Yoshikazu Kaneda

Isolated lung perfusion for patients with unresectable metastases from sarcoma: a phase I trial

BACKGROUNDnIn patients with unresectable pulmonary metastases from sarcoma, systemic chemotherapy has had limited efficacy possibly because of dose-limiting toxicities. Isolated lung perfusion is an alternative method of delivering high-dose chemotherapy to the lungs while minimizing systemic toxicities. We present the results of our Phase I trial of isolated lung perfusion with doxorubicin hydrochloride in such a group of patients.nnnMETHODSnFrom May 1995 to June 1997, 8 patients with unresectable metastases from sarcoma limited to the lungs underwent isolated lung perfusion with doxorubicin. A dose-escalation schedule starting at 40 mg/m2 was used. Seven patients were treated with a dose of 40 mg/m2 or less, and 1 patient received 80 mg/m2. Blood, tumor, and normal lung samples were obtained at various time points during the operation. Patients were evaluated for cardiac, pulmonary, and other toxicities.nnnRESULTSnThe doxorubicin concentrations in both normal lung and tumor correlated directly with the amount of doxorubicin in the perfusate. The tumors took up less doxorubicin than the lung. All patients had minimal or undetectable systemic levels of doxorubicin at the conclusion of the perfusion. There were no cardiac or other systemic toxicities. In the 7 patients perfused with 40 mg/m2 or less of doxorubicin, there was a significant decrease in the forced expiratory volume in 1 second and a trend toward a significant decrease in diffusing capacity. The patient who received 80 mg/m2 underwent lung scanning postoperatively, and scans showed no ventilation or perfusion in the perfused lung. There were no perioperative deaths. Two patients are alive with disease, and 6 patients died of disease. The median follow-up is 11 months and the longest, 31 months. There were no partial or complete responses. One patient had stabilization of disease in the perfused lung, whereas the lesions in the untreated lung progressed markedly.nnnCONCLUSIONnIsolated lung perfusion is well tolerated by patients and effectively delivers high doses of doxorubicin to the lung and tumor tissues while minimizing systemic toxicities. A single dose of 80 mg/m2 resulted in substantial injury to the lung. There were no partial or complete responses in patients perfused with doxorubicin at the maximum tolerated dose of 40 mg/m2. Isolated lung perfusion remains a model for testing new and innovative therapies for metastatic sarcoma.

Video-assisted thoracoscopic lobectomy reduces cytokine production more than conventional open lobectomy

OBJECTIVEnWe studied cytokine changes after video-assisted thoracoscopic lobectomy and conventional lobectomy in patients with stage IA lung cancer.nnnMETHODSnFrom June, 1997, 20 consecutive patients with stage IA non small-cell lung carcinoma underwent either conventional lobectomy via an open thoracotomy (n = 10) or video-assisted thoracoscopic lobectomy (n = 10). The cytokine concentration in serum and pleural fluid were measured for 6 days postoperatively.nnnRESULTSnInterleukin-6 and interleukin-8 leads peaked at 3 h or 1 day after surgery. Cytokine levels in pleural fluid were more than 100 times higher than corresponding systemic levels. The increase of interleukin-6 in pleural fluid 3 hours after surgery was significantly smaller in video-assisted thoracoscopic lobectomy (3971 +/- 2793 pg/mL for video-assisted thoracoscopic lobectomy vs. 23274 +/- 8426 pg/mL for open lobectomy). There were no significant differences in the serum interleukin-6 and interleukin-8 concentrations between the 2 groups.nnnCONCLUSIONnThe thoracoscopic approach lessened the increase of cytokines in pleural fluid, but benefits of reduced cytokine production in video-assisted thoracoscopy remain to be clarified.

Comparison of three tracers for detecting sentinel lymph nodes in patients with clinical N0 lung cancer

The goal of this pilot study was to compare three tracers for the detection of sentinel nodes in patients with lung cancer. Forty-eight patients with clinical N0 non-small cell lung cancer were enrolled. Indocyanine green (n=16) or isosulfan blue (n=18) was injected around the tumor intraoperatively, or technetium tin colloid was injected preoperatively under CT guidance (n=14). Sentinel nodes were detected in 6.3% of patients injected with indocyanine green, 50.0% of patients injected with isosulfan blue, and 64.3% of patients injected with technetium tin colloid. The detection rate achieved with indocyanine green was significantly lower than with the other two tracers. A false-negative sentinel node was seen in 1 patient using isosulfan blue. Both isosulfan blue and technetium tin colloid seem to be suitable for intraoperative sentinel node mapping in patients with lung cancer.

Isolated Lung Perfusion With Doxorubicin Prolongs Survival in a Rodent Model of Pulmonary Metastases

BACKGROUNDnWe developed a rodent model of unilateral pulmonary metastases to evaluate long-term survival after isolated lung perfusion with doxorubicin.nnnMETHODSnIn the model development study, on day 0, two groups of F344 rats (n = 15) underwent transient right pulmonary artery occlusion for either 5 or 10 minutes at the time of intravenous injection of methylcholantrene-induced sarcoma cells. On day 14, all animals were sacrificed and lung nodules counted. In the survival study, on day 0, 21 rats received intravenous injection of sarcoma cells with concomitant 10-minute right pulmonary artery occlusion. On day 7, eight rats underwent left isolated lung perfusion with doxorubicin (6.4 mg/kg); five rats underwent perfusion with buffered Hespan; six untreated rats were studied as controls.nnnRESULTSnTen of fifteen animals (67%) in the model study with 5-minute pulmonary artery occlusion had right-sided tumor nodules. Ten-minute occlusion resulted in a tumor-free right lung in all animals. In the survival study, all animals in the Hespan and control groups died of massive tumor replacement of the left lung, with median survival times of 20 and 18 days, respectively. The median survival time of 36 days for the animals undergoing isolated lung perfusion with doxorubicin was significantly longer (p < 0.00001). The left lung of two of the doxorubicin perfused rats was tumor-free at 6 weeks.nnnCONCLUSIONSnIsolated lung perfusion with doxorubicin results in a durable response and prolongs survival in the treatment of experimental sarcoma pulmonary metastases.

Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery

Abstract Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5u2009min, and at 1, 2, 4, 6 and 24u2009h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5–17u2009h), lower peak serum concentrations (aerosol 71u2009±u200931u2009ng/ml, IT 68u2009±u200950u2009ng/ml), and lower liver levels (aerosol 111u2009± 28u2009ng/g, IT 753u2009±u2009350u2009ng/g) than the same dose administered IV (2u2009h, 838u2009±u200956u2009ng/ml, 4258u2009±u20091006u2009ng/g, respectively; Pu2009<u20090.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing.

Endovascular Repair of Distal Arch Aneurysm With Double-Chimney Technique

We report 2 cases of distal arch aneurysm treated by thoracic endovascular aneurysm repair (TEVAR) with the double-chimney technique. This technique permitted the implantation of a thoracic stent graft in the ascending aorta over the arch branches while preserving perfusion of innominate and left common carotid arteries without debranching bypasses. The procedure is a feasible and less invasive treatment for distal arch aneurysm with a short proximal neck (<2 cm to the origin of the innominate artery) in patients at high risk when undergoing sternotomy and in emergent cases.

Characterization of local inflammatory response in an isolated lung perfusion model

AbstractBackground: Current phase I trials of isolated lung perfusion for treatment of pulmonary metastases have an arbitrarily determined length of perfusion. Our objective was to examine the temporal course of the local and distant inflammatory response as a function of the length of perfusion (ischemia) and subsequent reperfusion in an equivalent animal model.nMethods: Sixty male Fischer 344 rats were randomized into four groups (n=15). Each group underwent left isolated lung perfusion with buffered Hespan for 10, 30, 60, or 90 minutes. Subsequently, two subgroups of five animals within each group were allowed to reperfuse for 1 or 3 hours, respectively. Non-perfused right lung was used as control. At each time point, lung specimens were assayed for TNF-α by ELISA and histologic sections were examined.nResults: There was no significant difference between the left and right lung tissue levels of TNF-α at the termination of the ischemic period. However, on reperfusion, the left lung TNF-α levels increased significantly above the ischemia baseline in all groups, with a greater magnitude of rise in the groups with 60 and 90 minutes of preceding ischemia (12757 ± 1985 vs. 3524 ± 494 pg/g, and 16914 ± 1657 vs. 6530 ± 1104 pg/g, respectively;p<0.05). There was no significant elevation in tissue levels of TNF-α in the right lung. Histologic changes consistent with early pulmonary edema were first detected at 12 hours following onset of reperfusion.nConclusions: Reperfusion following prolonged pulmonary ischemia during isolated lung perfusion results in a significant elevation of local tissue levels of TNF-α and may render the perfused lung vulnerable to the adverse effects of the inflammatory cascade.

Chimney Technique for Aortic Dissection Involving an Aberrant Right Subclavian Artery

We report a case involving a ruptured acute type B aortic dissection originating from an aberrant right subclavian artery (ARSA). A thoracic stent-graft was deployed in the distal arch close to the origin of the ARSA; the entry site at the origin of the ARSA was embolized with metallic coils. Perfusion of the left subclavian artery was preserved without a surgical bypass by using a chimney graft. This procedure is a feasible and less invasive treatment for high-risk sternotomy patients and is an effective strategy for acute aortic dissections involving an ARSA.

Subjective symptoms and prognosis after lung volume reduction surgery in patients with severe pulmonary emphysema

Lung volume reduction surgery improves symptoms in patients with severe pulmonary emphysema, but patients are not always satisfied surgical results. Our purpose was to determine the profiles and prognosis of unsatisfactory cases of lung volume reduction surgery. A total of 58 patients with advanced symptomatic emphysema underwent thoracoscopic volume reduction of emphysematous lung tissue. Patients subjectively evaluated their condition 3 months after surgery as better, same, or worse than before surgery. Of these, 30 evaluated themselves as better (58%), 17 as the same (33%), and 4 (8%) as Worse. Most patients with vital capacity (VC) exceeding 2,000 mL (percentage of vital capacity for the predicted value (%VC) of > 60%) with upper-lobe-predominant and centrilobular emphysema were satisfied with surgical results. All patients with lower-lobe-predominant or whole-lung panacinar emphysema evaluated their results as worse. Six late deaths occurred due to pulmonary infection (3), respiratory failure (2), and an unknown sudden cause (1), with most of these patients having preoperative low VC and high postoperative partial carbon dioxide pressure in the arterial blood (PaCO2).

Single-stage thoracic and abdominal endovascular aneurysm repair for multilevel aortic disease

This investigation evaluated the results of single-stage thoracic endovascular aneurysm repair (TEVAR) and endovascular aneurysm repair (EVAR) for multilevel aortic disease in a series of nine patients. The lesions repaired included thoracic and abdominal aortic aneurysms (n = 7) and subacute type B dissections with abdominal aortic aneurysms (n = 2). All procedures were successfully performed, and none of the patients experienced postoperative stroke or spinal cord ischemia. The median follow-up period for these patients was 18.9 months (range 1.7–31.4 months) and none of the patients exhibited any signs of type I endoleaks or aneurysmal diameter enlargements more than 5 mm. In conclusion, single-stage TEVAR and EVAR procedures for multilevel aortic disease were found to be safe and feasible modalities for high-risk patients.