David A. Kooby

Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases

ObjectiveTo determine if transfusion affected perioperative and long-term outcome in patients undergoing liver resection for metastatic colorectal cancer. Summary Background DataBlood transfusion produces host immunosuppression and has been postulated to result in adverse outcome for patients undergoing surgical resection of malignancies. MethodsBlood transfusion records and clinical outcomes for 1,351 patients undergoing liver resection at a tertiary cancer referral center were analyzed. ResultsBlood transfusion was associated with adverse outcome after liver resection. The greatest effect was in the perioperative course, where transfusion was an independent predictor of operative mortality, complications, major complications, and length of hospital stay. This effect was dose-related. Patients receiving one or two units or more than two units had an operative mortality of 2.5% and 11.1%, respectively, compared to 1.2% for patients not requiring transfusions. Transfusion was also associated with adverse long-term survival by univariate analysis, but this factor was not significant on multivariate analysis. Even patients receiving only one or two units had a more adverse outcome. ConclusionsPerioperative blood transfusion is a risk factor for poor outcome after liver resection. Blood conservation methods should be used to avoid transfusion, especially in patents currently requiring limited amounts of transfused blood products.

Impact of steatosis on perioperative outcome following hepatic resection

Fatty liver disease may interfere with liver regeneration and is postulated to result in an adverse outcome for patients subjected to partial hepatectomy. This study examines the impact of steatosis on outcome following hepatic resection for neoplasms. All patients with fatty livers (n = 325) who underwent hepatectomy between December 1991 and September 2001 were identified from a prospective database. Slides were reviewed and steatosis was quantified as follows: <30% (mild) and ≧30% (marked). Patient data were gathered and compared with results in 160 control patients with normal livers; subjects were matched for age, comorbidity, and extent of liver resection. There were 223 patients with mild and 102 with marked steatosis. Those with steatosis were more likely to be men (59% marked vs. 55% mild vs. 43% control; P = 0.01)withahigherbodymassindex(29.7± 5.5 marked vs. 28.2 ± 5.5 mild vs. 26.0 ± 5.4 control; P<0.01), and treated preoperatively with chemotherapy (66% marked vs. 55% mild vs. 38% control; P < 0.01). Total (62%, 48%, and 35%; P< 0.01) and infective (43%, 24%, and 14%; P< 0.01) complications correlated with the degree of steatosis. No difference was observed in complications requiring major medical intervention, hospitalization, or admission to the intensive care unit between groups. On multivariate analysis, steatosis was an independent predictor of complications (P< 0.01, risk ratio = 3.04, 95% confidence interval = 1.7 to 5.54). There was a nonsignificant trend toward higher 60-day mortality in patients with marked steatosis who had lobe or more resections (9.4% marked vs. 5.0% mild vs. 5.0% control; P = 0.30). Marked steatosis is an independent predictor of complications following hepatic resection but does not have a significant impact on 60-day mortality. Steatosis alone should not preclude aggressive hepatic resection for neoplasms when indicated; however, patients with marked steatosis undergoing large resections should still be approached with due caution.

Biologic Predictors of Survival in Node-Negative Gastric Cancer

ObjectiveTo evaluate factors predictive of survival following curative resection for node-negative gastric adenocarcinoma. Summary Background DataPresence or absence of lymph node metastases is the most powerful predictor of survival following curative resection for gastric adenocarcinoma. Factors predictive of survival in node-negative gastric cancer have not been clarified. MethodsHistopathology and clinical outcome for all patients undergoing R0 resections for gastric adenocarcinoma at a tertiary center between 1985 and 2001 were reviewed. ResultsOf 1,256 R0 resections performed, 507 (40%) were node-negative, 465 were T1–T3, and 317 of these were adequately staged, as defined by histologic evaluation of at least 15 lymph nodes. Median age was 67 years, and 62% were male. Forty percent had T1 tumors, 34% were T2, and 26% were T3. Median tumor size was 3 cm. Vascular invasion (VI) was present in 17% of tumors and neural invasion (NI) in 31%. Extended (D2) lymphadenectomy was performed in 75% of cases. Five- and 10-year disease-specific survival rates were 79% and 67% respectively. Factors associated with poorer disease-specific survival on univariate analysis were male gender, serosal invasion, presence of VI, presence of NI, and resection other than distal subtotal gastrectomy. On multivariate analysis, NI was not an independent predictor of survival, but correlated directly with advancing T stage and tumor size. ConclusionsSerosal invasion and presence of VI are strong predictors of poor survival in this disease. NI correlates with T stage and tumor size and may serve as a marker of advanced disease.

Atypical lipomatous tumor/well-differentiated liposarcoma of the extremity and trunk wall: Importance of histological subtype with treatment recommendations

BackgroundThis study defines the behavior and classification of atypical lipomatous tumors (ALT) and well-differentiated liposarcomas (WDLS) of the extremity and trunk.MethodsA total of 91 well-differentiated lipomatous tumors of the extremity and trunk were identified from a soft tissue tumor database between July 1982 and June 2001. A soft tissue pathologist, blinded to prior diagnosis and clinical outcome, reviewed histology. Those composed predominantly of mature adipose tissue with scattered atypical stromal cells and scant lipoblasts or fibrosis were ALTs. Tumors with lipoblast but <25% fibrosis were termed lipoma-like WDLS, and those with >-25% fibrosis were identified as sclerosing WDLS. Clinical factors were analyzed to assess effects on local recurrence-free survival (LRFS).ResultsHistological review identified 34 ALTs and 57 WDLSs. Of the WDLSs, 29 were lipoma-like and 28 were sclerosing. Five-year and 10-year LRFS were 100%±0% and 78%±9%, respectively. Factors evaluated were age, sex, tumor site, tumor size, histology, presentation status, margin status, and adjuvant radiotherapy. Positive resection margins and sclerosing histology were associated with reduced LRFS. Dedifferentiation was observed in three tumors (3%)ConclusionsLipoma-like WDLSs and ALTs share similar histological features and favorable behavior. Margin-positive sclerosing WDLSs have a 10-year LRFS of only 17% and should undergo function-preserving re-excision when possible, or adjuvant radiotherapy.

Intravesical oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and Nv1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model

Attenuated, replication‐competent herpes simplex virus mutants are attracting interest because of their ability to replicate within and kill tumor cells while remaining of low pathogenicity to normal tissues. In this study we investigated the ability of two oncolytic candidates, G207 and NV1020, to infect and lyse human and murine transitional cell carcinoma (MBT‐2) cells in vitro and their in vivo efficacy in a well‐established immunocompetent animal model of bladder cancer. Both viruses were effective at infecting, replicating within, and achieving subsequent cell lysis for all four human bladder cancer cell lines and MBT‐2. We found a strong correlation between infection efficiency and subsequent cell death. In vivo studies demonstrated that these viruses were effective with a single intravesical instillation and even more effective with multiple instillations at reducing tumor burden and achieving cures of orthotopic bladder cancer in syngeneic C3h/Hej mice. Immunohistochemistry and histological studies demonstrated that viral replication and cell death were restricted to bladder cancer cells. These results suggest that both G207 and NV1020 hold particular promise for intravesical treatment of human bladder cancer and that ease of intravesical instillation facilitates efficient delivery of virus to tumor cells.

The management of variant arterial anatomy during hepatic arterial infusion pump placement.

BackgroundThe success of hepatic arterial infusion pump (HAIP) placement in patients with variant arterial anatomy has not been well described.MethodsPatients who underwent HAIP placement over a 5-year time period were evaluated. Arterial- and catheter-related pump complication rates and pump survival were compared between patients with normal and variant arterial anatomy.ResultsPumps were placed in 265 patients. Variant anatomy was present in 98 (37%) patients. The presence of variant versus normal anatomy did not increase pump complication rates (8% vs. 4%;P=.18) or decrease pump survival (P=.12). In all patients with an isolated variant right or left hepatic artery (n=56), ligation of the variant vessel and cannulation of the gastroduodenal artery (GDA) resulted in complete hepatic perfusion and no pump complications. Cannulation of vessels other than the GDA (n=22) was associated with increased pump complication rates (27% vs. 4%;P=.0001) and decreased pump survival (P=.002).ConclusionsIn this study, HAIP placement in patients with variant anatomy was not associated with increased pump complication rates or decreased pump survival. An optimal strategy for managing variant anatomy is to ligate isolated variant vessels and cannulate the GDA.

Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer

Oncolytic viral therapy is a promising new method of cancer treatment. Peritoneal dissemination of cancer is a common and fatal clinical condition seen in many malignancies, with few effective therapies available. G207, a multimutated replication-competent herpes simplex virus type-1, effectively treats disseminated peritoneal cancer. This study evaluates viral proliferation and subsequent tumoricidal effects in vitro and in vivo after regional viral delivery. In vitro studies demonstrate that G207 efficiently kills five human gastric cancer cell lines, and that permissiveness to viral replication is correlated with cytotoxicity. In a murine xenograft model of human gastric carcinomatosis, peritoneal delivery of G207 effectively kills tumor and prolongs survival. Data from quantitative PCR characterizes peritoneal clearance of virus after intraperitoneal injection, and identifies G207 replication within tumor cells in vivo, similar to in vitro proliferation. Further analysis of various organs confirms that G207 does not replicate within normal tissue after peritoneal delivery. Wild-type KOS viral replication was also demonstrated in vivo, with significant toxicity secondary to dissemination and encephalitis. In vivo viral proliferation of G207 is restricted to tumor cells, is correlated with in vitro assays, and is an important mechanism of anticancer efficacy.

Functional Interaction between Fluorodeoxyuridine-Induced Cellular Alterations and Replication of a Ribonucleotide Reductase-Negative Herpes Simplex Virus

ABSTRACT G207 is an oncolytic herpes simplex virus (HSV) which is attenuated by inactivation of viral ribonucleotide reductase (RR) and deletion of both γ 1 34.5 genes. The cellular counterparts that can functionally substitute for viral RR and the carboxyl-terminal domain of ICP34.5 are cellular RR and the corresponding homologous domain of the growth arrest and DNA damage protein 34 (GADD34), respectively. Because the thymidylate synthetase (TS) inhibitor fluorodeoxyuridine (FUdR) can alter expression of cellular RR and GADD34, we examined the effect of FUdR on G207 bioactivity with the hypothesis that FUdR-induced cellular changes will alter viral proliferation and cytotoxicity. Replication of wild-type HSV-1 was impaired in the presence of 10 nM FUdR, whereas G207 demonstrated increased replication under the same conditions. Combined use of FUdR and G207 resulted in synergistic cytotoxicity. FUdR exposure caused elevation of RR activity at 10 and 100 nM, whereas GADD34 was induced only at 100 nM. The effect of enhanced viral replication by FUdR was suppressed by hydroxyurea, a known inhibitor of RR. These results demonstrate that the growth advantage of G207 in FUdR-treated cells is primarily based on an RR-dependent mechanism. Although our findings show that TS inhibition impairs viral replication, the FUdR-induced RR elevation may overcome this disadvantage, resulting in enhanced replication of G207. These data provide the cellular basis for the combined use of RR-negative HSV mutants and TS inhibitors in the treatment of cancer.

Surgical Management of Hepatic Malignancy

Over the past twenty-five years, hepatic resection has evolved from a high risk, resource-intensive procedure with limited application to a safe and commonly performed operation with broad indications. This period has seen dramatic improvements in perioperative outcome, including reductions in mortality, blood loss, transfusion rates, and hospital stay. These improved perioperative results are largely responsible for the emergence of hepatic resection as a viable and effective treatment option for selected patients with 1° and 2° hepatobiliary malignancy. Continued advances in imaging technology, along with a heightened awareness of the clinical and tumor-related variables that dictate outcome, have allowed better preoperative assessment of disease extent and improved patient selection. Advances in other areas, such as minimally invasive and ablative techniques, have increased the treatment options and have had some impact on the approach to patients with malignant hepatobiliary disease; however, resection remains the most effective therapy. Although the long term results after resection are better than with other modalities, recurrence rates remain high, and further improvements in survival will require more effective systemic agents. As better adjuvant and neo-adjuvant therapies emerge, the results of resection are likely to improve and the indications for its application perhaps will extend to patients currently considered to have unresectable disease.

Efficient cotransduction of tumors by multiple herpes simplex vectors: implications for tumor vaccine production.

Many gene therapy strategies would be enhanced by efficient transfer of multiple genes into the same cell. Herpes simplex viral amplicon (HSV) vectors are good vehicles for gene transfer because they accommodate large pieces of foreign DNA and transfer genes rapidly and efficiently. The current studies examine whether efficient cotransduction of tumor cells can be accomplished using multiple HSV vectors in a manner useful for clinical gene therapy. Interleukin-12 (IL-12) exists as a heterodimer, with components (m35 and m40) coded for by genes on two separate chromosomes. We constructed HSV vectors carrying either IL12m35 (HSVm35) or IL12m40 (HSVm40) or both genes (HSVm75) separated by an internal ribosome entry site to assess whether gene transfer using a single HSV vector constructed to carry multiple genes has any advantage over gene transfer using multiple vectors that are each carrying single genes. Because IL-12 and IL-2 have been found to have synergistic antitumoral activity, we further analyzed the biologic activity of tumor cells cotransduced by separate HSV vectors carrying genes coding for these two cytokines. The results demonstrate that multiple genes can be inserted into the same cell efficiently using multiple HSV vectors, and that these vectors allow rapid production of tumor vaccines expressing multiple cytokine genes. Thus, gene transfer using HSV may not be limited by the size of the DNA that each vector can accommodate. Immunizations with tumors cotransduced with HSVm35 and HSVm40 were equally effective in eliciting a cytolytic T-lymphocyte response and in protecting against tumor growth in vivo as immunization with tumors treated with HSVm75. Immunization with tumors cotransduced with HSVm75 and HSVil2 was superior to immunization with tumors transduced with either alone. The combination of IL-2- and IL-12-secreting tumor cells may be used as an effective immunization strategy against solid tumors.