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W Roy Smythe

Publications and source records attributed to W Roy Smythe.

At least 19 recordsLinked to original sources
PubMed2007

Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma.

Mesothelioma is a neoplasm of the pleura that is currently incurable by conventional therapies. Previously, we demonstrated that mesothelioma overexpresses BCL-X(L), an anti-apoptotic member of the BCL-2 family. In addition, we have shown that down regulation of BCL-X(L) using a BCL-X(L) antisense oligonucleotide engenders mesothelioma apoptotic cell death in vitro and in vivo. The purpose of this study is to evaluate the efficacy of bcl2/bcl-x(L) inhibitor, 2-methoxy antimycin A3, in inducing apoptosis and increasing chemo-sensitivity in vitro and in vivo. Several bcl-x(L) high-expression tumor cell lines and one normal human cell line were exposed to 2-methoxy antimycin A3. 2-methoxy antimycin A3 demonstrated significant growth inhibition only in these tumor cell lines, with little effect on normal human cells. Treatment with 2-methoxy antimycin A3 alone resulted in a dramatic increase in the induction of apoptosis in the cancer cells. Apoptosis occurs through decreasing mitochondrial membrane potential and caspase activation. Notably, treatment with 2-methoxy antimycin A3 does not alter BCL-2 family protein expression. Synergistic inhibition of tumor growth by the coadministration of cisplatin and 2-methoxy antimycin A3 was observed in both in vitro and in vivo experiments. Together, these findings indicate that exposure of cancer cells to small molecule Bcl-2/x(L) inhibitors such as 2-methoxy antimycin A3 alone, or in the combination with other chemotherapeutics, may represent a novel therapeutic strategy in treatment of cancer, especially mesothelioma.

Antimycin A↗
PubMed2006

Cardiac autotransplantation for primary cardiac tumors.

BACKGROUND: Complete tumor resection is the optimal treatment of cardiac tumors. Anatomic accessibility and proximity to vital structures complicates resection of tumors involving the left heart. The results of standard resection and resection with orthotopic heart transplantation are dismal. We, therefore, reviewed our series of patients with complex left-sided primary cardiac tumors who underwent tumor resection with cardiac autotransplantation. METHODS: Since April 1998, 11 consecutive patients with complex left atrial or left ventricular intracavitary cardiac tumors underwent 12 resections using cardiac autotransplantation-cardiac explantation, ex vivo tumor resection with cardiac reconstruction, and cardiac reimplantation. Demographics, tumor histology, operative data, and mortality were analyzed. Follow-up was complete in all patients. RESULTS: Complete resection by cardiac autotransplantation was used in 7 patients with left atrial sarcoma, 1 patient with left ventricular sarcoma, 2 patients with left atrial paraganglioma, and 1 patient with a complex giant left atrial myxoma. Eight patients had previous resection of their cardiac tumor, and 1 patient had a repeat autotransplantation for recurrent disease. There were no operative deaths. Median overall survival was 18.5 months in patients with sarcomas. All patients with benign tumors are alive without evidence of recurrence. CONCLUSIONS: Cardiac autotransplantation is a feasible technique for resection of complex left-sided cardiac tumors. Recurrent disease after previous resections can be safely treated with this technique. Operative mortality and overall survival seems favorable in this series of patients. Benefits of this technique include improved accessibility and ability to perform a complete tumor resection with reliable cardiac reconstruction.

Adult↗
PubMed2005

Long-segment, supercharged, pedicled jejunal flap for total esophageal reconstruction.

OBJECTIVE: Many patients with cancer have limited esophageal reconstruction options when the stomach is unavailable as a replacement conduit or when long-segment discontinuity exists. Jejunum has been used as an alternative conduit, both as a pedicled or free flap interposition; however, reports of this are usually limited to short-segment repairs. Microvascular augmentation of a pedicled jejunal flap allows creation of a longer conduit, making it possible to replace the entire esophagus with jejunum. Few reports describe this technique in patients with cancer. We report our initial experience with "supercharged" pedicled jejunum as an alternative conduit for total esophageal reconstruction. METHODS: Review of a prospectively collected departmental database was performed to identify those patients who underwent total esophageal reconstruction with supercharged pedicled jejunum. Data regarding their perioperative course and postoperative function were gathered from the prospectively collected clinical data, review of hospital records, and patient interviews. RESULTS: Total esophageal reconstruction with supercharged pedicled jejunum was attempted in 26 patients (age range, 37-74 years) between March 2000 and April 2004. Twenty-four of 26 patients were ultimately discharged with an intact supercharged pedicled jejunum flap, for an overall success rate of 92.3%. One patient experienced intraoperative flap loss caused by technical difficulties harvesting the flap and never had the flap interposed. One other flap loss occurred in the early postoperative period in a patient who had multisystem organ failure after a prolonged reconstruction. Cervical anastomotic leaks occurred in 19.2% (5/26) of the patients. Two midconduit leaks occurred that were suspicious for iatrogenic perforation from nasogastric tube placement; one required reoperation. One additional early reoperation was performed for cecal ischemia. There were no mortalities. Functional results were available in 95.4% (21/22) of the patients receiving supercharged pedicled jejunum who survived at least 6 months after reconstruction. At the time of follow-up, 95% (20/21) of the patients were tolerating regular diet, and 76.2% (16/21) did not require any supplemental alimentation. Ninety-five percent (20/21) of the patients were free from reflux symptoms, and 80.9% (17/21) had no dumping symptoms. Only 1 patient required dilation of a midconduit stricture. One patient required late reoperation for conduit redundancy. CONCLUSIONS: Supercharged pedicled jejunum is a suitable alternative conduit for total esophageal replacement in patients with cancer with otherwise limited reconstructive options. Functional outcomes are excellent, despite the severity of disease and technical challenges in this patient population.

Adult↗
PubMed2005

Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma.

PURPOSE: To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy. RESULTS: After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space. CONCLUSION: Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.

Adult↗
PubMed2005

Enhancing TRAIL-induced apoptosis by Bcl-X(L) siRNA.

We previously found that a change in the balance between mitochondrial pro- and anti-apoptotic proteins caused by ectopic expression of the Bax gene led to increased induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To investigate whether a similar effect can be elicited by down-regulating Bcl-X(L), an anti-apoptotic protein, we tested the effects of a small interfering RNA (siRNA) specific for Bcl-X(L) in TRAIL-resistant cells. The down-regulation of Bcl-X(L) by siRNA inhibited cell proliferation and sensitized TRAIL-induced apoptosis in human cancer cells with both acquired and intrinsic TRAIL resistance. Combining the Bcl-X(L) siRNA with TRAIL protein treatment resulted in an increase in the percentage of apoptotic cells and increased cleavage of caspase-8, caspase-9, caspase-3 and PARP. Furthermore, the release of cytochrome c but not Smac from mitochondria was induced by Bcl-X(L) siRNA alone, and this release was dramatically amplified by combining the Bcl-X(L) siRNA and TRAIL protein treatment. Together, our data suggest that simultaneous triggering of the death receptor and mitochondrial apoptotic pathways leads to enhanced induction of apoptosis, which makes it potentially useful for the treatment of resistant cancers.

Apoptosis↗
PubMed2005

Preoperative chemoradiotherapy prior to esophagectomy in elderly patients is not associated with increased morbidity.

BACKGROUND: Preoperative chemotherapy and radiation therapy are often administered to patients with esophageal cancer. Despite an aging population, little data exist regarding feasibility of preoperative therapy in elderly patients. METHODS: Between January 1997 and December 2002, 312 consecutive patients underwent esophagectomy for esophageal cancer at our institution. Outcomes of patients 70 years old, who underwent preoperative therapy (n = 35; group II), were compared with those of patients who did not (n = 39; group I) and with those of patients younger than 70 years old who received preoperative therapy (n = 165; group III). RESULTS: The median age was 75 years old for group I and 72 years for group II (p < 0.001). The patients in group II were of more advanced clinical stage (p < 0.001). There were no differences in performance status, comorbidities, or preoperative symptoms between the two groups. Similar proportions of patients in the groups I and II underwent a transhiatal approach (52.5% vs 42.8%, p = not significant [NS]). Perioperative mortality for groups I and II was 0% and 3%, respectively (p = NS). Group II received more perioperative blood transfusions (71.4% vs 48.7%, p = 0.047). There were no differences in the rates of postoperative cardiac, pulmonary, neurologic, gastrointestinal, or anastomotic complications. Compared with group III, group II patients had higher rates of postoperative atrial arrhythmias (p = 0.013) and perioperative blood transfusions (p = 0.004). CONCLUSIONS: Elderly patients receiving preoperative therapy for esophageal cancer do not have an increased incidence of major postoperative complications. Elderly patients receiving preoperative therapy are more likely to develop postoperative atrial arrhythmias and require transfusion than younger patients.

Adenocarcinoma↗
PubMed2005

Extended surgical staging for potentially resectable malignant pleural mesothelioma.

BACKGROUND: Extrapleural pneumonectomy for malignant pleural mesothelioma (MPM) is a high-risk procedure, and patients require careful preoperative staging to exclude advanced disease. Computed tomography, magnetic resonance imaging, and positron emission tomography are useful staging modalities, but do not reliably identify contralateral mediastinal involvement or transdiaphragmatic invasion. We evaluated the role of extended surgical staging procedures, which generally includes a combination of laparoscopy, peritoneal lavage, and mediastinoscopy, to more precisely stage patients with MPM. METHODS: One hundred eighteen patients with MPM, deemed clinically and radiologically resectable, underwent extended surgical staging. Mediastinoscopy was performed in 111 patients, laparoscopy in 109 patients, and peritoneal lavage in 78 patients. RESULTS: Ten (9.2%) patients had gross evidence of transdiaphragmatic or peritoneal involvement. Peritoneal lavage was positive for metastatic MPM in 2 (2.6%) patients, neither of whom had obvious transdiaphragmatic invasion. Ipsilateral mediastinal nodes contained metastatic tumor in 10 of 62 (16.1%) patients. Contralateral nodes were positive in 4 of 111 (3.6%) patients. Of the patients who underwent biopsy of both ipsilateral and contralateral mediastinal nodes, and who had complete pathologic staging after extrapleural pneumonectomy (n = 46), 14 (30.4%) had N2-positive nodes. Only 5 of these patients were correctly identified by mediastinoscopy (sensitivity 36%, accuracy 80%). Extended surgical staging identified 16 (13.6%) patients who had contralateral nodal involvement, transdiaphragmatic invasion, or positive peritoneal cytology. CONCLUSIONS: Extended surgical staging defines an important subset of patients with unresectable MPM not identified by imaging. Because of the potential morbidity associated with extrapleural pneumonectomy, we advocate that extended surgical staging be performed in all patients with MPM before resection.

Adult↗
PubMed2005

Radiotherapy for mesothelioma.

Three to four thousand cases of malignant pleural mesothelioma will occur in the United States this year. Single-modality therapy with radiation plays a role for palliation. Radiation can prevent tumor recurrence at drain/instrumentation sites and provide symptomatic relief of pain and other complaints. Combinations of surgery and radiation also have been attempted with curative intent. The best local control has been found--EPP followed by radiotherapy. Locoregional tumor recurrence can be dramatically reduced with combinations of extrapleural pneumonectomy and radiation therapy. Survival in aggressively treated early-stage patients is excellent. However, the preponderance of death from distant metastases makes the development of better systemic therapy essential. Better therapy also must be developed for patients who are not candidates for extrapleural pneumonectomy.

Humans↗
PubMed2005

Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: Staging implications.

BACKGROUND: Integrated computed tomography-positron emission tomography imaging with coregistration of anatomic and functional imaging data may improve the accuracy of malignant pleural mesothelioma staging. We evaluate the use of integrated computed tomography-positron emission tomography in patients with malignant pleural mesothelioma who are being considered for extrapleural pneumonectomy. METHODS: Twenty-nine patients with malignant pleural mesothelioma who were judged to be candidates for extrapleural pneumonectomy after clinical and conventional radiologic evaluation underwent whole-body integrated computed tomography-positron emission tomography and pathologic staging. Two reviewers blinded to the results of clinical and pathologic staging retrospectively evaluated computed tomography, positron emission tomography, and coregistered computed tomography-positron emission tomography images. Staging was performed according to the International Mesothelioma Interest Group TNM staging system. Histopathology and/or results of further radiologic evaluation or follow-up served as the reference standard. RESULTS: Integrated computed tomography-positron emission tomography provided additional information in 11 of 29 patients that precluded extrapleural pneumonectomy. The overall tumor stage was correctly classified in 21 of 29 patients. The tumor stage was correctly determined in 15 of 24 patients, 6 of whom had T4 (nonresectable) disease. The node stage was accurately determined in 6 of 17 patients. Extrathoracic metastases not identified by routine clinical and conventional radiologic evaluation were detected in 7 of 29 patients and were found to be diffuse (n = 2) or solitary (n = 5). CONCLUSIONS: Integrated computed tomography-positron emission tomography increases the accuracy of malignant pleural mesothelioma staging and is important in determining the appropriate therapy in patients being considered for extrapleural pneumonectomy.

Adult↗
PubMed2005

Receptor tyrosine kinase and phosphoinositide-3 kinase signaling in malignant mesothelioma.

OBJECTIVE: The phosphoinositide-3 kinase signaling pathway is implicated in the development of malignancy and promotes cell-cycle progression and resistance to apoptosis. Malignant mesothelioma tumor specimens demonstrate high levels of the phosphoinositide-3 kinase downstream mediator phosphorylated Akt. Exposure of mesothelioma cell lines to LY294002, a phosphoinositide-3 kinase inhibitor, results in apoptotic cell death and decreased phosphorylated Akt in vitro and tumor burden reduction in vivo. Phosphoinositide-3 kinase is activated by cell-surface receptor tyrosine kinases. We sought to determine which receptors are present in mesothelioma and their role in cellular survival and phosphoinositide-3 kinase signaling. METHODS: Western blot analysis was performed to determine the relative expression of epidermal growth factor receptor, insulin-like growth factor receptor, and platelet-derived growth factor receptor in the mesothelioma cell lines I-45 and REN and the mesothelial line Met5a. After exposure of mesothelioma lines to kinase inhibitors, a cell viability assay was performed, cell-cycle analysis was performed to determine the percentage of apoptosis, and Western blot analysis was performed for phosphorylated Akt. RESULTS: Inhibition of epidermal growth factor receptor resulted in apoptotic cell death and Akt hypophosphorylation in mesothelioma cell lines. Insulin-like growth factor receptor inhibition led to apoptotic cell death without affecting Akt phosphorylation. Platelet-derived growth factor receptor inhibition did not affect cellular survival or phosphoinositide-3 kinase signaling. CONCLUSION: In malignant mesothelioma constitutive activation of phosphoinositide-3 kinase/Akt results in cellular survival and contributes to the malignant phenotype. We have demonstrated that epidermal growth factor receptor inhibition leads to apoptotic cell death through downregulation of phosphoinositide-3 kinase signaling in mesothelioma cell lines, whereas insulin-like growth factor receptor inhibition leads to apoptosis independent of phosphoinositide-3 kinase. Epidermal growth factor receptor, insulin-like growth factor receptor, and phosphoinositide-3 kinase inhibition might be clinically relevant in malignant mesothelioma.

Apoptosis↗
PubMed2005

The evolution of treatment outcomes for resected stage IIIA non-small cell lung cancer over 16 years at a single institution.

OBJECTIVES: The effect of multimodality treatment including surgical intervention, chemotherapy, and radiation for potentially resectable stage IIIA non-small cell lung cancer in a practice setting remains to be defined. To determine which treatment factors are associated with improved survival, we evaluated outcomes for these patients at our institution over a 16-year period. METHODS: We surveyed our institutional pathology database from 1986 through 2001 for patients with resected pathologic stage IIIA (N2) non-small cell lung cancer. Three hundred fifty-three patients were confirmed to have appropriate pathologic staging and attempted complete resection. These patients were assessed by means of univariate and multivariable analysis for factors associated with long-term survival. Stage migration was estimated by using a classification based on nodal station involvement. RESULTS: Median potential follow-up was 132 months. During the study period, 3- and 5-year survival increased; preoperative staging improved, relatively more lobectomies and fewer pneumonectomies were performed, and multimodality treatment was used more frequently. The number of positive N2 nodal stations did not change over time (P = .14). Surgical intervention alone resulted in 3-year survival of 30%, and perioperative chemotherapy, radiation, or both increased 3-year survival to 38% (P = .004). Multivariable analysis showed that male sex (hazard ratio, 1.44; 95% confidence interval, 1.13-1.84; P = .003), more than 2 positive mediastinal nodal stations (hazard ratio, 1.73; 95% confidence interval, 1.16-2.57; P = .007), R1 or R2 resection (hazard ratio, 1.72; 95% confidence interval, 1.22-2.41; P = .002), lower or middle lobe tumor location (hazard ratio, 1.63; 95% confidence interval, 1.28-2.08; P < .001), and surgical intervention alone (hazard ratio, 1.59; 95% confidence interval, 1.23-2.04; P < .001) were independent predictors of poor survival. CONCLUSIONS: The use of multimodality therapy appears to contribute to improved outcomes over time in patients with resected stage IIIA (N2) non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells.

5-Fluorouracil (5-FU) is commonly used to treat human colon cancers but resistance to this compound is frequently observed in clinics. To characterize mechanisms of resistance to 5-FU and to develop new strategies for overcoming it, we established two cell lines that were resistant to 5-FU but not other chemotherapeutic agents from parental 5-FU-sensitive cell lines. Western blot analysis revealed that these resistant cells overexpressed the proteins Bcl-XL, Bcl-Xs, and Bik, and further data showed that the cells were resistant to 5-FU-induced DNA damage and cell cycle disorder. However, in parental cells, enforced expression of Bcl-XL protein provided only limited protection from 5-FU-induced apoptosis and overexpression of Bcl-XL protein did not affect 5-FU-induced DNA damage or cell cycle changes; these findings suggested that overexpression of Bcl-XL protein was not the major contributor to 5-FU resistance in any of our cells lines. Even so, knockdown of Bcl-XL protein expression by Bcl-XL-specific small interfering RNA could inhibit proliferation more effectively in 5-FU-resistant cells than in 5-FU-sensitive cells, and the combination of Bcl-XL-specific small interfering RNA and 5-FU had additive effect on the inhibition of 5-FU-resistant cells. These results suggest that down-regulation of Bcl-XL protein expression might provide a new treatment strategy for human 5-FU-resistant colon cancer therapy.

Antineoplastic Agents↗
PubMed2004

2-Fluoro-2-deoxy-D-glucose positron emission tomography imaging is predictive of pathologic response and survival after preoperative chemoradiation in patients with esophageal carcinoma.

BACKGROUND: The current study was performed to assess the value of 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in predicting the pathologic response and survival of patients with esophageal carcinoma treated with preoperative chemoradiation (CRT) and tumor resection. Preliminary reports suggest that FDG-PET may be predictive of the response of esophageal carcinoma patients to preoperative CRT. METHODS: Eighty-three patients with resectable esophageal carcinoma who underwent preoperative CRT and FDG-PET and tumor resection were evaluated for pathologic response to CRT, percent residual tumor, and survival. RESULTS: The majority of patients in the current study were men (74 of 83 patients; 89%). Most tumors were adenocarcinomas (73 of 83 tumors; 88%) and clinical (EUS)T3/4 (69 tumors; 83%) or N1 (46 tumors; 55%). FDG-PET after preoperative CRT identified pathologic responders but failed to rule out microscopic residual tumor in 13 of 73 cases (18%). Pathologic response was found to correlate with the post-CRT FDG-PET standardized uptake value (SUV) (P = 0.03) and a post-CRT FDG-PET SUV of or 4 was found to be the only preoperative factor to correlate with decreased survival (2-year survival rate of 33% vs. 60%; P = 0.01). On univariate Cox regression analysis, only post-CRT FDG-PET was found to be correlated with post-CRT survival (P = 0.04). CONCLUSIONS: Post-CRT FDG-PET was found to be predictive of pathologic response and survival in patients with esophageal carcinoma who undergo preoperative CRT. Esophagectomy should still be considered even if the post-CRT FDG-PET scan is normal because microscopic residual disease cannot be ruled out.

Adenocarcinoma↗
PubMed2004

Prospective randomized study evaluating a biodegradable polymeric sealant for sealing intraoperative air leaks that occur during pulmonary resection.

BACKGROUND: To evaluate the safety and effectiveness of a new biodegradable polymeric sealant to close intraoperative air leaks after pulmonary resection. METHODS: In a multicenter prospective randomized trial, 161 patients with a median age of 67 years old (range 18-85 years old), were randomized in a 2:1 ratio to receive sealant or control for at least one significant air leak (> or = 2.0 mm in size) after pulmonary resection. In the sealant group, all significant air leaks underwent attempted repair by standard methods (sutures, staples, or cautery) prior to the application of sealant. The control group underwent only standard methods. Blood was analyzed for immunologic response. Patients were followed up 1 month after surgery. RESULTS: Intraoperative air leaks were sealed in 77% of the sealant group compared with 16% in the control group (p < 0.001). The sealant group had significantly fewer patients with postoperative air leaks compared with the control group (65% vs 86%, p = 0.005). Median length of hospitalization was 6 days (range, 3-23 days) for the sealant group compared with 7 days (range 4-38 days) for controls (p = 0.028). There was no difference in mortality, morbidity, duration of chest tubes, or immune responses between the two groups. CONCLUSIONS: This study demonstrates the effectiveness of a biodegradable polymer when used as an adjunct to standard closure methods for sealing significant intraoperative air leaks that develop from pulmonary surgery. Use of the sealant led to a reduction in postoperative air leaks, which may have decreased the length of hospitalization.

Adolescent↗
PubMed2004

Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer.

BACKGROUND: This study evaluates the utility of positron emission tomography (PET), endoscopic ultrasonography (EUS), and computed tomographic (CT) scans to predict pathologic response and survival following preoperative chemoradiation (CRT) in esophageal cancer. METHODS: One hundred three sequential patients with locoregionally advanced esophageal cancer, who were treated with CRT and esophageal resection between May 2001 and November 2003 at the University of Texas M.D. Anderson Cancer Center, were retrospectively reviewed. PET, EUS, and CT were performed before (pre) or after (post) CRT and before surgical resection. PET standardized uptake value (SUV) was defined as maximal uptake in primary tumor. RESULTS: Most patients were male (91 [88%]) with adenocarcinoma (90 [87%]). Pretreatment clinical stages were: IIA (42 [41%]), IIB (5 [5%]), III (50 [49%]), and IVA (6 [6%]). At the time of surgery, 58 patients (56%) had a pathologic response to CRT (< or =10% viable cells). Post-CRT measurements that correlated with pathologic response were: CT esophageal wall thickness (13.3 vs 15.3 mm, p = 0.04), EUS mass size (0.7 vs 1.7 cm, p = 0.01) and PET SUV (3.1 vs 5.8, p = 0.01). Post-CRT PET SUV equal to or greater than 4 had the highest accuracy for pathologic response (76%). Univariate and multivariate Cox regression analysis demonstrated that a post-CRT PET SUV equal to or greater than 4 was an independent predictor of survival (HR, 3.5, p = 0.04). CONCLUSIONS: The FDG-PET SUV is the most accurate noninvasive test to predict long-term survival after preoperative CRT and before surgical resection. Post-CRT FDG-PET cannot, however, rule out residual microscopic disease so esophagectomy should remain a therapeutic option even if the post-CRT imaging modalities are normal.

Adenocarcinoma↗
PubMed2004

Gene therapy for sarcoma utilizing adenoviral transfer of the beta-glucuronidase and bax genes and an anthracyline prodrug.

BACKGROUND: When acted on by beta-glucuronidase (BG), HMR1826 is metabolized to doxorubicin. Use of this prodrug with adenoviral transfer of beta-glucuronidase (AdBG) is limited by the drug's inability to enter cells and intracellular retention of BG after transduction. We evaluated a system combining AdBG, transfer of the proapoptotic gene bax (AdBax) at a low multiplicity of infection, and HMR1826 administration. MATERIALS AND METHODS: Fibrosarcoma cells were treated with AdBG alone, AdBG plus HMR1826, AdBG followed by beta-galactosidase (AdLacZ) plus HMR1826, and AdBG followed by AdBax with no prodrug. In the experimental group, cells were transfected with AdBG, followed by AdBax plus HMR1826. Viability was measured 24 h after transfection and prodrug administration. Western blots for BG were performed on cell lysates and supernatants. RESULTS: Minimal cellular killing was noted in the AdBG alone, AdBG plus HMR 1826, or AdBG:AdLacZ plus HMR 1826 groups, and Western blot did not demonstrate BG in the supernatant even though all AdBG-transfected cell lysates were positive. Cell killing was noted in the AdBG:AdBax group, but less than in the AdBG:AdBax plus HMR 1826 group (without prodrug versus with prodrug: 1:1 to 55.5% versus 75.9%, 5:1 to 10.0% versus 75.9%, 10:1 7.6% versus 49.0%, 20:1 4.6% versus 24.9%, P = 0.037). Western blot demonstrated BG in the supernatant of the AdBG:AdBax groups. CONCLUSIONS: We have devised a novel enzyme prodrug method of killing tumor cells and engendering a bystander effect. AdBax leads to BG release from dying cells after AdBG transduction and conversion of HMR1826 to an active anthracycline.

Adenoviridae↗
PubMed2004

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Academic Medical Centers↗