Neoadjuvant Therapy Vs Upfront Surgery for Clinical T2N0 Esophageal Cancer: A Systematic Review.

BACKGROUND: The optimal approach to clinical T2N0 (cT2N0) esophageal cancer is unclear. Our objective is to perform a systematic review investigating whether neoadjuvant therapy results in better outcomes compared with upfront surgery in cT2N0 esophageal cancer. METHODS: We performed a systematic review and meta-analysis of randomized and nonrandomized studies (1995 to 2017) comparing use of neoadjuvant therapy with upfront surgery in the treatment of cT2N0 esophageal cancer. Independent and duplicate assessment was used. All meta-analytical techniques were performed in RevMan 5.3. RESULTS: Nine cohort studies, including 5433 patients, were included for meta-analysis. Use of neoadjuvant therapy was associated with significantly higher complete resection rates compared with upfront surgery (risk ratio, 0.67; 95% confidence interval, 0.55 to 0.81; P < .001). There was no difference in 5-year overall or recurrence-free survival. There were no significant differences in perioperative mortality as well as perioperative complications, although meta-analysis results are limited by inconsistent reporting of such complications. Lymphovascular invasion and larger tumor size were significant predictors of upstaging. Four of the studies were at high risk of bias. The remaining 5 studies were larger and more robust but were assessed as being of uncertain risk of bias. CONCLUSIONS: Use of neoadjuvant therapy was associated with significantly higher complete resection rates compared with upfront surgery although this did not translate to differences in survival outcomes. No differences in perioperative morbidity or mortality were identified. Based on qualitative systematic review, lymphovascular invasion and larger tumor size are potential factors for helping to select those patients who may benefit from neoadjuvant therapy.

The Use of Standardized Measures to Predict and Assess Quality of Life after Laparoscopic Hiatal Hernia Repair.

The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P < 0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome.

Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial.

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

Positron Emission Tomography in Thymic Tumors: Analysis Using a Prospective Research Database.

BACKGROUND: Positron emission tomography may have a role in the pretreatment workup of patients with thymic malignancies. This study was undertaken to determine the utility of the maximum standardized uptake value (SUVmax) in predicting histologic type and tumor stage in a large cohort of thymic epithelial tumors. METHODS: The large, multiinstitutional, prospective database of The International Thymic Malignancy Interest Group (ITMIG) was queried for the use of positron emission tomography in the pretreatment workup of patients with thymic tumors. Data analyzed included demographics, SUVmax, histologic tumor type, and tumor stage. The distribution of SUVmax according to histologic type and Masaoka-Koga pathologic stage was determined, and the ability of SUVmax to predict these two variables was calculated using analysis of receiver operating characteristic curves. RESULTS: Since 2012, data from 926 patients with thymic malignancies were entered into the ITMIG prospective database, of which 154 had a reported value for SUVmax. The area under the receiver operating characteristic curve for SUVmax in predicting histologic type and pathologic stage was 0.79 (95% confidence interval, 0.70 to 0.88; p < 0.001) and 0.81 (95% confidence interval, 0.73 to 0.88; p < 0.001), respectively. In addition, there was a significant relationship between SUVmax and histologic type (p < 0.001) as well as Masaoka-Koga pathologic stage (p < 0.001). CONCLUSIONS: Positron emission tomography has utility in predicting clinicopathologic features of thymic malignancies. These results may have clinical application in the pretreatment workup of patients with these rare tumors.

Successful Treatment of an Iatrogenic Tracheal Laceration With a Temporary Polyurethane-Coated Nitinol Stent.

We report the case of a 63-year-old woman who required emergent intubation after a choking episode at home. It resulted in a 5-cm tear in the membranous trachea. She was treated by placement of a temporary tracheal stent, which was successfully removed 3 months later.

Postoperative Radiation Therapy Is Associated with Longer Overall Survival in Completely Resected Stage II and III Thymoma-An Analysis of the International Thymic Malignancies Interest Group Retrospective Database.

OBJECTIVES: The aim of this study was to determine whether postoperative radiation therapy (PORT) is associated with an overall survival (OS) benefit in patients with completely resected Masaoka or Masaoka-Koga stage II and III thymoma. METHODS: All patients with completely resected (R0) stage II or III thymoma were identified in a large database of the International Thymic Malignancy Interest Group. Clinical, pathologic, treatment, and follow-up information were extracted. OS was the primary end point. A univariate analysis using the log-rank test was performed, and a multivariate Cox model was created to identify factors associated with OS. RESULTS: Of 1263 patients meeting the selection criteria, 870 (69%) had stage II thymoma. The WHO histologic subtype was A/AB in 360 patients (30%) and B1/B2/B3 in 827 (70%). PORT was given to 55% of patients (n = 689), 15% (n = 180) received chemotherapy, and 10% (n = 122) received both. The 5- and 10-year OS rates for patients having undergone an operation plus PORT were 95% and 86%, respectively, compared with 90% and 79% for patients receiving an operation alone (p = 0.002). This OS benefit remained significant when patients with stage II (p = 0.02) and stage III thymoma (p = 0.0005) were analyzed separately. On multivariate analysis, earlier stage, younger age, absence of paraneoplastic syndrome, and PORT were significantly associated with improved OS. CONCLUSIONS: We observed an OS benefit with the use of PORT in completely resected stage II and III thymoma. In the absence of a randomized trial, this represents the most comprehensive analysis of individual patient data and strong evidence in favor of PORT in this patient population.

Long-term results of combined-modality therapy in resectable non-small-cell lung cancer.

PURPOSE: Assessment of long-term results of combined-modality therapy for resectable non-small-cell lung cancer is hampered by insufficient follow-up and small patient numbers. To evaluate this, we reviewed our collective experience. PATIENTS AND METHODS: This study was a retrospective chart review recording demographics, tumor stage, treatment, and outcome of consecutive patients undergoing surgery. Survival was analyzed by Kaplan-Meier, and prognostic factors were analyzed by log-rank and Cox regression. RESULTS: From January 1993 to December 1999, 470 patients were treated, with follow-up in 446: 27 stage I, 55 stage II, 316 stage III, 43 stage IV (solitary M1), and five uncertain. Chemotherapy was mitomycin/vinblastine/cisplatin (174 patients [39.0%]), carboplatin/paclitaxel (148 [33.2%]), and other combination (124 [27.8%]); 75 patients (16.8%) received induction radiation. Resection was complete in 77.4%, incomplete in 8.3%, attempted but with gross residual disease afterward in 1.8%, and not performed in 12.6%. Pathologic complete response occurred in 20 patients (4.5%). With median follow-up of 31.0 months for patients still alive, median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23% (P <.001). In a multivariate analysis, age, complete resection, pathologic stage, and pneumonectomy, but not induction regimen, significantly influenced survival. CONCLUSION: Although pathologic complete response outside the protocol setting is low, survival of this large patient cohort is comparable to that of patients in published combined-modality trials. Survival is significantly influenced by patient age, complete resection, pathologic stage, and pneumonectomy. These results can help guide standard clinical practice and emphasize the need for novel induction regimens.

Tumor size is a determinant of stage distribution in t1 non-small cell lung cancer.

STUDY OBJECTIVE: Despite renewed interest in early detection of lung cancer, the relationship between tumor size and survival remains controversial. The objective of this study was to evaluate the relationship between size and stage in patients with T1 (< or = 3.0 cm) non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A retrospective review of a lung cancer database from 1995 to 2003 identified 503 patients with completely resected invasive NSCLC with tumors < or = 3 cm. All clinical and pathologic characteristics were recorded. Univariate associations between nodal status and other prognostic factors were explored by chi2 and t tests. The independent effect of tumor size > 2 cm vs < or = 2 cm on the risk of nodal disease was analyzed using a logistic regression model. RESULTS: Of the 503 patients, 324 patients (64.4%) had stage IA disease, 52 patients (10.3%) had stage IB disease, 37 patients (7.4%) had stage IIA disease, 15 patients (3%) had stage IIB disease, 43 patients (8.6%) had stage IIIA disease, 24 patients (4.8%) had stage IIIB disease, and 8 patients (1.6%) had stage IV disease. One hundred patients (19.9%) had nodal metastases. The mean (+/- SD) tumor size of cases without nodal disease was 1.90 +/- 0.67 cm, compared to 2.18 +/- 0.69 cm for node-positive tumors (p = 0.0003; 95% confidence interval [CI] for mean difference, 0.13 to 0.43). Forty-eight of 308 patients (15.6%) with smaller carcinomas (< or = 2.0 cm) compared to 52 of 195 patients (26.7%) with carcinomas > 2.0 cm had nodal metastases (p = 0.002). Exploratory multivariate analysis revealed that only tumor size (< or = 2.0 cm [referent] vs > 2.0 cm) affected nodal status and thus stage (adjusted odds ratio, 2.0; 95% CI, 1.3 to 3.1; p = 0.002). CONCLUSIONS: Primary invasive NSCLC > 2.0 cm was twice as likely to have nodal metastases than carcinomas < or = 2.0 cm. Our results suggest that in lung cancer smaller lesions may represent earlier stage disease. These results also suggest the need for further subclassification by tumor size within the current International Union Against Cancer/American Joint Committee on Cancer stage I, with tumors < 2 cm in size contained in a separate substage. This refinement may help to better clarify which patients might benefit from novel adjuvant or neoadjuvant therapeutic interventions.

Surveillance computed tomography after complete resection for non-small cell lung cancer: results and costs.

OBJECTIVE: We sought to determine the prevalence of defined abnormalities on surveillance computed tomography after complete resection for non-small cell lung cancer, as well as the nature and cost of further testing prompted by these abnormalities. We also sought to determine whether resectable metachronous lung cancer can be detected with surveillance scans. METHODS: A retrospective analysis was performed of all patients who presented for follow-up in 2002 after complete resection for non-small cell lung cancer. Data collected included demographics, clinicopathologic features of the initial lung cancer, the number and results of surveillance computed tomographic scans performed in 2002, the attending surgeons' impressions of the surveillance scans, the nature of any abnormalities and further diagnostic testing prompted by these abnormalities, and the nature of any lung cancer detected on surveillance scans, as well as the treatment rendered. The cost of surveillance scanning and associated diagnostics was computed by using Medicare fee schedules. RESULTS: Two hundred thirteen patients met the criteria for inclusion in the study cohort. One hundred sixty-eight surveillance scans were performed in 140 of these patients. One hundred five scans were interpreted as abnormal by the radiologist with regard to pulmonary nodules, adenopathy, or pleural fluid, but the surgeon was suspicious for recurrent or new primary lung cancer in only 32 of 105 scans. Further workup revealed recurrent or new primary lung cancer in 16 of 32 patients, with 6 undergoing resection for localized disease. The cost of the surveillance scans and associated care in the study cohort were 16.6% higher than the cost of care in a hypothetically identical cohort not subjected to surveillance scanning. CONCLUSIONS: Surveillance computed tomography is frequently abnormal after complete resection for non-small cell lung cancer; however, the majority of these abnormalities are not clinically suspicious. Resectable metachronous lung cancer is detected by using surveillance scanning; however, the use of this modality can be associated with increased cost.

Adenovirus vector-mediated overexpression of a truncated form of the p65 nuclear factor kappa B cDNA in dendritic cells enhances their function resulting in immune-mediated suppression of preexisting murine tumors.

PURPOSE: The purpose of this study was to evaluate the effect of the Rel homology domain (RHD) of the transcription factor, nuclear factor kappa B (NF kappa B), on proinflammatory gene expression in bone marrow-derived dendritic cells (BMDCs). EXPERIMENTAL DESIGN: We used an adenovirus vector encoding only the RHD of the NF kappa B (p65 family member) cDNA (AdRHD) to transduce murine BMDCs ex vivo. Endpoints measured included BMDC expression of activation markers, cytokine secretion, peptide antigen presentation, and the ability of these transduced cells to induce antitumor immunity in vivo. RESULTS: AdRHD-transduced BMDCs secreted higher levels of the cytokines interleukin (IL) 1 beta, IL-6, and IL-12 (p40) compared with sham-transduced BMDCs or those transduced with an empty vector. AdRHD induced heightened surface expression of the activation markers CD40, B7.1, B7.2, and MHC class II on BMDCs, and these cells were able to present a peptide antigen to a T-lymphocyte hybridoma more efficiently than controls in vitro. Growth of syngeneic, established tumors (CT26 and B16.F10) was inhibited, and survival was prolonged in the mice that received intratumoral AdRHD-modified BMDCs compared with controls. Splenocytes from CT26 tumor-bearing animals that received intratumoral AdRHD-modified BMDCs were able to lyse CT26 target cells more efficiently than controls. Similar experiments using host mice harboring targeted mutations in CD4 and CD8, as well as BMDCs from mice lacking MHC class I, MHC class II, or IL-12 revealed that this tumor immunity was dependent on the presence of CD4+ and CD8+ cells in the tumor-bearing host, as well as MHC class I, MHC class II, and IL-12 expression by the administered BMDCs. Furthermore, induction of IL-12 (p40) expression by AdRHD was completely abrogated in BMDCs lacking the c-Rel NF kappa B family member. CONCLUSIONS: We made the following conclusions: (a) gene transfer-mediated overexpression of the RHD of NF kappa B activates BMDCs; (b) AdRHD-transduced BMDCs induce antitumor immunity when administered intratumorally, an effect mediated by both the CD4+ T cell/MHC class II and the CD8+ T cell/MHC class I pathways, as well as IL-12; and (c) IL-12 (p40) up-regulation by the RHD transgene in BMDCs is dependent on the presence of the c-Rel NF kappa B family member.

Surgical resection for esophageal carcinoma: speaking the language.

The terminology used to describe esophagectomy for carcinoma can be confusing, even for specialists in gastrointestinal disease. As a result, specific terms are often used out of their intended context. To simplify the nomenclature, two points regarding procedures for surgical resection of the esophagus are critical: the extent of resection (radical vs standard) and the operative approach (choice of incisions). It is important to understand that the radicality of the resection may have little to do with the operative approach, with the exception of esophagectomy without thoracotomy (transhiatal esophagectomy), which mandates the performance of a standard or non-radical resection. Esophagectomy has emerged as the standard curative treatment option for patients with esophageal carcinoma; however, unlike the surgical resection of other types of solid tumors, many different surgical options and/or approaches exist for these patients. This heterogeneity of care may result from the fact that the esophagus is accessible through more than one body cavity (left hemithorax, right hemithorax, abdomen). In addition, and partially as a result of its accessibility, different types of surgical specialists harbor this operation in their armamentarium, including general surgeons, thoracic surgeons, and surgical oncologists. Despite this enthusiasm amongst surgeons, little consensus exists as to which option is most oncologically sound. Further, the details of the various surgical approaches and procedures for resection of the esophagus are often difficult to comprehend, even for specialists in gastrointestinal disease, with much of the relevant terminology used out of its intended context. To facilitate the understanding of the surgical options for esophageal carcinoma, it is useful to view the operation from two angles: the extent of resection (Aradical@ vs Astandard@) and the operative approach (choice of incisions).

Nodal Upstaging in Robotic and Video Assisted Thoracic Surgery Lobectomy for Clinical N0 Lung Cancer.

BACKGROUND: Recent multiinstitutional published data have demonstrated increased pathologic nodal upstaging by robotic lobectomy compared with historical video-assisted thoracic surgery (VATS) lobectomy data. To eliminate potential variability from multiple surgical techniques, we compared the rate of nodal upstaging at a single institution where robotic and VATS lobectomy are both performed. METHODS: We retrospectively reviewed clinically node-negative patients with lung cancer undergoing VATS or robotic lobectomy. Clinical data were recorded in concordance with The Society of Thoracic Surgeons database elements. The rates of pathologic nodal upstaging as well as disease-free and overall survival were calculated. RESULTS: A total of 211 patients underwent anatomic lobectomy by VATS (n = 158) or robotics (n = 53) from 2009 to 2014. The two groups were statistically similar in their clinical stage, tumor size, location, and histologic evaluation. Within the VATS group, 24 patients experienced nodal upstaging (15.2%), with 13 patients having pN1 disease, and 11 patients having pN2 disease. The robotics group contained 7 patients (13.2%) with nodal upstaging, with 5 patients exhibiting pN1 disease and 2 patients with pN2 disease. When VATS and robotics were compared, there was no significant difference in pathologic upstaging (p = 0.72), 2-year overall survival (88% vs 95%, respectively; p = 0.40), or 2-year disease-free survival (83% vs 93%, respectively; p = 0.48). CONCLUSIONS: In this comparison of robotic and VATS lobectomy for clinically node-negative lung cancer that was managed with consistent surgical technique and pathologic evaluation, the rate of nodal upstaging achieved by robotics appears similar to VATS. In addition, there were no appreciable differences in disease-free or overall survival.

AKAP4 is a circulating biomarker for non-small cell lung cancer.

Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer.

Cisplatin augments cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung cancer.

OBJECTIVE: Many tumors are poorly immunogenic and resistant to cytotoxic T-lymphocyte-mediated cell lysis. Because cisplatin has been demonstrated to increase tumor cell Fas receptor expression, we hypothesized that cisplatin will enhance cytotoxic T-lymphocyte tumor cell killing and augment the antitumor effect of an active immunotherapy strategy in a poorly immunogenic murine lung cancer model. METHODS: Lewis lung carcinoma cells were exposed to cisplatin in vitro, and Fas receptor expression and apoptosis in response to an agonistic anti-Fas antibody were quantified using flow cytometry. Wild-type and Fas ligand-deficient mice bearing Lewis lung carcinoma flank tumors were then treated with intraperitoneal cisplatin as well as an intratumoral injection of an adenovirus gene transfer vector encoding CD40 ligand. End points included tumor size, animal survival, and Fas expression (determined using immunofluorescence). Cytotoxicity assays were performed using splenocytes from adenovirus gene transfer vector encoding CD40 ligand-treated animals as effectors and cisplatin-treated Lewis lung carcinoma cells as targets. RESULTS: Cisplatin induced heightened expression of Fas receptor on Lewis lung carcinoma cells in vitro and in vivo and enhanced apoptosis in cells exposed to an agonistic anti-Fas antibody. In vivo, the combination of 1 dose of intraperitoneal cisplatin and intratumoral adenovirus gene transfer vector encoding CD40 ligand inhibited tumor growth and prolonged survival compared with adenovirus gene transfer vector encoding CD40 ligand alone, resulting in a higher cure rate. This effect was lost in Fas ligand-deficient mice. Splenocytes from adenovirus gene transfer vector encoding CD40 ligand-treated wild-type mice lysed cisplatin-treated Lewis lung carcinoma cells more efficiently than untreated Lewis lung carcinoma cells, an effect lost in splenocytes from Fas ligand-deficient mice. CONCLUSION: Cisplatin augments the antitumor effect of a cytotoxic T-lymphocyte-mediated immunotherapy strategy, resulting in a higher cure rate than seen with immunotherapy alone. This effect is associated with the enhanced ability of cytotoxic T lymphocytes to lyse tumor cells that have been exposed to cisplatin through Fas/Fas ligand interactions.

Tumor size predicts survival within stage IA non-small cell lung cancer.

STUDY OBJECTIVES: The basic premise of CT screening is that size is an important determinant of survival in lung cancer. We sought to examine this hypothesis within stage IA non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of all patients with pathologically confirmed stage IA NSCLC resected from 1991 to 2001 was conducted. All but seven patients underwent anatomic lung resection and mediastinal lymph node dissection. Kaplan-Meier survival analysis was performed to estimate the 5-year overall and disease-specific survival probability stratified by tumor size. The influence of age, gender, histology, and tumor size on survival was also analyzed using a Cox proportional hazards regression model. RESULTS: There were 244 patients (mean age, 66.7 years; 45.1% were men). Lobectomy was performed in 229 patients, segmentectomy in 8 patients, and wedge resection in 7 patients. Operative mortality was 0.4%. Histologic breakdown was as follows: adenocarcinoma (59.4%), squamous (18.9%), bronchoalveolar (15.2%), large cell (4.5%), and poorly differentiated (2.0%). The median follow-up time for all patients was 2.6 years. The 5-year survival probability for all patients was 71.1% (95% confidence interval [CI], 63.6 to 78.6%). For 161 patients with tumor sizes < or = 2.0 cm, the 5-year survival probability was 77.2% (95% CI, 68.6 to 85.8%) in comparison with 60.3% (95% CI, 46.7 to 73.8%) in 83 patients with tumor size > 2.0 cm (p = 0.03 by log-rank test). The overall 5-year disease-specific survival was 74.9% (95% CI, 67.6 to 82.2%). Disease-specific survival was 81.4% (95% CI, 73.3 to 89.4%) for patients with tumors < or = 2.0 cm and 63.4% (95% CI, 49.6 to 77.1%) for patients with tumors > 2.0 cm. CONCLUSIONS: These data suggest that size within stage IA is an important predictor of survival and that further substaging should be considered.

In vivo gene transfer of pigment epithelium-derived factor inhibits tumor growth in syngeneic murine models of thoracic malignancies.

OBJECTIVE: Pigment epithelium-derived factor is known to be an inhibitor of angiogenesis. We hypothesized that in vivo gene transfer of pigment epithelium-derived factor may inhibit tumor angiogenesis and growth in syngeneic models of thoracic malignancies. METHODS: An adenovirus vector encoding the human pigment epithelium-derived factor cDNA (AdPEDF) was used to transduce human lung cancer cells in vitro. Transgene expression was assessed using Western analysis. Three different murine flank tumors (2 lung, 1 colon) were then established in syngeneic mice and treated intratumorally with phosphate-buffered saline, AdPEDF, or an empty vector (AdNull). Endpoints measured included transgene expression, tumor size, and animal survival, as well as microvessel density within the tumor. Additionally, a murine pulmonary metastasis model was established by intravenous injection of a syngeneic colon adenocarcinoma cell line expressing a marker gene (beta-galactosidase). One day later, treatment (phosphate-buffered saline, AdNull, or AdPEDF) was administered intrapleurally. Tumor burden (gross and histologic inspection, lung weight, and beta-galactosidase expression) was then evaluated 13 days after vector dosing, and survival was recorded. RESULTS: AdPEDF-derived expression of pigment epithelium-derived factor was demonstrated in vitro and in vivo. In syngeneic murine lung cancer flank tumors, intratumoral administration of AdPEDF significantly inhibited tumor growth (P <.01), prolonged mouse survival (P <.01), and decreased microvessel density (P <.01) compared with control groups. In the pulmonary metastasis model, AdPEDF-treated mice exhibited significantly reduced lung lesions, lung weight (P <.0005), beta-galactosidase expression (P <.05), and animal survival was prolonged (P <.05). CONCLUSION: Gene transfer of pigment epithelium-derived factor suppresses tumor vascularization and growth, while prolonging survival in syngeneic murine models of thoracic malignancies.

Augmenting major histocompatibility complex class I expression by murine tumors in vivo enhances antitumor immunity induced by an active immunotherapy strategy.

OBJECTIVE: Tumors down-regulate major histocompatibility complex class I expression, escaping recognition by the cellular immune response. We hypothesized that augmentation of tumor cell class I expression by interferon-gamma would enhance the cellular antitumor immune response and cure rate of an active immunotherapy strategy. METHODS: B16.F10 tumor cells were exposed to interferon-gamma in culture, and class I expression was quantified using flow cytometry. Syngeneic mice bearing established tumors were injected with interferon-gamma (5000 U, intraperitoneal), and class I expression was assessed using immunohistochemistry. Tumor-specific cytotoxic T lymphocytes were induced in mice by an intratumoral injection of AdCD40L (5 x 10(10) particles), an adenovirus gene transfer vector-based immunotherapy strategy previously demonstrated to augment cellular antitumor immunity. A conjugate-formation assay and the enzyme-linked immunospot assay were used to evaluate the binding and activation of cytotoxic T lymphocytes, respectively. Interferon-gamma was administered to tumor-bearing mice concomitantly with intratumoral AdCD40L. End points measured included the frequencies of cytotoxic T lymphocytes using the enzyme-linked immunospot assay, tumor size, and mouse survival. The role of class I expression was further evaluated by monoclonal antibody blockade in both in vitro and in vivo experiments. RESULTS: B16.F10 cells exposed to interferon-gamma expressed significantly more class I, both in vitro and in vivo, and were able to bind to and activate cytotoxic T lymphocytes more efficiently than untreated cells. Cytotoxic T-lymphocyte frequencies, tumor regression, and the cure rate induced by AdCD40L were augmented by the addition of a single dose of interferon-gamma in tumor-bearing mice. These in vitro and in vivo effects of interferon-gamma were attenuated by class I monoclonal antibody blockade. CONCLUSIONS: Up-regulation of class I expression using interferon-gamma enhances the cellular antitumor immune response and cure rate of AdCD40L, an active immunotherapy strategy. This approach may be useful for human tumors that lack class I expression.

Surgical resection for lung cancer in the octogenarian.

BACKGROUND: As the US population ages, clinicians are increasingly confronted with octogenarians with resectable non-small cell lung cancer. Earlier reports documented substantial risk for surgical resection in this age group. METHODS: We reviewed our surgical experience in octogenarians who underwent curative resection from 1990 to 2003. RESULTS: Sixty-one patients underwent resection: 46 lobectomies, 6 segmentectomies, 5 wedge resections, and 4 pneumonectomies. There was one perioperative death (1.6%). The overall complication rate was 38% with a major complication rate of 13%. The average postoperative length of stay was 7 days. Overall 5-year survival was 38%, and 82% for stage IA patients. Patients with more advanced disease had a significantly worse survival. CONCLUSIONS: Appropriately selected octogenarians with early stage disease should be offered anatomic surgical resection for cure. These patients can anticipate a long-term survival, and should not be denied an operation on the basis of age alone.

Adenovirus vector-mediated transfer of the vascular endothelial growth factor cDNA to healing abdominal fascia enhances vascularity and bursting strength in mice with normal and impaired wound healing.

BACKGROUND: We hypothesized that adenovirus-mediated transfer of the vascular endothelial growth factor (VEGF121) complementary DNA (cDNA) to murine laparotomy fascial wounds would enhance vascularity and bursting strength. METHODS: Microfibrillar collagen sponges saturated with adenovirus (Ad) vectors encoding for the human VEGF121 cDNA (Ad(CU)VEGF121.1), a control marker gene (Ad beta gal, AdLuc) or no transgene (AdNull) were sutured to fascial edges during laparotomy closure in normal mice and mice treated with dexamethasone. Endpoints addressed included transgene expression in the fascia and surrounding tissue, the number of blood vessels in the healing wound determined using immunostaining, and wound bursting strength using a calibrated tensinometer. RESULTS: Transgene expression was detected readily in the fascial edges, but only marginally detectable in neighboring tissues. In normal mice and mice treated with dexamethasone, no differences were observed at 7 days. Strikingly, however, 21 days after wound closure/therapy, significantly more blood vessels were present in the wounds that received the VEGF121 vector compared with controls (normal: AdNull: 4.2 +/- 1.8; Ad(CU)VEGF121.1: 11.2 +/- 1.2; P <.05; dexamethasone: AdNull: 1.4 +/- 0.8; Ad(CU)VEGF121.1: 5.4 +/- 1.2; P <.05), and bursting strength was significantly higher in VEGF121-treated wounds (normal: AdNull: 665 +/- 68 mN/mm; Ad(CU)VEGF121.1: 956 +/- 82 mN/mm; P <.0005; dexamethasone: AdNull: 234 +/- 111 mN/mm; Ad(CU)VEGF121.1: 592 +/- 121 mN/mm; P <.03). CONCLUSIONS: Adenovirus-mediated gene transfer to healing fascial wounds is achieved readily using a microfibrillar collagen sponge, with transfer of the human VEGF121 cDNA significantly enhancing wound vascularity and bursting strength in normal mice, as well as in mice treated with dexamethasone.

Active, specific immunotherapy for lung cancer: hurdles and strategies using genetic modification.

Active immunotherapy for lung cancer has been a challenge because of the poor antigenic characterization of these tumors and their ability to escape the immune response. However, knowledge of the mechanisms of anti-tumor immunity has expanded significantly over the past decade, leading to the development of more novel, specific strategies for augmenting the immune response. Genetic manipulation of tumor cells, immune cells, or both, may help overcome some of the previously encountered difficulties of immunotherapy. Laboratory and clinical investigations are currently ongoing to evaluate the feasibility and potential benefit of these novel approaches.