Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity.

BACKGROUND: Evolving evidence suggests that, in selected patients with tumour category 1 (T1) extremity soft tissue sarcoma (ESTS), surgery alone offers satisfactory results without decreasing survival. This study assessed the effect of sarcoma treatments on survival outcomes of T1 ESTS in a population-based data set. METHODS: Using the Surveillance, Epidemiology, and End Results database, 1618 patients with primary ESTS underwent limb-sparing surgery. Multivariable analysis was used to assess the impact of radiotherapy on overall survival (OS) and sarcoma-specific survival (SSS), adjusting for co-variables. RESULTS: Some 803 patients (49.6 per cent) underwent surgery alone for T1 ESTS. Radiotherapy in patients with low- and high-grade tumours did not result in any significant difference in OS or SSS. When stratified by grade, multivariable analysis showed that adjuvant radiotherapy was not an independent predictor of SSS (hazard ratio (HR) 1.05; P = 0.906) or OS (HR 0.89; P = 0.695) in low-grade tumours. Neither was radiotherapy a significant predictor of SSS (HR 0.87; P = 0.608) or OS (HR 0.67; P = 0.071) in high-grade tumours. CONCLUSION: This population-based appraisal validated previous evidence supporting a role for surgery alone in the treatment of T1 ESTS. Future policies should be tailored to offer patients minimal yet effective therapy, rather than maximum tolerated therapy.

Intraductal papillary mucinous neoplasms of the pancreas.

The introduction of the exocrine pancreatic classification by the World Health Organization and improvements in pancreatic imaging have led to an improved understanding of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. As a result, IPMNs of the pancreas are increasingly being recognized as a separate disease entity. IPMNs are characterized by the cystic dilatation of the pancreatic duct and its branches, with papillary projections. There are three histological subtypes of IPMNs: main duct, branch duct, and mixed. The degree of atypia ranges from adenoma to frank invasive carcinoma. The lymph nodes are involved considerably less frequently than they are in pancreatic adenocarcinoma. Most patients are symptomatic at diagnosis and require a diagnostic workup similar to that for patients with pancreatic adenocarcinoma. Although some investigators continue to advocate total pancreatectomy, the evidence in support of this is decreasing. Partial pancreatectomy remains the treatment option. Intraoperative assessment of the resection surgical margins is an important component of surgical resection. Additionally, controversy also exists regarding the nature of the follow-up and the need for adjuvant chemoradiation therapy in the patient. Unlike ductal adenocarcinomas, IPMNs follow a relatively indolent course; the 5-year survival rate in patients with invasive IPMNs is 57%. A mural nodule and a main pancreatic duct diameter greater than 5 mm have been found to be predictors of malignancy.

Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate.

In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine alpha,gamma-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.

Methioninase gene therapy of human cancer cells is synergistic with recombinant methioninase treatment.

Results obtained over the past 40 years have demonstrated that tumor cells of all types tested have an elevated growth requirement for methioninase compared with normal cells. Recombinant methioninase (rMETase) cloned from Pseudomonas putida has been found previously to be an effective antitumor agent attributable to deprivation of the extracellular methionine source of the tumor. To degrade intracellular methioninase, we have now developed an adenoviral vector inserted with the P. putida methioninase (MET) gene (rAd-MET). The in vitro efficacy of rAd-MET was tested on the OVCAR-8 human ovarian cancer cell line, the HT1080 human fibrosarcoma cell line, and human normal fibroblasts. rAd-MET transduction of OVACAR-8 and HT1080 resulted in high levels of methioninase expression up to 10% or more of the total protein of the cells, depending on the multiplicity of infection. The IC50 of rAd-MET for OVCAR-8 cells in 96-well plates was approximately 2 x 106 plaque-forming units (pfu)/well. The IC50 of control adenovirus (control-rAd) was 4 x 10(7) pfu/well, 20 times higher than rAd-MET. In the presence of the IC50 of 2 x 10(6) pfu/well of rAd-MET, the addition of 0.025 units/ml of rMETase, which is 25% of the IC50, resulted in a 90% inhibition of tumor cell number. This indicated that rAd-MET enhanced the efficacy of rMETase. In contrast, 2 x 10(6) pfu/well of control-rAd in combination with 0.025 units/ml of rMETase had an efficacy of only 10% inhibition of cell number. The synergistic effect of the combination of rMETase and rAd-MET was quantitated by calculating the combination index (CI). The CIs for all combinations of rAd-MET and rMETase tested on OVCAR-8 were <0.7 with a mean of 0.5, indicating synergy. Similar synergy of rAd-MET and rMETase was seen on HT1080 human fibrosarcoma cells with a mean of 0.74. In contrast, the CIs of all combinations of rMETase and control adenovirus concentrations tested on both cell lines had a mean CI of approximately 1, which indicated that this combination had only an additive effect. The normal fibroblasts, on the other hand, appeared relatively resistant to the MET gene because in the presence of rMETase, 2.5 x 10(7) pfu/well of rAd-MET or control rAd had almost an identical effect on cell survival. The selectively strong synergy of rAd-MET and rMETase on cancer cells allows reduced levels of each agent to be used, thus decreasing potential side effects.

Survival efficacy of the combination of the methioninase gene and methioninase in a lung cancer orthotopic model.

We have previously demonstrated the antitumor efficacy of recombinant methioninase (rMETase) derived from Pseudomonas putida. To enhance the efficacy of rMETase, we have constructed the pLGFP-METSN retrovirus encoding the P. putida methioninase (MET) gene fused with the green fluorescent protein (GFP) gene. pLGFP-METSN or control vector pLGFPSN was introduced into the human lung cancer cell line H460. The methionine level of H460-GFP-MET cells was reduced to 33% of that of H460-GFP cells. rMETase (0.08 U/mL) in the medium resulted in 10% survival of H460-GFP-MET cells compared with untreated cells in vitro. In contrast, rMETase-treated H460-GFP cells survived at 90% of control. Tissue fragments harvested from subcutaneous tumors of H460-GFP-MET or H460-MET were implanted by surgical orthotopic implantation into the lungs of nude mice. A suboptimal dose of rMETase was administered intraperitoneally daily to mice in each group. Overall survival of rMETase-treated animals with H460-GFP-MET tumors was significantly longer than either rMETase-treated or -untreated animals with H460-GFP tumors (P < .05 in log-rank test). In two repeat experiments, rMETase-treated animals with H460-GFP-MET tumors had a 30-day survival of 80% and 83%, respectively. Untreated animals with H460-GFP-MET tumors had a 30-day survival of 40% and 58%, respectively. rMETase-treated animals with H460-GFP tumors had a 30-day survival of 0% and 33%, respectively. Untreated animals with H460-GFP tumors had a 30-day survival of 0% and 33%, respectively. The retrovirus-mediated gene transfer of METase decreased the intracellular methionine level of tumor cells and consequently enhanced the efficacy of treatment with the rMETase protein. We have thus demonstrated a new strategy of combination tumor therapy with the gene and gene product of MET.