age was 58 years (range 24 to 76). Histology was as follows: eight neuroendocrine carcinoma, three sarcoma, two cholangiocarcinoma, one ampullary carcinoma, one gallbladder carcinoma, one gastric carcinoma recurrence, and one benign fibrosis. All 17 patients underwent resection of two or more hepatic segments. Nine patients underwent a distal pancreatectomy and eight underwent a pancreaticoduodenectomy. Median operative time was 6 hours (range 4 to 8) and the median blood loss was 900 mL (range 150 to 2,500). Postoperative complications occurred in eight patients (47%), and there were three perioperative deaths (18%). All three deaths occurred in patients who underwent a pancreaticoduodenectomy combined with a hemi-hepactomy or greater. Eight patients are free of disease with a median followup of 54 months. Six patients have recurred, two of whom have died of disease with a median disease-free interval of 8 months. CONCLUSIONS: MHP is associated with a high morbidity and mortality and should only be considered in highly selected patients when a significant potential oncologic benefit is possible.

Adult↗

PubMed2004

Selective use of diagnostic laparoscopy prior to planned hepatectomy for patients with hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) are frequently found to be inoperable at surgical exploration. Laparoscopy may reduce the rate of unnecessary laparotomy in these patients. However, there are no criteria for selective use of laparoscopy. METHODS: Sixty patients with potentially operable HCC underwent laparoscopy prior to planned partial hepatectomy. Intraoperative findings and postoperative course were analyzed, and factors for the selective use of laparoscopy were identified. RESULTS: Fourteen of 19 inoperable patients (74%) were identified by means of laparoscopy, which increased the resectability rate from 68% to 89%. Compared with patients undergoing exploratory laparotomy only, patients determined to be inoperable on laparoscopy had significantly less intraoperative blood loss, a shorter operating room time, and a briefer hospital stay. In a multivariate analysis, clinically apparent liver cirrhosis and radiologic evidence of major vascular invasion or bilobar tumors predicted the likelihood of finding inoperable disease at laparoscopy. The initial use of laparoscopy avoided unnecessary laparotomy in almost 30% of patients with-but only 5% of patients without-these features. CONCLUSIONS: If high-risk patients with HCC are selectively targeted, the yield of laparoscopy is increased and unnecessary laparotomy may be avoided. In patients without cirrhosis, major vascular invasion, or bilobar tumors, the yield of laparoscopy is low and is therefore not generally recommended.

Adult↗

PubMed2004

Employing tumor hypoxia to enhance oncolytic viral therapy in breast cancer.

BACKGROUND: Hypoxia is a common tumor condition correlated with therapeutic resistance. Ribonucleotide reductase (RR) is a rate-limiting enzyme for viral replication. We hypothesize that hypoxia-driven transcription of UL39, the gene encoding the large subunit of RR, would enhance herpes oncolytic viral therapy in breast cancer. METHODS: Hypoxia-inducible factor 1alpha (HIF-1alpha) ELISA was performed on MCF7 human breast cancer cells in hypoxia (1% O2) or normoxia (21% O2). A multimerized hypoxia-responsive enhancer was constructed (10xHRE) and functionally tested in a luciferase assay. 10xHRE was cloned upstream of the UL39 gene (10xHRE-UL39). MCF7 cells were transfected with 10xHRE-UL39, incubated in hypoxia or normoxia, and infected with G207. Cytotoxicity assays and viral titers were performed. RESULTS: HIF-1alpha levels increased 7-fold in hypoxic MCF7 cells (P < .001). 10xHRE increased luciferase gene expression 61-fold in hypoxia versus controls (P < .01). G207 cytotoxicity of 10xHRE-UL39-transfected, hypoxic MCF7 cells increased 74% versus mock-transfected, hypoxic MCF7 cells (P < .001). In normoxia, 10xHRE-UL39 transfection did not significantly improve G207 cytotoxicity. 10xHRE-UL39 transfection improved peak viral titers 69-fold in hypoxia (P < .005), with no significant difference in normoxia. CONCLUSION: Hypoxia-driven RR production significantly enhances G207 cytotoxicity in hypoxic breast cancer cells, which would otherwise be resistant to herpes viral therapy alone.

Breast Neoplasms↗

PubMed2004

Carcinoembryonic antigen directed herpes viral oncolysis improves selectivity and activity in colorectal cancer.

BACKGROUND: G207 is an oncolytic herpes virus whose replicative cycle requires cellular ribonucleotide reductase (RR) for viral DNA synthesis. We attempt to enhance viral cytotoxicity in carcinoembryonic antigen (CEA)-producing colorectal cancer (CRC) cells through CEA-driven RR production. METHODS: CEA enzyme-linked immunosorbent assay was performed on LS174T and HCT-8 human CRC cells. The CEA enhancer-promoter (CEA E-P) was functionally assessed by luciferase assay. CEA E-P was cloned upstream of UL39, the gene encoding the large subunit of RR. Cells were transfected with CEA E-P/UL39 and infected with G207 for cytotoxicity assays. LS174T, with or without CEA E-P/UL39, were implanted into athymic mouse flanks (n = 28) and treated with G207. RESULTS: CEA levels were 7-fold higher in LS174T versus HCT-8 ( P <.00001). CEA E-P increased luciferase expression 7.5-fold in LS174T ( P <.01), with no increase in HCT-8. G207 cytotoxicity of'CEA E-P/UL39-transfected LS174T cells increased 69% by day 10 versus nontransfected cells ( P <.001), with no significant increase in HCT-8. Combining CEA E-P/UL39 with G207 in LS174T flank tumors resulted in a 65% decrease in tumor volume versus G207, phosphate-buffered saline, or'CEA E-P/UL39 alone ( P <.0001). CONCLUSIONS: CEA-driven RR production by CEA-secreting CRC cells significantly improves oncolytic viral cytotoxicity and specificity in vitro, and reduces tumor burden in vivo.

Carcinoembryonic Antigen↗

PubMed2004

Hepatocellular carcinoma: current surgical management.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world, responsible for 500,000 deaths globally every year. Although HCC is a slow-growing tumor, it is often rapidly fatal because it is usually not discovered until the disease is advanced. HCC occurs primarily in individuals with cirrhosis, a condition that increases the risk of performing potentially curative surgical therapy. Over the last 2 decades, however, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative care. As such, the operative mortality rate for hepatectomy has decreased from the 10%-20% level seen in the 1980s to less than 5% today. The ultimate goal of treatment of HCC is to prolong the quality of life by eradicating the malignancy while preserving hepatic function. For treatment with a curative intent, the gold standard remains surgical resection, by either partial hepatectomy or total hepatectomy followed by liver transplantation. Resectability and choice of procedure depend on many factors, including baseline liver function, absence of extrahepatic metastases, size of residual liver, availability of resources including liver graft, and expertise of the surgical team. Patients without cirrhosis can tolerate extensive resections, and partial hepatectomy should be considered first. For Child class B and C patients with a small HCC, liver transplantation offers the best results, whereas partial liver resection is indicated in patients with well-compensated cirrhosis. Living donor liver transplantation should be considered using the same criteria as that used for cadaveric transplantation.

Carcinoma, Hepatocellular↗

PubMed2004

Oncolytic herpes simplex virus-1 mutant expressing green fluorescent protein can detect and treat peritoneal cancer.

NV1066 is a herpes simplex virus-1 (HSV-1) oncolytic mutant that contains the gene for enhanced green fluorescent protein (EGFP). We sought to determine (1) whether NV1066 is effective against human peritoneal cancer, (2) whether EGFP is detectable in an animal model of gastric cancer, and (3) whether EGFP expression can be used to assess oncolytic therapy in a minimally invasive, laparoscopic system. The current study demonstrates that NV1066 is cytotoxic to OCUM human gastric cancer cells in vitro and in an in vivo model of disseminated peritoneal gastric cancer. In vitro this human gastric cancer cell line is sensitive to NV1066. Lysis occurs in a dose-dependent fashion, achieving near-complete lysis even at multiplicities of infection (MOIs) as low as 0.01 by 7 days. NV1066 also replicates within OCUM cells and induces expression of GFP in a dose-dependent manner. At MOIs of 0.01 to 1, EGFP expression is seen by flow cytometry in 100% of OCUM cells within 5 days after infection. NV1066 effectively treats OCUM carcinomatosis in an in vivo model. After intraperitoneal administration of NV1066, macroscopic tumor foci express EGFP by direct laparoscopy with the appropriate fluorescent filtering. Noncancerous organs are not infected and do not express EGFP. We conclude that NV1066 has significant oncolytic activity in vitro and in vivo and reliably induces EGFP expression in infected tumor cells. Furthermore, EGFP expression in intraperitoneal tumors can be visualized laparoscopically, allowing detection and localization of viral gene therapy.

Animals↗

PubMed2004

Utilizing tumor hypoxia to enhance oncolytic viral therapy in colorectal metastases.

OBJECTIVE: To determine the effects of hypoxia-induced ribonucleotide reductase (RR) production on herpes oncolytic viral therapy. SUMMARY BACKGROUND DATA: Hypoxia is a common tumor condition correlated with therapeutic resistance and metastases. Attenuated viruses offer a unique cancer treatment by specifically infecting and lysing tumor cells. G207 is an oncolytic herpes virus deficient in RR, a rate-limiting enzyme for viral replication. METHODS: A multimerized hypoxia-responsive enhancer was constructed (10xHRE) and functionally tested by luciferase assay. 10xHRE was cloned upstream of UL39, the gene encoding the large subunit of RR (10xHRE-UL39). CT26 murine colorectal cancer cells were transfected with 10xHRE-UL39, incubated in hypoxia (1% O2) or normoxia (21% O2), and infected with G207 for cytotoxicity assays. CT26 liver metastases, with or without 10xHRE-UL39, were created in syngeneic Balb/C mice (n = 40). Livers were treated with G207 or saline. Tumors were assessed and stained immunohistochemically for G207. RESULTS: 10xHRE increased luciferase expression 33-fold in hypoxia versus controls (P < 0.001). In normoxia, 10xHRE-UL39 transfection did not improve G207 cytotoxicity. In hypoxia, G207 cytotoxicity increased 87% with 10xHRE-UL39 transfection versus nontransfected cells (P < 0.001). CT26 were resistant to G207 alone. Combining 10xHRE-UL39 with G207 resulted in a 66% decrease in tumor weights (P < 0.0001) and a 65% reduction in tumor nodules (P < 0.0001) versus G207 monotherapy. 10xHRE-UL39-transfected tumors demonstrated greater viral staining. CONCLUSIONS: Hypoxia-driven RR production significantly enhances viral cytotoxicity in vitro and reduces tumor burden in vivo. G207 combined with RR under hypoxic control is a promising treatment for colorectal cancer, which would otherwise be resistant to oncolytic herpes virus alone.

Animals↗

PubMed2004

Utilizing alpha-fetoprotein expression to enhance oncolytic viral therapy in hepatocellular carcinoma.

OBJECTIVE: To determine whether alpha-fetoprotein (AFP)-regulated ribonucleotide reductase (RR) production would promote more vigorous and specific viral killing in AFP-expressing hepatocellular carcinoma (HCC). BACKGROUND: AFP is expressed in over 70% of primary HCC but not in normal adult liver. AFP production by HCC can be exploited to target viral killing of tumor cells. G207 is an oncolytic herpes virus lacking UL39, the gene encoding RR. RR is an enzyme required for viral DNA synthesis and cytotoxicity. METHODS: Enzyme-linked immunosorbent assay (ELISA) was performed for AFP levels on Hep3B and PLC5 human HCC cells. An AFP-albumin enhancer-promoter complex (AFP-alb) was constructed in a luciferase vector to assess function. AFP-alb was cloned upstream of UL39 (AFP-alb/UL39) and transfected into HCC cells for G207 cytotoxicity assays. Viral plaque forming assays evaluated G207 replication. Hep3B flank tumors, with and without AFP-alb/UL39 transfection, were established in athymic mice (n = 28) and treated with G207. RESULTS: Hep3B had 5-fold higher AFP levels than PLC5 (P < 0.00001). AFP-alb increased luciferase expression 72-fold in Hep3B (P < 0.001) and 3-fold in PLC5 (P < 0.001). AFP-alb/UL39 transfection increased G207 cytotoxicity 93% in Hep3B (P < 0.0005), with no significant increase in PLC5. Peak viral titers were 46-fold higher in Hep3B transfected with AFP-alb/UL39 versus mock-transfected cells (P < 0.01), with no significant change in PLC5. Flanks tumors transfected with AFP-alb/UL39 and treated with G207 demonstrated a 76% volume reduction versus mock-transfected tumors infected with G207 (P < 0.0001). CONCLUSIONS: AFP-driven RR production by hepatoma cells significantly enhances herpes viral cytotoxicity and specificity in vitro and reduces tumor burden in vivo.

Adult↗

PubMed2004

Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer.

BACKGROUND: In patients with gallbladder cancer, jaundice suggests tumor involvement of the porta hepatis. This study reports on the prevalence, etiology, and clinical significance of jaundice in patients with gallbladder cancer. METHODS: Patients who presented with gallbladder cancer from 1995 to 2002 were entered into a prospective database. Disease-specific survival and clinicopathologic correlates were analyzed. RESULTS: Eighty-two (34%) of 240 patients with gallbladder cancer presented with jaundice. Jaundiced patients (96%) were more likely (P <.001) to have advanced-stage disease than nonjaundiced patients (60%). Only six (7%) jaundiced patients were resected with curative intent, and only four (5%) had negative surgical margins. This was significantly different from the nonjaundiced group, in which 62 patients (39%) had negative margins (P <.001). The median disease-specific survival in patients presenting with jaundice was 6 months and was significantly lower compared with 16 months in patients without jaundice (P <.0001). In the group presenting with jaundice, there were no disease-free survivors at 2 years, compared with 21% in the group without jaundice. CONCLUSIONS: Jaundice is common (34%) in patients who present with gallbladder cancer and is an indicator of advanced malignancy. These data do not support routine operative exploration of patients with jaundice secondary to gallbladder cancer.

Adult↗

PubMed2003

Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies.

BACKGROUND: Current approaches to adjuvant treatment after resection of gallbladder carcinoma (GBCA) and hilar cholangiocarcinoma (HCCA) are based on an incomplete understanding of the recurrence patterns of these diseases. Through an in-depth analysis of the sites of initial recurrence after resection of GBCA and HCCA, the current study aimed to highlight differences in the biology of these tumors and to provide further insight for adjuvant therapeutic strategies. METHODS: Patients with either GBCA or HCCA who underwent a potentially curative resection were identified prospectively from a maintained database. Specific sites of initial disease recurrence were identified retrospectively and categorized as locoregional (resection margin, porta hepatis, or retroperitoneal lymph nodes) or distant (peritoneal, extraabdominal, or discontiguous liver metastases). Differences in disease recurrence patterns, time to disease recurrence, and overall and site-specific survival were analyzed. RESULTS: Between May 1990 and August 2001, 177 patients underwent potentially curative resection, 97 for GBCA and 80 for HCCA. Disease recurrence and follow-up data were available for 156 patients (80 with GBCA and 76 with HCCA). The median time to disease recurrence was shorter for patients with GBCA compared with patients with HCCA (11.5 vs. 20.3 months; P = 0.007). Overall, 52 (68%) patients with HCCA and 53 (66%) patients with GBCA had disease recurrene at a median follow-up of 24 months. Of those who developed disease recurrence, isolated locoregional disease as the first site of failure occurred in 15% of patients with GBCA compared with 59% of patients with HCCA (P < 0.001). By contrast, an initial GBCA recurrence involving a distant site, with or without concomitant locoregional recurrence, occurred in 85% of patients compared with 41% of patients with HCCA (P < 0.001). This pattern of disease recurrence was diagnosis specific and did not change significantly when patients were stratified by several clinicopathologic factors, including disease stage and its component variables. Using multivariate analysis, diagnosis was an independent predictor of the site of disease recurrence. Among patients who experienced disease recurrence, survival was greater among the patients with HCCA compared with patients with GBCA (29 months vs. 20.6 months, respectively; P = 0.037). For both tumors, the site of initial disease recurrence had no apparent impact on survival time. CONCLUSIONS: After resection, recurrent GBCA is much more likely than recurrent HCCA to involve a distant site. GBCA is also associated with a much shorter time to recurrence and a shorter survival period after recurrence. The results demonstrated significant differences in the clinical behavior of these tumors and suggested that an adjuvant therapeutic strategy targeting locoregional disease, such as radiotherapy, is unlikely to have a significant impact in the overall management of GBCA. Conversely, there is at least some rationale for such an approach in patients with HCCA based on the pattern of initial recurrence.

Adult↗

PubMed2003

Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats.

Radionuclide imaging has been demonstrated to be feasible to monitor transgene expression in vivo. We hypothesized that a potential application of this technique is to non-invasively detect in deep tissue, such as cancer cells metastatic to the liver, a specific molecular response following systemic drug treatment. Utilizing human colon adenocarcinoma cells derived from a patient's liver lesion we first developed a nude rat xenograft model for colorectal cancer metastatic to the liver. Expression of a dihydrofolate reductase-herpes simplex virus 1 thymidine kinase fusion (DHFR-HSV1 TK) transgene in the hepatic tumors was monitored in individual animals using the tracer [(124)I]2'-fluoro-2'-deoxy-5-iodouracil-beta- d-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [(131)I]FIAU and a clinical gamma camera. Growth of the human metastatic colorectal cancer cells in the rat liver was detected using magnetic resonance imaging and confirmed by surgical inspection. Single as well as multiple lesions of different sizes and sites were observed in the liver of the animals. Next, using a subset of rats bearing hepatic tumors, which were retrovirally bulk transduced to express the DHFR-HSV1 TK transgene, we imaged the fusion protein expression in the hepatic tumor of living rats using the tracer [(124)I]FIAU and a microPET. The observed deep tissue signals were highly specific for the tumors expressing the DHFR-HSV1 TK fusion protein compared with parental untransduced tumors and other tissues as determined by gamma counting of tissue samples. A subsequent study used the tracer [(131)I]FIAU and a gamma camera to monitor two groups of transduced hepatic tumor-bearing rats. Prior to imaging, one group was treated with trimetrexate to exploit DHFR-mediated upregulation of the fusion gene product. Imaging in the living animal as well as subsequent gamma counting of tissue samples showed increased signal and tracer accumulation, respectively, as compared to the group not treated with the antifolate. It is concluded that the two examined nucleotide imaging methods are feasible techniques for monitoring of DHFR-HSV TK fusion protein expression in hepatic colorectal tumor tissue in living animals.

Animals↗

PubMed2003

Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer.

PURPOSE: To investigate the role of thymidylate synthase (TS),p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors in predicting overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) in patients with resectable metastatic colorectal cancer who were randomly assigned to receive either systemic chemotherapy (SYS) alone or systemic and hepatic arterial infusion (HAI+SYS) chemotherapy following liver surgery. PATIENTS AND METHODS: Tissues from metastatic tumors were collected during liver resection from 156 patients, and marker expressions were determined using immunohistochemistry on frozen samples. Univariate associations between marker expressions and baseline variables with OS, PFS, and HPFS were examined. Independent predictors of outcome were determined using a multivariate Cox model. RESULTS: In multivariate analyses, TS overexpression was found to be an independent factor of poor prognosis in OS (P <.01), PFS (P =.06), and HPFS (P <.01). In addition, resection margin was a significant independent factor for all three outcomes. Patients who received HAI+SYS experienced delayed progression in general, and in the liver, specifically. Increased levels of serum alkaline phosphatase correlated with hepatic progression. We also found a significant TS-treatment interaction for OS (P =.01) in multivariate analysis. In particular, TS+ patients receiving HAI+SYS had significantly higher survival than those receiving SYS (64 month sv 21 months; P =.01). CONCLUSION: TS levels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereas p53 and EGFR are not independent predictors. Treatment with HAI + SYS significantly improved the survival profile of TS+ patients.

Adult↗