Faculty Bibliography

BACKGROUND: Photodynamic 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. METHODS: A 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. RESULTS: Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x 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. CONCLUSIONS: Foscan-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

Unusual bronchial tumors represent 4% to 6% of all lung tumors. These lesions include hamartomas, bronchial carcinoids, adenoid cystic carcinoma, mucoepidermoid carcinoma, and other more rare tumors. In the majority of patients these lesions are diagnosed using transthoracic FNA and different bronchoscopic biopsy techniques such as bronchial lavage, bronchial brushing, endobronchial biopsy, transbronchial biopsy, and transbronchial needle aspiration. Thoracoscopic wedge biopsy is diagnostic in the remainder of cases. Occasionally, because of tumor location, thoracoscopically-guided FNA or thoracoscopic ultrasound are helpful in obtaining a diagnosis. Staging of these lesions is assessed after proper resection; however, mediastinoscopy should be performed if preoperative mediastinal adenopathy is appreciated.

OBJECTIVE: The use of cardiopulmonary bypass in lung transplantation remains controversial. Previous studies have concluded that cardiopulmonary bypass is deleterious, but these studies were confounded by the inclusion of patients with different diagnoses undergoing single- and double-lung transplantation with elective or emergency use of bypass. The goal of this study was to determine whether cardiopulmonary bypass has deleterious effects on lung function or clinical outcome by analyzing the cases of patients with a single disease entity and elective use of bypass for bilateral sequential lung transplantation. METHODS: A retrospective review of 50 patients with chronic obstructive pulmonary disease who underwent bilateral sequential lung transplantation was performed. Fourteen patients who underwent elective cardiopulmonary bypass for 218.3 +/- 75.4 minutes were compared to 36 control patients. RESULTS: After the operation, the bypass and nonbypass groups were not significantly different with respect to median duration of mechanical ventilation (1 day vs 1 day, P =.76), median stay in the intensive care unit (4 days vs 4 days, P =.44), median hospital stay (15.5 days vs 16 days, P =.74), mean increase in serum creatinine level (1.4 +/- 1.9 mg/dL vs 0.9 +/- 1.0 mg/dL, P =.33), and mean ratio of Pao(2) to fraction of inspired oxygen at 1 hour (376.6 +/- 123 vs 357.0 +/- 218, P =.75), at 24 hours (309.9 +/- 92 vs 350.6 +/- 122, P =.26), and at 48 hours (335.0 +/- 144 vs 316.2 +/- 120, P =.64). Late outcome markers compared between the bypass and nonbypass groups were the following: 1-year percentage predicted forced expiratory volume in 1 second (76.1% +/- 17.0% vs 85.3% +/- 21.7%, P =.24), 30-day mortality (7.1% vs 8.3%, P >.999), 1-year survival (85.7% vs 80.1%, P =.66), 3-year survival (64.3% vs 58.3%, P =.70), and the prevalence of bronchiolitis obliterans syndrome (0% vs 36.1%, P =.01). CONCLUSION: Cardiopulmonary bypass appears to have no deleterious effect on early lung function or clinical outcome. We hope that this pilot study removes some of the unwarranted fear of the use of bypass in lung transplantation for chronic obstructive pulmonary disease.

PURPOSE: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer. PATIENTS AND METHODS: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days. RESULTS: A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 x 10(9) plaque-forming units (PFU)/m(2) was established for outpatient dosing. After an initial dose of 12 x 10(9) PFU/m(2), patients tolerated an MTD for subsequent doses of 120 x 10(9) PFU/m(2). The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site-specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination. CONCLUSION: PV701 warrants further study as a novel therapeutic agent for cancer patients.

The field of gene therapy is still in its infancy, but significant accomplishments have been achieved. The ability to transfer genes safely and successfully into animals and patients clearly has been established. It is highly likely that in the near future, gene therapy will be shown to have clear therapeutic efficacy in diseases such as the treatment of hemophilia (using adeno-associated virus vectors) and the stimulation of angiogenesis in peripheral vascular disease and myocardial ischemia. Although only Phase 1 cancer gene therapy trials for thoracic malignancy have been conducted (usually in patients with large tumor burdens and at submaximal doses), there are some hints of efficacy at higher doses of vector in trials for localized malignancy. The studies reviewed in this article demonstrate the first attempts to use gene therapy vectors for lung cancer and mesothelioma. Although none of the diseases studied was "cured," valuable lessons have been learned from these trials, especially in defining the challenges of relatively inefficient and transient delivery of transgene in vivo. Using this knowledge, the second phase of gene therapy research has begun, with a strong focus on developing improved vector technology. Given the progress so far, there is little doubt that gene therapy will become a key approach for the treatment of thoracic malignancies in the near future.

The incidence of malignant mesothelioma (MM) shows a strong epidemiological association with exposure to asbestos fibers. Recently, simian virus 40 (SV40) DNA sequences have been reported in MM tumor specimens from the United States and several European countries, and the SV40 tumor virus has been implicated as a potential co-factor in the etiology of this disease. However, several large studies from the US, Finland, and Turkey did not detect SV40 sequences in MM samples. To address this discrepancy, MM specimens from Turkey and the US were analyzed in the same laboratory under identical conditions to detect the presence of SV40 DNA. We detected SV40 sequences in 4 of 11 specimens from the United States, but in none of the 9 Turkish samples examined. These findings suggest that geographical differences exist with regard to the involvement of SV40 in human tumors.

Malignant mesothelioma remains an incurable disease for which immune-modulatory therapies, such as exogenous cytokines, have shown some promise. One such cytokine, IFN-beta, has potent antiproliferative and immunostimulatory activity in vitro, but its in vivo use has been limited by toxicity. We thus conducted studies evaluating intracavitary delivery of a replication-deficient adenoviral (Ad) vector encoding for the murine IFN-beta gene (Ad.muIFN-beta) in mouse models of malignant mesothelioma. In contrast to multiple injections of recombinant protein, a single i.p. injection of Ad.muIFN-beta into animals with established tumors elicited remarkable antitumor activity leading to long-term survival in >90% of animals bearing either AB12 or AC29 i.p. mesotheliomas. A control adenovirus vector had minimal antitumor effect in vivo. Significant therapeutic effects were also seen in animals treated with large tumor burdens. Importantly, treatment of i.p. tumor also led to reduction of growth in tumors established at a distant site (flank). A number of experiments suggested that these effects were attributable to an acquired CD8(+) T-cell-mediated response including: (a) the induction of long-lasting antitumor immunity; (b) loss of efficacy of Ad.muIFN-beta in tumor-bearing, immune-deficient (SCID, SCID/beige) mice; (c) detection of high levels of specific antitumor cytolytic activity from unstimulated splenocytes harvested from Ad.muIFN-beta-treated animals that was abolished by CD8(+) T-cell depletion; and (d) abrogation of antitumor effects of Ad.muIFN-beta in tumor-bearing CD8(+) T-cell-depleted animals. These data show that intracavitary IFN-beta gene therapy using an adenoviral vector provides strong CD8(+) T-cell-mediated antitumor effects in murine models of mesothelioma and suggest that this may be a promising strategy for the treatment of localized tumors such as mesothelioma or ovarian cancer in humans.

STUDY OBJECTIVES: We describe a series of patients with symptomatic, refractory malignant pleural effusion (MPE) and underlying trapped lung syndrome who underwent placement of a small-bore, flexible indwelling pleural catheter for home drainage of recurrent MPE. DESIGN: The medical records of 11 consecutive patients who underwent pleural catheter placement for MPE with trapped lung syndrome were reviewed retrospectively. SETTING: Patients were evaluated and followed up in the Pulmonary Outpatient Practice at the Hospital of the University of Pennsylvania. PATIENTS: Nine men and two women with underlying malignancies including lung cancer, lymphoma, and mesothelioma underwent pleural catheter placement. INTERVENTIONS: Thirteen pleural catheters were placed in 11 patients, all under local anesthesia. Patients received detailed instructions for drainage and catheter care. They were reevaluated weekly for the first 2 weeks, and then as clinically indicated. Patients typically performed pleural drainage at home up to 1,000 mL two or three times weekly. MEASUREMENTS AND RESULTS: All patients reported symptomatic benefit, defined as improved dyspnea and exercise tolerance, except for one patient. In 10 patients, the pleural catheters remained in place until death, for 15 to 234 days. The mean length of placement was 115 days. One patient required revision after catheter occlusion. Other complications included catheter infection, localized skin breakdown, and possible cellulitis. CONCLUSION: We have described a series of patients with MPE and trapped lung syndrome for whom placement of a permanent pleural catheter provided a convenient, effective alternative to the procedures currently in use. Our patients reported good symptomatic relief following catheter placement with few major complications.

We report a case of heterotopic ossification of a pedicled intercostal muscle flap that had been wrapped circumferentially around a bronchial sleeve anastomosis. This ossification caused severe bronchial stenosis and recurrent pneumonias. Stent insertion failed, and the patient ultimately required completion pneumonectomy. We recommended that caution be used when wrapping intercostal muscle around any important lumen.