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Background: Coronary artery calcification (CAC) may provide insight to the patients' coronary artery disease (CAD) risks and influence early intervention. With increasing use of non-gated CT scans in clinical practice, the visual coronary artery scoring system (Weston Method) could quickly provide clinicians with important information of CAC for patient triage and management. Methods: We retrospectively studied the available CT imaging data and estimated CAC burden using the Weston method in 493 emergency room or other hospitalized patients. The Weston scores were calculated by the sum of the score for each vessel including the left main, left anterior descending, left circumflex artery and right coronary artery (range 0-12). The primary endpoint was a composite of the major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, stroke, and coronary revascularization. Results: During a median follow-up of 85 months, a total of 25 (5.1%) MACE were recorded and 57 (11.2%) patients died from any causes. Detectable CAC was most common (96%) in the left anterior descending coronary arteries. Multivariable analysis showed that CAC total scores were independent predictors for MACE and all-cause mortality. Receiver operating characteristic analysis showed that CAC total score ≥5 was the optimal cutoff value for predicting MACEs. Conclusions: In the emergency room and hospitalized patients, the semi-quantitation of CAC burden using the Weston score system was related to the long-term cardiovascular outcomes including mortality. Clinicians and radiologists should maximize the value of non-contrast chest CT images by reporting CAC details., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Vavrenyuk, Ren, Desai, Bahgat, Bernstein, Ebright, Gowda, Rose, Fallahi, Stainken and Hsi.)

Objectives: Venovenous extracorporeal carbon dioxide removal may be lifesaving in the setting of status asthmaticus., Design: Retrospective review., Setting: Medical ICU., Patients: Twenty-six adult patients with status asthmaticus treated with venovenous extracorporeal carbon dioxide removal., Interventions: None., Measurements and Main Results: Demographic data and characteristics of current and prior asthma treatments were obtained from the electronic medical record. Mechanical ventilator settings, arterial blood gases, vital signs, and use of vasopressors were collected from the closest time prior to cannulation and 24 hours after initiation of extracorporeal carbon dioxide removal. Extracorporeal carbon dioxide removal settings, including blood flow and sweep gas flow, were collected at 24 hours after initiation of extracorporeal carbon dioxide removal. Outcome measures included rates of survival to hospital discharge, ICU and hospital lengths of stay, duration of invasive mechanical ventilation and extracorporeal carbon dioxide removal support, and complications during extracorporeal carbon dioxide removal. Following the initiation of extracorporeal carbon dioxide removal, blood gas values were significantly improved at 24 hours, as were peak airway pressures, intrinsic positive end-expiratory pressure, and use of vasopressors. Survival to hospital discharge was 100%. Twenty patients (76.9%) were successfully extubated while receiving extracorporeal carbon dioxide removal support; none required reintubation. The most common complication was cannula-associated deep venous thrombosis (six patients, 23.1%). Four patients (15.4%) experienced bleeding that required a transfusion of packed RBCs., Conclusions: In the largest series to date, use of venovenous extracorporeal carbon dioxide removal in patients with status asthmaticus can provide a lifesaving means of support until the resolution of the exacerbation, with an acceptably low rate of complications. Early extubation in select patients receiving extracorporeal carbon dioxide removal is safe and feasible and avoids the deleterious effects of positive-pressure mechanical ventilation in this patient population.

Background: Surgical resection is the most effective curative therapy for non-small cell lung cancer (NSCLC). However, many patients are unable to tolerate resection secondary to poor reserve or comorbid disease. Radiofrequency ablation (RFA) and microwave ablation (MWA) are methods of percutaneous thermal ablation that can be used to treat medically inoperable patients with NSCLC. We present long-term outcomes following thermal ablation of stage IA NSCLC from a single center., Methods: Patients with stage IA NSCLC and factors precluding resection who underwent RFA or MWA from July 2005 to September 2009 were studied. CT and PET-CT scans were performed at 3 and 6 month intervals, respectively, for first 24 months of follow-up. Factors associated with local progression (LP) and overall survival (OS) were analyzed., Results: Twenty-one patients underwent 21 RFA and 4 MWA for a total of 25 ablations. Fifteen patients had T1a and six patients had T1b tumors. Mean follow-up was 42 months, median survival was 39 months, and OS at three years was 52%. There was no significant difference in median survival between T1a nodules and T1b nodules (36 vs . 39 months, P=0.29) or for RFA and MWA (36 vs . 50 months, P=0.80). Ten patients had LP (47.6%), at a median time of 35 months. There was no significant difference in LP between T1a and T1b tumors (22 vs . 35 months, P=0.94) or RFA and MWA (35 vs . 17 months, P=0.18). Median OS with LP was 32 months compared to 39 months without LP (P=0.68). Three patients underwent repeat ablations. Mean time to LP following repeat ablation was 14.75 months. One patient had two repeat ablations and was disease free at 40-month follow-up., Conclusions: Thermal ablation effectively treated or controlled stage IA NSCLC in medically inoperable patients. Three-year OS exceeded 50%, and LP did not affect OS. Therefore, thermal ablation is a viable option for medically inoperable patients with early stage NSCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: Transoral incisionless fundoplication (TIF) is a completely endoscopic approach to treat gastroesophageal reflux disease (GERD). We previously reported our initial results demonstrating safety and early effectiveness. We now present an updated experience describing outcomes with longer follow-up., Methods: For a three-year period, TIF procedures were performed on 80 patients. Preoperative workup routinely consisted of contrast esophagram and manometry. PH testing was reserved for patients with either atypical symptoms or typical symptoms unresponsive to proton-pump inhibitors (PPIs). Heartburn severity was longitudinally assessed using the GERD health-related quality of life index. Safety analysis was performed on all 80 patients, and an effectiveness analysis was performed on patients with at least 6-month follow-up., Results: Mean procedure time was 75 minutes. There were seven (8.75%) grade 2 complications and one (1.25%) grade 3 complication (aspiration pneumonia). The median length of stay was 1 day (mean, 1.4). Forty-one patients had a minimum of 6-month of follow-up (mean, 24 months; range, 6-68 months). The mean satisfaction scores at follow-up improved significantly from baseline (P < 0.001). Sixty-three percent of patients had completely stopped or reduced their PPI dose. Results were not impacted by impaired motility; however, the presence of a small hiatal hernia or a Hill grade 2/4 valve was associated with reduced GERD health-related quality of life scores postoperatively., Conclusions: At a mean follow-up of 24 months, TIF is effective. Although symptoms and satisfaction improved significantly, many patients continued to take PPIs. Future studies should focus on longer-term durability and comparisons with laparoscopic techniques.

A solitary fibrous tumor of the pleura (SFTP) presenting with an aberrant arterial supply from the abdominal aorta is extremely rare, and it may be difficult to distinguish from intralobar sequestration (ILS). We report the case of a 38-year-old woman who presented with acute chest pain and was subsequently found to have a 17.5-cm intrathoracic mass. After preoperative arterial embolization of its feeding vessel, this presumed ILS was resected. However, the intraoperative findings revealed a benign SFTP. Here we discuss a unique presentation of a large SFTP radiographically mimicking an ILS, and we propose a safe management strategy for this entity., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Identification of small peripheral lung nodules during minimally invasive resection can be challenging. Electromagnetic navigational bronchoscopy (ENB) with injection of dye to identify nodules can be performed by the surgeon immediately prior to resection. We evaluated the effectiveness of ENB with dye marking to aid minimally invasive resection., Methods: Patients with peripheral pulmonary nodules underwent ENB before planned thoracoscopic or robotic-assisted thoracoscopic resection. Methylene blue was injected directly into the lesion for pleural-based lesions or peripherally for lesions deep to the pleural surface. Surgical resection was then immediately performed. Technical success was defined as identification of the dye marking within/close to the lesion with pathological confirmation after minimally invasive surgical resection., Results: Seventeen patients (19 nodules) underwent ENB with dye marking followed by minimally invasive resection. Median lesion size was 9 mm (4-32 mm) and the median distance from the pleura was 9.5 mm (1-40 mm). Overall success rate was 79% (15/19). In two cases the dye was not visualized and in the remaining two there was extravasation of dye into the pleural space. There were trends favoring technical success for nodules that were larger or closer to the pleural surface. Five patients required adhesiolysis to visualize the target lesion and all were successful. There were no significant adverse events and a definitive diagnosis was ultimately accomplished in all patients., Conclusions: ENB with dye marking is useful for guiding minimally invasive resection of small peripheral lung nodules. ENB can be undertaken immediately before performing resection in the operating room. This improves workflow and avoids the need for a separate localization procedure., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Patients undergoing esophagectomy for cancer are in the highest-risk group for venous thromboembolism, with a 7.3% incidence reported by the National Surgical Quality Improvement Program. Venothromboembolism (VTE) doubles esophagectomy mortality. The Caprini risk assessment model (RAM) is a method to stratify postoperative thromboembolism risk for consideration of prolonged preventive anticoagulation in higher-risk patients. Our aim was to examine the potential use of this model for reducing the VTE incidence in esophagectomy patients., Methods: The records of patients who underwent an esophagectomy by the thoracic surgery service at our institution between June 2005 and June 2013 were reviewed. The inclusion criteria were a diagnosis of esophageal cancer treated with esophagectomy (any approach) and with available 60-day postoperative follow-up. Exclusion criteria were the presence of an inferior vena cava filter or chronic anticoagulation therapy. The Caprini risk score and the number of VTE events were recorded retrospectively for each patient., Results: Seventy patients satisfied eligibility criteria. The VTE incidence was 14.3%. Patients with esophageal thromboembolism had a higher Caprini score distribution than patients without thromboembolism (p < 0.001). Adjusted logistic regression analysis demonstrated increased odds of VTE with increasing score (p < 0.05), with good discrimination., Conclusions: In this first report examining the Caprini model categories in an esophagectomy population, the VTE incidence in true high-risk patients was high. From this retrospective calculation of risk and events, patients in the highest-risk Caprini group may benefit from an enhanced course of postoperative anticoagulation., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Mediastinal parathyroid adenomas can be resected by sternotomy or video-assisted thoracoscopic surgery. Robot-assisted thoracic surgical approaches have recently been described. We report robot-assisted thoracic surgical resection of a mediastinal parathyroid in a morbidly obese patient. Additional comorbidities included multiple pathological fractures related to hypercalcemia. Intraoperative parathyroid hormone levels confirmed successful removal of the adenoma. Hungry bone syndrome developed after surgery but eventually resolved. Robot-assisted thoracic surgery avoided the need for sternotomy and associated concerns related to poor bone healing. Robot-assisted thoracic surgery has potential advantages over video-assisted thoracoscopic surgery in patients with obesity because of easier instrument articulation within the thoracic cavity rather than at the chest wall.

Introduction: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing the functional HRR status in cells. Here, we monitored the ability of non-small-cell lung cancer (NSCLC) cells to form subnuclear foci of DNA repair proteins as a surrogate of HRR proficiency., Methods: We assessed clonogenic survival of 16 NSCLC cell lines in response to cisplatin, mitomycin C (MMC), and the PARP inhibitor olaparib. Thirteen tumor explants from patients with NSCLC were subjected to cisplatin ex vivo. Cells were assayed for foci of repair-associated proteins such as BRCA1, FANCD2, RAD51, and γ-H2AX., Results: Four cell lines (25%) showed an impaired RAD51 foci-forming ability in response to cisplatin. Impaired foci formation correlated with cellular sensitivity to cisplatin, MMC and olaparib. Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways. Because baseline foci in untreated cells did not predict drug sensitivity, we adapted an ex vivo biomarker assay to monitor damage-induced RAD51 foci in NSCLC explants from patients. Ex vivo cisplatin treatment of explants identified two tumors (15%) exhibiting compromised RAD51 foci induction., Conclusions: A fraction of NSCLC harbors HRR defects that may sensitize the affected tumors to DNA-damaging agents including PARP inhibitors. We propose that foci-based functional biomarker assays represent a powerful tool for prospective determination of treatment sensitivity, but will require ex vivo techniques for induction of DNA damage to unmask the underlying HRR defect.

Objective(s): Recommendations for surveillance after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) are not well defined. Prospective studies evaluating the efficacy of SBRT have used interval posttreatment imaging with computed tomography (CT). We set out to determine whether positron emission tomography (PET) combined with diagnostic chest CT (PET/d-chest) can enhance detection of potentially salvageable recurrence after SBRT., Methods: We performed a retrospective analysis of posttreatment imaging for 35 patients consecutively treated with SBRT for biopsy-proven early-stage NSCLC. PET/d-chest was generally performed every 3 months after treatment. A board-certified radiologist who did not have access to the PET results retrospectively interpreted the CT scans. CT results were reported according to response criteria used in Radiation Therapy Oncology Group 0236 and compared with PET/d-chest readings. Local and regional recurrence-free survival was compared using the Mantle-Cox (log-rank) test., Results: Median follow-up was 12.8 months. Twenty-four patients had stage IA, 7 stage IB, 3 stage IIA, and 1 stage IIB biopsy-proven NSCLC. Two-year overall survival was 62%. CT scans indicated no regional recurrences. PET/d-chest indicated 10 regional recurrences. The 1-year rate of regional recurrence-free survival as evaluated by CT and PET/d-chest was 100% and 69.4%, respectively (P = .0045). Four of 10 patients with a diagnosis of regional recurrence underwent salvage treatment with definitive chemoradiotherapy., Conclusions: PET/d-chest enhances the detection of regional progression of NSCLC after SBRT over currently recommended practices. In patients who are fit for salvage treatment, where early detection of recurrence can increase the likelihood of successful treatment, PET/d-chest appears critical for follow-up., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Electromagnetic (EM) navigation is increasingly used to assist with bronchoscopic interventions such as biopsy or fiducial placement. Electromagnetic navigation can also be a useful adjunct to computed tomography (CT)-guided thermal ablation and biopsy of lung tumors. This study compares procedures carried out using an EM navigation system (Veran Medical Technologies Inc, St Louis, MO) with procedures using CT fluoroscopy only., Methods: Over a 23-month period, 17 patients scheduled for thermal ablation were prospectively enrolled in this study. The mean age was 72 years (range, 60-84 years). Seven patients were women. Patients were randomized to EM navigation (n = 7) or CT fluoroscopy alone (n = 10). In some cases, additional ablation or biopsies were performed with or without EM navigation depending on the randomization arm. All procedures were performed under general anesthesia either by a thoracic surgeon or a radiologist., Results: A total of 23 procedures were performed in 17 patients: 20 were ablation procedures and 3 were biopsies. Fourteen were performed for non-small cell lung cancer, and 9 for pulmonary metastases from other organs. Despite randomization, patients receiving EM navigation had a trend for smaller tumors (mean diameter, 1.45 vs 2.90 cm; P = 0.06). For thermal ablation procedures, the time to complete intervention was significantly less when EM navigation was used (mean, 7.6 vs 19 minutes; P = 0.022). Although not statistically significant, there were fewer skin punctures (mean, 1 vs 1.25; P = 0.082), fewer adjustments (mean, 5.6 vs 11.8; P = 0.203), less CT fluoroscopy time (mean, 21.3 vs 34.3 seconds; P = 0.345), and fewer CT scans (mean, 7 vs 15; P = 0.204) whenever EM navigation was used., Conclusions: Electromagnetic navigation reduces the time to successfully place an ablation probe in a target tumor. Further study is required to determine whether EM navigation may also reduce the number of adjustments, skin punctures, and CT scans as well as decrease CT fluoroscopy time.

Objective: Transoral incisionless fundoplication (TIF) is a promising approach for gastroesophageal reflux disease (GERD) that may decrease morbidity compared with conventional antireflux procedures. We report our initial experience with this minimally invasive approach., Methods: Over a 24-month period, 46 patients (mean age, 49 years; 50% female) underwent 48 TIF procedures. All procedures were performed under general anesthesia. Two surgeons participated in all cases; one served as the endoscopist, and the other performed the partial fundoplication. Heartburn severity was measured using the GERD health-related quality of life (GERD-HRQL) instrument (best score = 0, worst score = 45), which includes an additional question assessing overall satisfaction., Results: Preoperatively, 33 (72%) of 46 patients had small (<3 cm) hiatal hernias, and none had undergone any previous antireflux procedures. Preoperative workup included manometry and barium esophagogram, with pH testing reserved for patients with atypical symptoms or typical symptoms and a lack of response to proton-pump inhibitors. The mean procedure time was 83 minutes (range, 36-180 minutes). The mean procedure time decreased after the first 5 cases from 122 to 78 minutes (P = .001). Mean length of stay was 1.3 days. One patient was readmitted with aspiration pneumonia. Three patients had minor complications (1 had minor bleeding from a suture site and 2 had urinary retention). There were no perioperative deaths. Mean follow-up was 140 days. The mean GERD-HRQL scores improved significantly (23 vs 7; P < .001). There were 22 patients with follow-up greater than 90 days (mean follow-up, 240 days). GERD-HRQL scores remained significantly improved for these patients (23 vs 8; P = .001). Four patients from the entire group (8.6%) had no improvement, in 3 instances due to breakdown of the wrap. Two patients were treated with repeat endoscopic fundoplication and 1 was treated with laparoscopic Nissen fundoplication, and all had a significant improvement in symptoms after reoperation., Conclusions: TIF is effective at short-term follow-up and safe for patients with GERD. However, long-term follow-up and randomized trials are required to assess the efficacy and durability of this approach compared with conventional surgical repair., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: This study examined the impact of neoadjuvant chemotherapy and concurrent high-dose radiation therapy on survival in patients with node-negative T3 and T4 non-small cell lung cancer., Methods: A total of 110 consecutive patients underwent surgical resection for invasive T3N0M0 (94 patients) and T4N0M0 (16 patients) non-small cell lung cancer between 1979 and 2008. Forty-seven patients received neoadjuvant chemotherapy and concurrent high-dose (5940 cGy) radiation therapy before resection (Chemo-RT group). Sixty-three patients underwent surgical resection without receiving induction chemoradiotherapy (Surg group), of whom 21 received neoadjuvant radiation, 19 received adjuvant radiation, 17 received surgery alone, 2 received adjuvant chemotherapy, 2 received adjuvant chemoradiotherapy, and 2 received brachytherapy. Survival of the Chemo-RT and Surg groups was compared using both crude and adjusted Cox proportional hazards models., Results: The 5-year, 10-year, and median survivals were 61%, 50%, and 90 months, respectively, in the Chemo-RT group versus 22%, 14%, and 22 months, respectively, in the Surg group. Subjects in the Surg group had an increased risk of death (hazard ratio, 2.60; 95% confidence interval, 1.62-4.18; P = .0001) compared with the Chemo-RT group. After adjustment for potential confounding variables of age, sex, tumor size, tumor location, type of operation, and decade of care, subjects in the Surg group remained at increased risk of death (hazard ratio, 2.81; 95% confidence interval, 1.45-5.44, P = .002) compared with the Chemo-RT group., Conclusions: Aggressive treatment of node-negative invasive T3 and T4 NSCLC with induction chemoradiotherapy may significantly prolong survival. This approach should be evaluated in a prospective multicenter national trial., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

David Palma and colleagues report on the impact of stereotactic body radiation therapy (SBRT) on treatment patterns of elderly patients in the Netherlands. This study, published recently in the Journal of Clinical Oncology, is a retrospective review of data collected by the Amsterdam Cancer Registry. This study highlights many of the difficulties encountered when comparing the effectiveness of surgical resection and SBRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Currently, lobectomy is the preferred treatment for early-stage, non-small cell lung cancer primarily because of the increased local recurrence rate that has been reported with sublobar resection. Sublobar resection is typically used for high-risk, but still operable, patients with lung cancer. Several recent studies have demonstrated comparable recurrence and survival rates between lobectomy and sublobar resection for small, stage I lung cancers. In particular, attention to technical details such as performing a segmentectomy or a wide wedge resection (rather than a simple wedge resection), or the addition of brachytherapy, can result in improved outcomes. Also, the potential for better preservation of pulmonary function with sublobar resection has fueled the debate arguing for sublobar resections even for patients who are considered to be "good risk" and able to tolerate a lobectomy. This article reviews the current status of sublobar resection for early-stage lung cancer, with particular attention to issues such as tumor size, type of sublobar resection, use of adjuvant brachytherapy, and preservation of pulmonary function.

Background: Thermal ablation is increasingly used to treat pulmonary tumors in medically inoperable patients. Most procedures are performed with sedation in the radiology suite. Ideally, the ablation should encompass the entire tumor volume with a surrounding margin of necrosis; however, ablation may not be as effective in the normal aerated lung surrounding a denser tumor. Inducing atelectasis of the lung may potentially increase ablation volumes and increase local cancer control. This study examines the effect of single-lung ventilation on ablation size using a microwave system., Methods: Twenty microwave ablation procedures were performed in the lungs of 10 swine. Bilateral thoracotomy using a clamshell approach was used. In one lung, ablation was performed with continuous ventilation. In the contralateral lung, single-lung ventilation was achieved by clamping the bronchus before ablation. The ablated lobes were resected and sent for pathologic analysis. Routine and supravital staining was performed., Results: The ablation zone was clearly demarcated on gross examination, and in all cases 100% ablation occurred, without skip areas of viability. The ablation zones were elliptical with the long axis parallel to the axis of the ablation probes (active tip, 3.7 cm). Ablation diameters and volume were compared between the ventilated and nonventilated lungs. Ablation volume was superior in nonventilated lungs (10.74 cm(3) versus 7.35 cm(3); p = 0.039) primarily because of differences in the short axis of the ablation zone., Conclusions: Microwave energy can effectively ablate normal pulmonary parenchyma without skip areas of viable tissue within the gross ablation field. The volume of necrosis is increased in nonventilated lungs, suggesting that ablation results can be improved in patients by using general anesthesia with single-lung ventilation. Future studies will be required to confirm this hypothesis., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated an electromagnetic (EM) navigation system (Veran Medical Technologies Inc, St. Louis, MO) to determine its potential to reduce the number of skin punctures and instrument adjustments during computed tomographic-guided percutaneous ablation and biopsy of lung nodules., Description: Ten patients undergoing lung percutaneous ablation were prospectively enrolled. The mean age was 70 years. Positioning of the needle device was verified with computed tomographic fluoroscopy prior to the execution of any biopsy or ablation. Each EM navigation-guided procedure was defined as an EM-intervention., Evaluation: Nineteen EM interventions were performed. When an EM-guided biopsy was performed, the intervention was done immediately prior to ablation. For all 19 EM interventions, only one skin-puncture was required. The mean number of instrument adjustments required was 1.2 (range, 0 to 2). The mean time for each EM intervention was 5.2 minutes (range, 1 to 20 minutes). Pneumothorax occurred in 5 patients (50%). Only the number of instrument adjustments was significantly related to the pneumothorax rate (p = 0.005)., Conclusions: The EM navigation is feasible and seems to be a useful aid for image-guided procedures. Early experience suggests a low number of skin-puncture and instrument adjustments using the EM navigation system. Instrument adjustments were a key factor in pneumothorax development., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) has gained importance in non-small cell lung cancer given impressive responses to agents targeting this molecule, particularly in bronchioloalveolar carcinoma (BAC) and adenocarcinomas, mixed subtype, with BAC components (adeno/BAC). This study assesses EGFR signaling in these tumors., Methods: One hundred fifty tumors were classified as BAC or adeno/BAC. Tumor marker expression was determined by immunohistochemistry. Correlations with expression were examined for all tumors (BAC and adeno/BAC), and by BAC and adeno/BAC subset analyses., Results: Positive immunophenotype was observed in 40.6% of tumors for EGFR, 51.3% for p-AKT, 58.7% for p-ERK, and 28.0% for PTEN, with increased overexpression of EGFR (p = 0.025) and p-AKT (p < 0.0001) in adeno/BAC. Epidermal growth factor receptor immunophenotype was greater in never-smokers (p = 0.008) and correlated with improved overall survival (p = 0.018). On subset analysis, EGFR correlated with improved overall survival (p = 0.05) and disease-free interval (p = 0.044) only in adeno/BAC. Epidermal growth factor receptor independently predicted improved disease-free interval in adeno/BAC (p = 0.03; hazard ratio, 0.47; 95% confidence interval, 0.23 to 0.94)., Conclusions: Overexpression of EGFR in lung adenocarcinomas with components of BAC histology correlate with never-smoker status and improved overall survival and disease-free interval. Epidermal growth factor receptor immunophenotype may be a useful predictor of clinical outcomes in this tumor subset.

Replication-competent oncolytic herpes simplex viruses (HSV), modified by deletion of certain viral growth genes, can selectively target malignant cells. The viral growth gene gamma(1)34.5 has significant homology to GADD34 (growth arrest and DNA damage protein 34), which promotes cell cycle arrest and DNA repair in response to stressors such as radiation (XRT). By upregulating GADD34, XRT may result in greater oncolytic activity of HSV strains deficient in the gamma(1)34.5 gene. The human cholangiocarcinoma cell lines KMBC, SK-ChA-1 and YoMi were treated with NV1023, an oncolytic HSV lacking one copy of gamma(1)34.5. Viral proliferation assays were performed at a multiplicity of infection (MOI, number of viral particles per tumor cell) equal to 1, either alone or after XRT at 250 or 500 cGy. Viral replication was assessed by plaque assay. In vitro cytotoxicity assays were performed using virus at MOIs of 0.01 and 0.1, with or without XRT at 250 cGy and cell survival determined with lactate dehydrogenase assay. Established flank tumors in athymic mice were treated with a single intratumoral injection of virus (10(3) or 10(4) plaque forming units), either alone or after a single dose of XRT at 500 cGy, and tumor volumes measured. RT-PCR was used to measure GADD34 mRNA levels in all cell lines after a single dose of XRT at 250 or 500 cGy. NV1023 was tumoricidal in all three cell lines, but sensitivity to the virus varied. XRT enhanced viral replication in vitro in all cell lines. Combination treatment with low-dose XRT and virus was highly tumoricidal, both in vitro and in vivo. The greatest tumor volume reduction with combination therapy was seen with YoMi cells, the only cell line with increased GADD34 expression after XRT and the only cell line in which a synergistic treatment effect was suggested. In KMBC and SK-ChA-1 cells, neither of which showed increased GADD34 expression after XRT, tumor volume reduction was less pronounced and there was no suggestion of a synergistic effect in either case. Oncolytic HSV are effective in treating human cholangiocarcinoma cell lines, although sensitivity to virus varies. XRT-enhanced viral replication occurs through a mechanism that is not necessarily dependent on GADD34 upregulation. However, XRT-induced upregulation of GADD34 further promotes tumoricidal activity in viral strains deficient in the gamma(1)34.5 gene, resulting in treatment synergy; this effect is cell type dependent. Combined XRT and oncolytic viral therapy is a potentially important treatment strategy that may enhance the therapeutic ratios of both individual therapies.

Background: Overexpression of squamous cell carcinoma-related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non-small cell lung cancer. We assessed the role of SCCRO as a tumor marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC., Methods: We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma-related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma-related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test., Results: Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features; p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (p = 0.05)., Conclusions: Squamous cell carcinoma-related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host-tumor effects.

Replication-competent herpes simplex oncolytic viruses are promising anticancer agents that partly target increased DNA synthesis in tumor cells. Investigators have proposed that these DNA viruses may be combined with liver resection to enhance killing of liver malignancies. Whether or not the cellular alterations associated with hepatic regeneration affect the efficacy and toxicity of these promising anticancer agents is unknown. This study examined the behavior of two oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered during the peak of liver regeneration, replication and appearance of both G207 and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical staining for the marker gene lac Z, immunohistochemical staining, and quantitative polymerase chain reaction. This increased appearance of virus in liver tissue correlates with increases in cellular ribonucleotide reductase activity and DNA synthesis and is also associated with increased viral binding. However, increased viral presence is transient, and viral detection declines to baseline within 7 days. When these viruses were delivered to animals even as early as 7 days after hepatectomy, there proved to be no measurable viral replication in any organ and no increased morbidity or mortality. In conclusion, the early stages of hepatic regeneration after resection provide an environment suitable for viral replication. Administration of replication-competent herpes simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits viral productivity in tissue that otherwise does not support viral growth. The increase in hepatotoxicity after hepatectomy is short-lived and can be predicted by peak hepatocyte DNA synthesis.

Background: The aim of the study was to determine whether hepatic regeneration stimulates growth of tumour residing within the liver, and whether a difference in the rate of DNA synthesis in liver and tumour may be used to target cancer using the radiolabelled thymidine analogue 5-iodo-2'-deoxyuridine (IUdR)., Methods: Partial hepatectomy was performed on Buffalo rats bearing solitary nodules of syngeneic Morris hepatoma. Liver and tumour DNA synthesis was measured by incorporation of radioactive IUdR. [(125)I]IUdR was tested as an adjuvant therapy after hepatectomy in Buffalo rats bearing diffuse microscopic Morris hepatomas to simulate the clinical situation., Results: Liver regeneration enhanced liver and tumour DNA synthesis as measured by incorporation of radioactive IUdR. Liver DNA synthesis returned to baseline by 7 days, whereas tumour DNA synthesis remained above baseline level. Hepatectomy enhanced the growth of microscopic liver tumours. [(125)I]IUdR (250 micro Ci or 1 mCi/kg) administered 4 days after hepatectomy significantly reduced tumour growth without signs of systemic toxicity or liver dysfunction., Conclusion: The local environment of the regenerating liver stimulates tumour growth. The thymidine analogue [(125)I]IUdR may be used preferentially to target tumour DNA synthesis in the regenerating liver, and may prove useful as an adjuvant therapy for hepatic tumours after surgical resection., (Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: The histologic criteria defining bronchioloalveolar carcinoma (BAC) were recently revised, but it is unclear whether these criteria predict clinical behavior. This study determined the outcome of resected BAC in relationship to clinical and radiologic disease pattern, and pathologic features., Methods: Between 1989 and 2000, 100 consecutive surgically treated patients with adenocarcinomas exhibiting various degrees of BAC features were retrospectively studied. Histology was reviewed; tumors were classified as pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. Clinical and radiologic pattern were classified as unifocal, multifocal, or pneumonic. Demographic data, tumor stage, and outcome were recorded. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were determined by the log-rank test., Results: Patient median age was 65, and 74% of the patients were female. Pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features occurred in 47, 21, and 32 patients, respectively. Unifocal disease occurred in 64 patients, multifocal in 29, and pneumonic in 7. Seventy-one patients had stage I/II tumors, 22 had stage III/IV, and 7 patients had Stage X tumors. Overall 5-year survival was 74%. There was no significant difference in survival among the three histologic subtypes. The pneumonic pattern had significantly worse survival compared with unifocal and multifocal patterns. Pathologic stage predicted survival, with 5-year survivals for I/II and III/IV of 83.7% and 59.6%, respectively., Conclusions: Clinical pattern and pathologic stage, but not the degree of invasion on histologic examination predict survival. Multifocal disease is associated with excellent long-term survival after resection. The favorable survival of stage III/IV BAC indicates that the current staging system does not fully describe this disease in patients undergoing resection because of its distinct tumor behavior.

Objective: To evaluate the use of herpes simplex viral (HSV) amplicon vectors for production of tumor vaccines and to determine if such vaccines expressing combinations of immunostimulatory agents may be effective in the treatment of experimental liver cancer., Methods: A hepatic metastatic tumor model using CT-26 colorectal cancer in syngeneic Balb/C mice was utilized. Tumor vaccines were produced by brief (20 minutes) exposure of irradiated tumor cells to herpes amplicon vectors carrying the transgene for RANTES, B7.1, or GM-CSF. The antitumor efficacy of vaccination using tumor cells secreting GM-CSF (single agent) or a combination of RANTES/B7.1/GM-CSF (multiagent) was tested. The effect of 60% hepatectomy or T-cell depletion was also tested in this model., Results: In vitro assays confirmed high-level cytokine or costimulatory molecule production by cells transduced with amplicons. Antitumor efficacy was observed with single-agent or multiagent treatment. Without hepatectomy, immunization with single-agent or multiagent vaccine therapy appears equivalent. When administered in the setting of hepatectomy, multiagent regimens produced a higher cure rate than single-agent therapy (50% vs. 12.5%, =.03). Animals treated with GM-CSF alone had an average nodule count of 40 +/- 19 ( <.006 vs. Hep control 232 +/- 30), while animals treated with multiagent therapy had an average nodule count of 11 +/- 7 ( <.0004 vs. control). CD4 and CD8 lymphocyte blockade abrogated observed efficacy, confirming a lymphocyte-mediated response., Conclusions: Tumor vaccines produced using HSV amplicon-mediated gene transfer may be useful in the treatment of liver malignancies. In the setting of hepatectomy, multiagent vaccine therapy offers an advantage over single-agent therapy. These data encourage consideration of such HSV-based neoadjuvant immunotherapy for treatment of liver malignancies.

Objective: Innovative treatments are needed for metastatic disease involving the pleura. NV1020 is a novel, multimutated, replication-restricted herpes simplex virus under investigation for its ability to selectively kill tumors by means of direct cell lysis. This study examines NV1020 in a rat model of pleura-based lung cancer., Methods: Cytotoxicity and viral proliferation were evaluated in vitro by exposure of the human non-small cell lung cancer cell line A549 to virus. NV1020 was also tested in an in vivo pleura-based cancer model established by injecting 1 x 10(7) A549 cells into the thoracic cavity of nude rats. Intrapleural treatments (1 x 10(7) viral particles) were given 3 hours or 3 days after tumor injection to model treatment of microscopic or macroscopic disease (n = 8-9/group). Tumor burden was assessed at 5 weeks. NV1020 infection and dissemination within the thoracic cavity was determined by means of immunohistochemistry., Results: In vitro, at multiplicities of infection (viral particles per tumor cell) of 0.01, 0.1, and 1.0, cell killing of A549 by NV1020 was 66%, 90%, and 97%, respectively, at 7 days after infection. Viral burst occurred by day 2. Intrapleural treatment was effective for both the microscopic (P <.001) and macroscopic (P <.05) in vivo tumor models. Virus was detectable by means of immunohistochemistry in tumors but not in adjacent normal intrathoracic tissues., Conclusions: NV1020 is not only highly cytotoxic to the human lung cancer line A549 in vitro but can be delivered in a clinically relevant fashion to safely and effectively treat pleura-based tumor in vivo in a rat model.

Background: Herpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone., Materials and Methods: A replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV- IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2)., Results: Tumor burden was significantly reduced in all treatment groups in both rats and mice treated with high-dose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4(+) and CD8(+) lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated., Conclusions: Vascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies.