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Objective: The purpose of this article is to review the safety and efficacy of thermal ablation of lung malignancies after pneumonectomy., Materials and Methods: We reviewed patients who underwent thermal ablation for malignant lung tumors after pneumonectomy between 1999 and 2009. Patient demographics, complications, procedural success, and oncologic outcomes were recorded. Technique effectiveness was evaluated at imaging 4-6 weeks after ablation. The Kaplan-Meier method was used to evaluate overall survival. A cumulative incidence and competing risk method was used to account for progression-free tumors at the time of patient death., Results: Of 619 lung ablations, 17 were performed to treat 13 tumors (nine primary and four metastatic) in 12 patients with a single lung. The median tumor size was 2 cm (range, 1.2-4 cm). Technical success was documented in all 17 cases. Technical effectiveness was documented in 10 of 12 patients. Local tumor progression occurred in five lesions within a median of 12 months (range, 10-22 months) after ablation and was treated with repeat ablation in four lesions. Complications included six (35%) of 17 pneumothoraces requiring thoracostomy. Deaths occurred within 2-12 days after three (19%) of 16 ablation sessions. The median time to primary local tumor progression was 18 months (95% CI, 12 months through not reached), and the median time to assisted (after repeat ablation) local tumor progression was 33 months (95% CI, not reached). Median overall survival was 21 months (95% CI, 18-53 months). After excluding the two early deaths complicating the initial ablation procedure, median overall survival was 37 months., Conclusion: Thermal ablation can offer local tumor control after pneumonectomy, despite a relatively high postprocedure clinical risk.

Objective: Dehiscence or leakage after bowel anastomoses is associated with high morbidity and mortality. Perfusion and local tissue oxygenation (StO2), independent of systemic oxygen saturation, are fundamental determinants of anastomotic viability. Because current technology is limited for monitoring local StO2 at bowel anastomoses, our goal was to construct a wireless pulse oximeter (WiPOX) to monitor real-time intraoperative tissue oxygenation, permitting identification of compromised anastomotic perfusion., Methods: We have: (a) designed a handheld device capable of real-time monitoring of serosal and mucosal StO2 through endoscopic ports with wireless data transmission to standard intraoperative monitors, (b) constructed the WiPOX using materials meeting FDA regulations for intraoperative use and reuse, (c) performed accuracy testing in humans by comparing the WiPOX to standard pulse oximeters, and (d) tested WiPOX efficacy for detecting early tissue hypoxia in stomach, intestines, and kidneys in anesthetized rats and swine., Results: In humans, WiPOX demonstrated accuracy within 3% compared with commercially available pulse oximeters. Application of the WiPOX in rats and swine demonstrated normal serosal and mucosal StO2 and pulse rates in healthy small bowel and stomach. Within 30 s of compromised perfusion, the WiPOX detected bowel hypoxia over a wide range of oxygen saturation (p<0.005). A greater degree of hypoxia was detected in mucosal versus serosal measurements during early ischemia, despite normal appearance of tissue. The onboard sensor-processor unit permitted noninvasive pulse oximetry and integration with current intraoperative monitoring. The contact pressure-sensing head allowed for consistent, high-quality StO2 waveform readouts despite the presence of body fluids., Conclusions: We have constructed, validated, and successfully tested a novel wireless pulse oximeter capable of detecting intraoperative tissue hypoxia in open or endoscopic surgery. This device will aid surgeons in detecting anastomotic vascular compromise and facilitate choosing an ideal site for bowel anastomosis by targeting well-perfused tissue with optimal healing capacity.

Objective: Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy., Summary Background Data: What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data., Methods: A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression., Results: For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4., Conclusions: Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and >or=7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and >or=30 for pT3/T4 is recommended.

The treatment of esophageal cancer with curative intent remains highly controversial, with advocates of surgery alone, chemoradiotherapy alone, surgery with adjuvant therapy (including neoadjuvant and postoperative), and trimodality therapy each contributing prospective randomized controlled trials (PRCTs) to the body of scientific publications between 2000 and 2008. Any improvements in survival have been small in absolute percentage terms, and as such PRCTs published over the last decade have met the same primary obstacle encountered by the studies from the two prior decades, namely lack of power to detect small differences in outcome. Variations in staging methods, surgical technique, radiotherapy technique, and chemotherapy regime have in turn been the subject of PRCTs over the last nine years. In many cases primary end points have not been survival but rather rates of complication or response. As well as giving an overview of PRCTs, this article collates the level Ia evidence published to date.

Introduction: We have previously shown that in early clinical stage esophageal adenocarcinoma, a positron emission tomography standardized uptake values (PET SUVmax) of <4.5 is associated with earlier pathologic stage and predicts better survival. In this study, we analyze the impact of the pretreatment PET SUVmax in patients with locally advanced esophageal adenocarcinoma who undergo preoperative chemoradiotherapy., Methods: We performed a retrospective analysis, selecting patients with adenocarcinoma of the esophagus who had a pretreatment PET scan and who received chemoradiotherapy before esophagectomy. Data recorded included demographics, PET SUVmax, treatment details, pathologic details, and survival data. Comparison of categorical variables was done by chi analysis, continuous variables by t test, survival analysis by the Kaplan-Meier method, and comparisons of survival using the log-rank test., Results: Between January 1996 and September 2007, 189 patients were appropriate for this analysis. The initial PET SUVmax was <4.5 in 28 patients and >or=4.5 in 161 patients. The two groups were similar with regards to demographics and treatment details. Patients in the low SUV group were less likely to show evidence of treatment response after chemoradiotherapy, including a higher likelihood of residual nodal disease and a lower likelihood of a pathologic complete response and estimated treatment response. However, both groups had similar survival., Conclusions: Although the initial PET SUVmax does not predict survival in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy, patients with a high initial SUVmax respond better to preoperative therapy. These results can be used to better select esophageal cancer patients for combined modality treatment.

Objective: Thymic carcinomas are considered to be more aggressive than thymomas and carry a worse prognosis. We reviewed our recent experience with the surgical management of thymic tumors and compared the outcomes and patterns of relapse between patients with thymic carcinoma and those with thymoma., Methods: We performed a single-institution retrospective cohort study. Data included patient demographics, stage, treatment, pathologic findings, and postoperative outcomes., Results: During the period 1995-2006, 120 patients with thymic tumors underwent surgical intervention, including 23 patients with thymic carcinoma and 97 patients with thymoma, as classified according to the World Health Organization 2004 histologic classification. The overall 5-year survival was significantly different between patients with thymic carcinoma and those with thymoma (thymic carcinoma, 53%; thymoma, 89%; P = .01). Data on relapse were available for 112 patients. The progression-free 5-year survival was also significantly different between patients with thymic carcinoma and those with thymoma (thymic carcinoma, 36%; thymoma, 75%; P < .01). Using multivariate analysis, thymic carcinoma and incomplete resection were found to be independent predictors of progression-free survival. Relapses in patients with thymic carcinoma tended to occur earlier, and occurred significantly more frequently at distant sites than in patients with thymoma (60% vs 13%, P = .01)., Conclusions: Patterns of relapse differ significantly between patients with thymic carcinoma and those with thymoma, with lower progression-free survival, earlier onset, and more distant relapses in patients with thymic carcinoma. Given the greater propensity for distant failures, the inclusion of systemic therapy in the treatment of thymic carcinoma might take on greater importance. Despite significantly higher rates of distant relapse, good overall survival in patients with thymic carcinoma can be achieved.

Background: The optimal surgical technique for lobectomy in lung cancer is not well defined. Proponents of video-assisted thoracic surgery (VATS) hypothesize that less trauma leads to quicker recovery, whereas those who advocate thoracotomy claim it as an oncologically superior procedure. However, a well-balanced comparison of the two procedures is lacking in the literature., Methods: All patients who underwent lobectomy for clinical stage 1A lung cancer by computed tomographic and positron emission tomographic scan were identified from a prospective database. Patient characteristics were compared by the Student t test, Pearson chi(2), and Fisher exact test. A propensity score-matched analysis was performed. Survival was assessed by Kaplan-Meier and Cox proportional hazards analysis. Complications were assessed by a multivariate logistic regression model evaluating age, sex, comorbidities, pulmonary function, tumor size, nodal status, surgeon, and histologic characteristics., Results: From May 2002 to August 2007, 398 patients underwent an attempt at VATS lobectomy and 343 underwent thoracotomy. An "intent-to-treat" analysis was performed. There was 1 postoperative death in each group. Survival by Cox model was no different for VATS versus thoracotomy (hazard ratio 0.72; P = .12), whereas age (hazard ratio 1.03; P < .001), larger tumor size (hazard ratio 1.34; P < .001), and higher nodal stage (hazard ratio 1.92; P < .001) were associated with worse survival. Logistic regression demonstrated fewer complications for VATS lobectomy (odds ratio 0.73; P = .06), whereas age (odds ratio 1.04; P < .001) and tumor size (odds ratio 1.2; P < .020) correlated with a greater number of complications. Patients undergoing VATS lobectomy demonstrated a 2-day shorter length of stay than patients undergoing thoracotomy (P < .001). Propensity score-matched analysis supported these findings., Conclusions: VATS lobectomy and thoracotomy demonstrated similar 5-year survivals. However, VATS lobectomy was associated with fewer complications and shorter length of hospital stay.

Purpose: Endoscopic biopsy after chemoradiation therapy (CRT) for esophageal cancer has been used to determine response to treatment. We wanted to determine if endoscopic biopsy can accurately establish evidence of local pathologic complete response (pCR) in patients undergoing CRT., Methods: We queried a prospectively maintained database for patients seen at Memorial Sloan-Kettering Cancer Center from 1996 to the present who underwent, (1) CRT for local-regionally advanced esophageal cancer, (2) post-CRT endoscopic biopsy, and (3) esophagectomy. Data points included pathology of post-CRT endoscopy and surgical specimens, tumor histology, and survival. Correlations were analyzed by the chi2 test and one-way analysis of variance. Survival comparisons were assessed using the Kaplan-Meier method and log-rank analysis., Results: One hundred fifty-six patients were identified. Over 80% of patients received cisplatin-based chemotherapy and 5040 cGy of radiation. One hundred eighteen patients had no tumor identified on endoscopic biopsy. A negative biopsy at endoscopy was a poor predictor of pCR (negative predictive value: 31%), with 69% having local disease at esophagectomy. A positive biopsy was predictive of residual disease (positive predictive value: 95%). Negative endoscopic biopsy better predicted a pCR for squamous cell carcinomas versus adenocarcinomas (P[r] < 0.001). Nodal status of surgical specimens was not correlated with post-treatment endoscopic findings. Survival was equivalent after surgery in patients with a negative endoscopic biopsy versus patients with positive pathology., Conclusion: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival.

Introduction: In a previous study of prognostic factors in patients with loco-regionally advanced adenocarcinoma of the esophagus treated with chemo-radiotherapy (CRT) followed by resection, we found that residual nodal disease was most prognostic of outcome. In this study, we evaluated prognostic factors among patients with squamous cell carcinoma (SCC) of the esophagus who have undergone a similar treatment regimen., Methods: A retrospective review of patients with SCC of the esophagus who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses., Results: From 1996 to 2006, 91 patients were appropriate for this analysis. Complete pathologic response in the primary tumor (pt-pCR) occurred in 49 patients (53.8%), including 10 of 91 (10.9%) who had a pt-pCR but residual nodal disease. Recursive partitioning analysis identified three prognostic groups: (1) group 1 (n = 52), patients with minimal residual local disease (pt-pCR and T1-N any); (2) group 2 (n = 28), patients with residual T2 disease (N0 and N1) and patients with T3-4N0 disease; and (3) group 3 (n = 11), patients with residual T3-4N1 disease. Three-year survival was 68.4% in group 1, 45.6% in group 2, and 0 % in group 3 (p < 0.001)., Conclusions: Unlike adenocarcinoma, in which residual nodal disease after CRT is the most significant predictor of survival, in SCC of the esophagus, pt-pCR or minimal residual local disease after CRT predicts the best survival. These findings aid the design of future clinical trials.

Objective: Extended resections for advanced-stage thymomas are not commonly performed because of the potential morbidity in the face of unclear survival or palliative benefit. We reviewed our experience with multimodality treatment for Masaoka stage IVA thymomas for feasibility and outcomes., Methods: We conducted a retrospective review of a single-institution surgical database. Data included patient demographics, preoperative staging and treatment, perioperative events, pathologic findings, and postoperative outcomes., Results: During the period from 1996 to 2006, 18 patients who had Masaoka stage IVA thymoma underwent surgical resection. All patients received preoperative chemotherapy. Four patients with extensive pleural involvement underwent concomitant extrapleural pneumonectomy and postoperative hemithoracic radiation. Complete resection was achieved in 12 (67%) patients. There was no operative mortality. With a median follow-up of 32.2 months (range 1.4-129.9 months), 3-year, 5-year, and 10-year survivals were 91%, 78%, and 65%, respectively, and median survival has not yet been reached., Conclusion: Multimodality therapy including extended surgical resection can be performed in select patients with stage IVA thymoma with low morbidity and mortality and can result in excellent long-term survival.

Background: Endoscopic ultrasound (EUS) is the most accurate locoregional staging tool for gastroesophageal junction (GEJ) adenocarcinoma, and it may allow pretreatment risk stratification. The purpose of this study was to compare preoperative EUS staging with postoperative pathologic staging and to assess the ability of EUS to predict survival after resection for GEJ adenocarcinoma., Study Design: Patients with GEJ adenocarcinoma, who had preoperative staging with EUS followed by resection, were identified from a prospectively maintained database. Patients receiving neoadjuvant therapy were excluded. EUS stage was compared with pathologic stage. Survival analyses were performed in patients who underwent complete gross resection., Results: From 1985 through 2003, 209 patients underwent preoperative EUS followed by surgery without neoadjuvant therapy for GEJ adenocarcinoma. EUS correlated with pathologic T stage in 128 of 209 (61%) patients and with pathologic nodal stage in 154 of 206 (75%) patients. EUS accurately stratified patients into "early" (T0-2 N0) or "advanced" (T3-4 or N1) disease categories in 173 (83%) patients. Curative (R0) resection was performed in 184 patients: EUS "early" (n=84) and "advanced" (n=122) stages were associated with R0 rates of 100% and 82%, respectively (p=0.001). EUS "early" versus "advanced" stage was highly predictive of outcomes (p < 0.0001). The 5-year disease-specific survival for EUS "early" patients was 65% compared with 34% for EUS "advanced" stage., Conclusions: EUS accurately predicts pathologic stage. In addition, EUS is predictive of outcomes after complete gross resection without neoadjuvant treatment for GEJ adenocarcinoma and identifies a high-risk population that might benefit from preoperative therapy.

Objective: To determine whether the length of esophageal resection or the operative approach influences outcome for patients with adenocarcinoma of the gastroesophageal junction (GEJ)., Summary Background Data: While R0 resection remains the mainstay of curative treatment of patients with GEJ cancer, the optimal length of esophageal resection remains controversial., Methods: Patients with Siewert I, II, or III adenocarcinoma who underwent complete gross resection without neoadjuvant therapy were identified from a prospectively maintained database. Proximal margin lengths were recorded ex vivo as the distance from the gross tumor edge to the esophageal transection line. Operative approaches were grouped into gastrectomy (limited esophagectomy) or esophagectomy (extended esophagectomy)., Results: From 1985 through 2003, 505 patients underwent R0/R1 gastrectomy (n = 153) or esophagectomy (n = 352) without neoadjuvant treatment. There were no differences in R1 resection rate, number of nodes examined or operative mortality between gastrectomy and esophagectomy. Univariate analysis found >3.8 cm to be the ex vivo proximal margin length (approximately 5 cm in situ) most predictive of improved survival. Multivariable analysis in patients who underwent R0 resection with >or=15 lymph nodes examined (n = 275) found the number of positive lymph nodes, T stage, tumor grade, and ex vivo proximal margin length >3.8 cm to be independent prognostic factors. Subset analysis found that the benefit associated with >3.8 cm margin was limited to patients with T2 or greater tumors and

Purpose: In patients with adenocarcinoma of the esophagus who receive preoperative chemoradiotherapy (CRT), American Joint Committee on Cancer (AJCC) stage, pathologic complete response (pCR), and estimated treatment response are various means used to stratify patients prognostically after surgery. However, none of these methods has been formally evaluated. The purpose of this study was to establish prognostic pathologic variables after CRT., Patients and Methods: A retrospective review was performed of patients with esophageal adenocarcinoma who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses., Results: Two hundred seventy-six patients were appropriate for this analysis. Kaplan-Meier analysis indicates that the current AJCC system poorly distinguishes between stages 0 to IIA (P = .52), IIB to III (P = .87), and IVA to IVB (P = .30). The presence of a pCR conferred improved survival over residual disease (P = .01). Recursive partitioning analysis indicates that involved lymph nodes and metastatic disease are the best predictors of survival and that depth of invasion and degree of treatment response are less predictive., Conclusion: The current AJCC staging system is not a good predictor of survival after CRT. Although patients with a pCR do have improved long-term survival relative to patients with residual disease, this method places too much emphasis on residual depth of invasion and fails to identify patients with residual disease who have good long-term survival. Recursive partitioning analysis more accurately identifies nodal disease and metastatic disease as the most important prognostic variables. Degree of treatment response is less prognostic than nodal involvement.

Introduction: Adequate staging of gastric cancer requires examination of at least 15 lymph nodes. Most resected patients are inadequately staged potentially confounding the interpretation of clinical data. The aim of this study was to determine whether adequate staging revealed different prognostic factors or improved survival compared with patients with <15 nodes examined after R0 resection for GEJ cancer., Methods: A prospectively maintained database identified 366 patients with Siewert types II and III adenocarcinoma of the GEJ who underwent R0 resection without neoadjuvant therapy at a single institution. Patients were grouped into adequately (>or=15 nodes examined) or inadequately staged (<15 nodes examined). Median follow up was 51 months., Results: From 1985 through 2003, 250/366 (68%) patients were adequately staged and 116/366 (32%) were inadequately staged. There was no difference in operative mortality between adequately staged (5.2%) and inadequately staged patients (4.3%, P = NS). Adequately staged patients had more positive lymph nodes (median 2) compared with inadequately staged patients (median 1, P < 0.01). Multivariable analysis of adequately staged patients found the number of positive lymph nodes, T stage, and lymphovascular invasion to be independent prognostic factors for overall survival (OS). For inadequately staged patients only the number of positive lymph nodes and T stage were independent prognostic factors. Adequate staging was an independent prognostic factor for patients with advanced (T >or= 2 Nany) tumors. For T1 tumors adequate staging was not associated with improved survival., Conclusions: Patients with GEJ cancer should undergo adequate lymphadenectomy to permit examination of >or=15 lymph nodes allowing the accurate identification of prognostic variables. Removal of >or=15 lymph nodes is associated with more accurate survival estimates for patients with advanced disease.

Background: As the general population ages, it becomes increasingly important to understand the potential contribution of chronologic age to mortality after esophagectomy. Because this risk is poorly defined, we sought to determine whether extreme age (>80 years) is an independent risk factor after esophagectomy., Methods: We analyzed a prospectively maintained, single-institution database of 858 consecutive patients who underwent esophagectomy between January 1996 and May 2005. Data evaluated included patient demographics, medical comorbidity, types of resections performed, length of stay, postoperative adverse events, and overall survival. We used univariate, multivariate, and Kaplan-Meier analysis to determine the influence of age on postoperative morbidity, in-hospital survival, and overall survival., Results: Of 858 patients, 31 (10 female, 21 male) were older than 80 years of age. Preliminary analysis indicated that patients younger than 50 years (n = 107) had significantly fewer comorbidities; these were excluded from the analysis. In the remaining 751 patients, the age older than 80 cohort was compared with patients aged 50 to 79. Patients aged 50 to 79 were grouped because of similar characteristics (length of stay, hospital death). There were no significant differences in comorbidities, types of resections, or postoperative complication type or severity between the two groups. Postoperative death, length of stay, and survival, however, were significantly worse in patients older than 80. In a logistic regression model controlling for comorbidity, age older than 80 was significantly associated with increased perioperative mortality (hazard-ratio, 3.9; p < 0.01)., Conclusions: Patients older than 80 years have increased mortality risk after esophagectomy, independent of comorbidity. Octogenarian status should be a consideration in the management of these patients.

Background: Efforts to improve surgical outcomes have traditionally focused on improving preoperative patient selection and reducing the risk of postoperative medical complications. Strategies to optimize surgical technique have been less well studied. We sought to assess the relation between complications related to surgical technique and outcomes after esophagogastrectomy for cancer., Study Design: Medical records of 510 consecutive patients undergoing esophagogastrectomy for invasive squamous cell carcinoma or adenocarcinoma at Memorial Sloan-Kettering Cancer Center from 1996 to 2001 were reviewed. Data on diagnosis, stage of disease, therapies received, surgical approach, patient comorbidities, technical complications, and postoperative medical complications and outcomes including length of stay and overall survival were determined by one reviewer of the medical records. The primary predictor was surgical complications and the primary outcome was survival., Results: Of the 150 patients studied 138 (27%) had complications directly attributable to surgical technique, such as an anastomotic leak, a paralyzed vocal cord, or chylothorax. At 3 years 43 of 138 patients (31%) with technical complications were alive, whereas 179 of 372 patients (48%) without technical complications were alive. Technical complications were associated with increased length of stay (median 23 days versus 11 days, p < 0.001), increased in-hospital mortality (12.3% versus 3.8%, p < 0.001), and a higher rate of medical complications (77.5% versus 47.3%, p < 0.001). After controlling for age, medical comorbidities, use of induction therapy, tumor stage, histology, and location, and completeness of resection the presence of a technical complication was highly predictive of poorer overall survival; the multivariable hazard ratio was 1.41 (1.22 to 1.63, p = 0.008)., Conclusions: Technical complications have a large negative impact on survival after esophagogastrectomy for cancer. Strategies to optimize surgical technique and minimize complications should improve outcomes in this cancer operation.

Colorectal cancer is one of the most prevalent malignancies in the United States. It has a well-recognized tendency to metastasize to the lungs, and under certain circumstances, these metastases are resectable. Data accumulated over the last 40 years support a survival benefit from resection of these lesions and have given a better understanding of the indications that should be adhered to in performing metastasectomy for colorectal cancer., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Because many tumors have mutated p53, one potential strategy proposed for cancer gene therapy is the introduction of the wild-type p53 gene into tumor cells. One puzzling aspect of this approach is that currently available gene transfer protocols result in a small percentage of tumor cells being transduced in vivo, thus implicating a "bystander effect" to achieve therapeutic efficacy. Because bystander effects in the context of p53-mediated gene therapy have not been well characterized, we evaluated the role of in vitro and in vivo bystander effects of adenovirally delivered p53 (AdWTp53). Using human tumor cell lines that did not express p53 protein but were infectible with adenovirus and showed sensitivity to p53-mediated apoptosis, we were unable to demonstrate an AdWTp53-mediated in vitro bystander effect, despite seeing strong bystander effects when cells were infected with an adenovirus containing the suicide gene herpes simplex virus thymidine kinase and treated with ganciclovir. In contrast, in vivo flank mixing studies using one of these cell lines showed a weak but significant p53-mediated bystander effect (a 40% inhibition of tumor growth). This bystander effect translated into a small survival advantage in an established intraperitoneal tumor model when tumor burden was low at the time of viral instillation. The survival advantage was lost, however, when tumor burden was increased. This study indicates that treatment of human tumors using AdWTp53 may be possible; however, because of the weak bystander effect in vivo, effective treatment will likely require a large percentage of tumor cells to be transduced.

Modified, nonneurovirulent herpes simplex viruses (HSVs) have shown promise in the treatment of brain tumors. However, HSV-1 can infect and lyse a wide range of cell types. In this report, we show that HSV-1716, a mutant lacking both copies of the gene coding ICP-34.5, can effectively treat a localized i.p. malignancy. Human malignant mesothelioma cells supported the growth of HSV-1716 and were efficiently lysed in vitro. i.p. injection of HSV-1716 into animals with established tumor nodules reduced tumor burden and significantly prolonged survival in an animal model of non-central nervous system-localized human malignancy without dissemination or persistence after i.p. injection into SCID mice bearing human tumors. These findings suggest that this virus may be efficacious and safe for use in localized human malignancies of nonneuronal origin such as malignant mesothelioma.