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Background The purpose of this study was to assess survival for patients with malignant pleural mesothelioma (MPM), epithelial subtype, utilizing extended pleurectomy-decortication combined with intraoperative photodynamic therapy (PDT) and adjuvant pemetrexed-based chemotherapy. Methods From 2005 to 2013, 90 patients underwent lung-sparing surgery and PDT for MPM. All patients had a preoperative diagnosis of epithelial subtype, of which 17 proved to be of mixed histology. The remaining 73 patients with pure epithelial subtype were analyzed. All patients received lung-sparing surgery and PDT; 92% also received chemotherapy. The median follow-up was 5.3 years for living patients. Results Macroscopic complete resection was achieved in all 73 patients. Thirty-day mortality was 3% and 90-day mortality was 4%. For all 73 patients (89% American Joint Commission on Cancer stage III/IV, 69% N2 disease, median tumor volume 550 mL), the median overall and disease-free survivals were 3 years and 1.2 years, respectively. For the 19 patients without lymph node metastases (74% stage III/IV, median tumor volume 325 mL), the median overall and disease-free survivals were 7.3 years and 2.3 years, respectively. Conclusions This is a mature dataset for MPM that demonstrates the ability to safely execute a complex treatment plan that included a surgical technique that consistently permitted achieving a macroscopic complete resection while preserving the lung. The role for lung-sparing surgery is unclear but this series demonstrates that it is an option, even for advanced cases. The overall survival of 7.3 years for the node negative subset of patients, still of advanced stage, is encouraging. Of particular interest is the overall survival being approximately triple the disease-free survival, perhaps PDT related. The impact of PDT is unclear, but it is hoped that it will be established by an ongoing randomized trial. [ABSTRACT FROM AUTHOR]

Purpose: An endobronchial valve developed for treatment of severe emphysema has characteristics favorable for bronchoscopic treatment of air leaks. We present the results of a consecutive case series treating complex alveolopleural fistula with valves. Description: Patients with air leaks that persisted after treatment gave consent and compassionate use approval was obtained. Bronchoscopy with balloon occlusion was used to identify the airways to be treated. IBV Valves (Spiration, Redmond, WA) were placed after airway measurement. Evaluation: During a 15-month period, 8 valve placement procedures were performed in 7 patients and all had improvement in the air leak. The median duration of air leakage was 4 weeks before and 1 day after treatment, with a mean of 4.5 days. Discharge within 2 to 3 days of the procedure occurred in 57% of the patients. A median of 3.5 valves (mode, 2.4) were used, and all valve removals were successful. There were no procedural or valve-related complications. Conclusions: Removable endobronchial valves appear to be a safe and effective intervention for prolonged air leaks. [Copyright &y& Elsevier]

We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-β (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-β vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-β through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-β were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days. [ABSTRACT FROM AUTHOR]

Although the exact incidence of nonbronchogenic endobronchial metastatic (EBM) disease is unknown, it appears a rare cause of central airway obstruction. It is likely that nonpulmonary endobronchial metastases are underdiagnosed, as many patients with known or suspected lung parenchymal metastases do not undergo bronchoscopy as part of their clinical evaluation. Colorectal carcinoma, the third most common cancer, remains a predominant cause of nonlung EBM. Other gastrointestinal tumors (gastric, pancreatic, hepatocellular, ampullary, and esophageal carcinoma) are also known to metastasize to the central airways. A high index of suspicion must be maintained for the possibility of EBM in patients with known metastatic disease elsewhere, as the symptoms may be subtle. Bronchoscopy offers the best method to evaluate the airway for EBM and evaluate therapeutic options. Currently, the standard of care for EBM is interventional bronchoscopy with endoluminal ablation and adjunctive techniques to provide rapid, effective, and safe restoration of the central airway lumen and maintain patency of the airway lumen. Most patients require multimodality approaches. Referral should be made to a center of excellence with the experience and availability of technology that allow multiple modalities to be used. [Copyright &y& Elsevier]

Objectives: Minimally invasive endoscopic treatment of emphysema could provide palliation with less risk than lung volume reduction surgery and offer therapy to patients currently not considered for lung volume reduction surgery. The Intrabronchial Valve is used to block bronchial airflow in the most emphysematous areas of lung. Methods: Patients with severe chronic obstructive pulmonary disease and heterogeneous upper lobe–predominant emphysema were eligible. Patients underwent flexible bronchoscopic placement of valves into segmental or subsegmental airways in both upper lobes. Outcomes assessed over a minimum of 6 months of follow-up included the safety, feasibility, tolerance, and success of valve placement; health-related quality of life; exercise capacity; pulmonary function; and gas exchange. Results: Five centers treated 30 patients. Patient follow-up ranged from 1 to 12 months. A mean of 6.1 valves were placed per patient. Valves were positioned by means of flexible bronchoscopy in 99% of desired airways, and the procedure duration ranged from 15 to 125 minutes (mean, 65 minutes). Hospital discharge occurred within 2 days in 27 of 30 patients. There were no deaths or episodes of valve migration, tissue erosion, or significant bleeding. Eighty-three percent of patients had no adverse events judged probably or definitely related to the device. Patients experienced significant improvement in health-related quality of life, although the physiologic and exercise outcomes did not show statistically significant improvements. Conclusions: These first multicenter results with the Intrabronchial Valve demonstrate significant improvements in health-related quality of life and acceptable safety, ease of use, and procedural complication rates. The valve might be a safer and less-invasive alternative to surgical therapy for patients with severe emphysema. [Copyright &y& Elsevier]

Surgical debulking of malignant mesothelioma (MM) ultimately fails due to local recurrence. Suramin, an inhibitor of extracellular growth factors (ECGFs), has demonstrated efficacy in the treatment of malignant mesothelioma in a small case series. Our goal was to study survival benefits and disease progression in several MM animal models treated with suramin as a potential agent for adjuvant therapy. In vitro growth of human (REN, I-45), rat (II-45) and murine (AB12) mesothelioma cell lines were measured with or without suramin exposure. Human and murine MM tumors were implanted subcutaneously into murine flanks or injected intraperitoneally (i.p.) into murine abdominal cavities. Dose and treatment schedules were optimized to reduce the rate of tumor progression and to improve survival curves. Suramin inhibited the in vitro growth of all cell lines, reaching statistical significance (P<0.01) three doubling cycles after suramin administration, with a maximum inhibition of 10–25% of control growth. A significant time- and dose-dependent effect was observed. In vivo, suramin inhibited the growth of MM in the xenogeneic model (55% of control growth, P<0.01), and in the syngeneic model at both the low and high loading doses (46 and 36% of control growth, respectively, P<0.01). Suramin treatment inhibited in vivo growth in the REN intraperitoneal model shown grossly by necropsy of same day deaths comparing treatment and control animals. Tumor inhibition with the higher dose was also reflected by the lower mean tumor burden scores (control: 4.0 and high dose: 3.4). Suramin inhibits the growth of human, murine, and rat MM in vitro, in a time- and dose-dependent manner. Suramin also inhibits the growth of human MM flank and intraperitoneal xenografts in vivo in an immunodeficient host, as well as the growth of syngeneic murine flank tumors in an immunocompetent host. These studies demonstrate that suramin may have the potential to provide effective therapy for MM, and that further studies are necessary to elucidate the survival advantage of suramin mediated MM growth inhibition. [Copyright &y& Elsevier]

: BackgroundPhotodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT.: MethodsA total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy–decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax.: ResultsFour dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J · cm−2 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications.: ConclusionsFoscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted. [Copyright &y& Elsevier]

Nonanastomotic bronchial stenosis is a rare complication of lung transplantation. We report a case of a bilateral lung transplant recipient who experienced recalcitrant stenosis of the bronchus intermedius. All attempts at conservative management failed, and the stricture was successfully treated by a parenchymal-sparing segmental sleeve resection. Although rare, this is an important technique in the management of this difficult problem. [Copyright &y& Elsevier]

Our group is investigating intrapleural (IPl) interferon-beta (IFN- β) gene transfer for malignant pleural mesothelioma (MPM) and malignant pleural effusions (MPE). We previously conducted trials involving adenoviral (Ad)-mediated herpes simplex virus thymidine kinase gene (Ad.HSVtk) delivery and ganciclovir (GCV) in 34 MPM patients. These studies demonstrated dose-related gene transfer and anti-Ad immune responses. Two of 3 surviving patients have minimal residual disease 7.5 years after Ad.HSVtk/GCV. Because of the slow tumor course and anti-tumor immune responses, we next assessed cytokine gene delivery. Experiments in immunocompetent mice demonstrated MPM eradication with a single dose of Ad.muIFN-β. Based on these results, we initiated a Phase 1 trial of Ad.huIFN-β (Biogen-IDEC, Cambridge, MA) in patients with MPM and MPE.Ten patients underwent IPl infusion of a single dose of Ad.IFN-β at two dose levels. Seven had MPM; two had Stage IIIB non- small cell lung cancer; the other patient had metastatic ovarian cancer. One MPM patient received a second IPl dose under an FDA-approved amendment. The first three patients received 9×1011 vp of Ad.IFN-β. All tolerated dosing with mild to moderate toxicities. None experienced a dose limiting toxicity (DLT) or a serious adverse event (SAE). Lymphopenia was the most common side effect. Two of three patients in the first cohort are alive 30 and 25 months post Ad.IFN-β.Four patients with mesothelioma were enrolled at Dose Level 2 (3×1012 vp). One patient experienced transitory hypoxia post Ad.IFN-β. This patient has completed 19 months of evaluations without further complications. The next two patients at Dose Level 2 tolerated dosing and completed their six month evaluations; one died at 9 months from progressive disease; the other had progressive pleural involvement with minimal symptoms. The fourth patient developed transitory elevations in LFT's. MTD was established at 9×1011 vp. Three additional patients were dosed at MTD without SAE's.All 10 patients treated with IPl Ad.IFN-β underwent repeat Day 60 imaging. One patient with ovarian cancer had abdominal and pleural responses by PET scan.In our second cohort two MPM patients had stable disease at 60 days and 6 months. One had stable disease on CT and PET scans 12 months post, but showed evidence of disease progression at 18 months. Another patient with sarcomatoid MPM had evidence of metabolic response on PET scan at Day 60.We have thus completed the first Phase 1 dose escalation trial testing the safety and efficacy of single dose of Ad.IFN beta in patients with MPM and MPE. Based on preclinical data showing superior efficacy with repeated Ad.IFN beta, we have begun a new Phase 1 trial with two doses of Ad.IFN beta 2 weeks apart.Molecular Therapy (2006) 13, S425–S425; doi: 10.1016/j.ymthe.2006.08.1211 [ABSTRACT FROM AUTHOR]

Background: Severe airway obstruction can occur in the setting of benign granulation tissue forming at bronchial anastomotic sites after lung transplantation in up to 20% of patients. Many of these benign lesions respond to stent placement, laser ablation, or balloon bronchoplasty. However, in certain cases, proliferation of granulation tissue may persist despite all therapeutic attempts. This study describes a series of refractory patients treated with high-dose-rate (HDR) brachytherapy for benign proliferation of granulation tissue, causing airway compromise. Methods and Materials: Between April 2002 and June 2005, 5 patients with significant airway compromise from recurrent granulation tissue were treated with HDR brachytherapy. All patients had previously failed to maintain a patent airway despite multiple bronchoscopic interventions. Treatment was delivered using an HDR brachytherapy afterloader with 192Ir. Dose prescription was to a depth of 1 cm. All patients were treated weekly, with total doses ranging from 10 Gy to 21 Gy in two to three fractions. Results: The median follow-up was 12 months. All patients experienced a reduction in therapeutic bronchoscopic procedures after HDR brachytherapy compared with the pretreatment period. With the exception of possible radiation-induced bronchitis in 1 patient, there were no other treatment related complications. At the time of this report, 2 patients have died and the other 3 are alive with marked symptomatic improvement and reduced bronchoscopic procedures. Conclusion: High-dose-rate brachytherapy is an effective treatment for benign proliferation of granulation tissue causing airway obstruction. The early response to therapy is encouraging and further follow-up is necessary to determine long-term durability and late effects. [Copyright &y& Elsevier]

• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 are possible MPM biomarkers. • SMRP and fibulin-3 serological levels correlated with initial tumor volumes. • SMRP and fibulin-3 longitudinal serological levels are not useful for immunotherapy response. Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements. Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally. [ABSTRACT FROM AUTHOR]

• TDLN in patients with NSCLC had a different immunophenotype from paired NDLN. • TDLN had significantly more Tregs and fewer effector CD4 + T cells. • Regional CD4 + T cell depletion was greater when tumor PD-L1 expression was ≥50%. • Immunophenotyping was successfully performed with samples from routine EBUS-TBNA. Tumor draining lymph nodes (TDLN) are key sites of early immunoediting in patients with non-small cell lung cancer (NSCLC) and play an important role in generating anti-tumor immunity. Immune suppression in the tumor microenvironment has prognostic implications and may predict therapeutic response. T cell composition of draining lymph nodes may reflect an immunophenotype with similar prognostic potential which could be measured during standard-of-care bronchoscopic assessment. In this study, we compared the immunophenotype from different sites within individuals to primary tumor characteristics in patients with NSCLC to see whether there were tumor-regional differences in immunophenotype which could be evaluated from transbronchial needle aspirates. Twenty patients were enrolled in this study and had tissue (lymph node aspirates and/or peripheral blood) obtained during standard of care bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis or staging of known or suspected NSCLC. Aspirates and blood underwent flow-assisted cell sorting and a subset of sorted effector T cells underwent RNA quantitation to determine feasibility of this approach. Immunophenotypic patterns from twelve patients with paired data from tumor-draining and non-tumor draining lymph nodes (NDLN) were compared relative to one another and based on PD-L1 immunohistochemistry and primary tumor histology. TDLN had significantly fewer CD4+ T cells (12.68% vs 27%, p = 0.002) and significantly more regulatory T cells (Treg, 12.03% vs 9.52%, p = 0.03) relative to paired NDLN suggesting tumor-regional immunosuppression. There were significantly more Treg in NDLN relative to paired PBMC (9.52% vs 5.6%, p = 0.016). Patients with PD-L1 expression ≥50% had significantly greater tumor-regional CD4+ T cell depletion compared to patients with PD-L1 expression <50% (−35.98% vs −1.89%, p = 0.0357; negative values represent absolute difference between paired TDLN and NDLN). In patients with NSCLC, TDLN have a suppressive immunophenotype correlating with tumor PD-L1 status and can be assessed during routine EBUS-TBNA. [ABSTRACT FROM AUTHOR]

Adenoviral immuno-gene therapy using interferon-β has been effective in an orthotopic model of lung cancer. However, pulmonary inflammation induced by adenoviral (Ad) vectors will almost certainly limit the maximally tolerated dose. On the other hand, the strong innate immune response generated by the vector may be helpful in initiating the adaptive immune response required for efficacy. The goals of this study were to develop an effective approach to inhibit Ad.IFNβ-mediated acute pulmonary inflammation and to determine whether this reduction of Ad-mediated inflammation decreased the therapeutic efficacy of Ad.IFNβ in a mouse model of bronchioloalveolar cancer. Our data show that anti-TNF-α antibodies can blunt the innate pulmonary immune response induced by Ad vectors, even in sensitized animals. However, this effect also inhibited the ability of the animal to generate anti-tumor immune responses and reduced survival in an orthotopic lung cancer model responsive to Ad.IFNβ treatment. Interestingly, in a flank model of tumor using a cell line derived from the lung tumor, TNF-α blockade did not inhibit efficacy. These data suggest that the innate immune response to adenovirus in the lung may be important in immuno-gene therapy of lung cancer. Therapeutic application of anti-inflammatory therapy in immuno-gene therapy strategies should thus be undertaken with caution.Molecular Therapy (2006) 13, 910–917; doi: 10.1016/j.ymthe.2005.12.012 [ABSTRACT FROM AUTHOR]