Howard M. Ross

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

BACKGROUND In 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. METHODS From 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. RESULTS The 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. CONCLUSION Isolated 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.

Epithelioid sarcoma: Clinical behavior and prognostic factors of survival

AbstractBackground: Epithelioid sarcoma is a rare histologic subtype of sarcoma. The clinical behavior and prognostic factors influencing survival in this disease are examined. Methods: A review of clinicopathologic features of patients with epithelioid sarcoma prospectively followed between July 1982 and July 1995 at Memorial Sloan-Kettering Cancer Center was performed. Kaplan-Meier and log-rank analysis were used. Results: Eleven men (69%) and five women (31%) were treated during this period. Mean age at diagnosis was 33 years, and length of symptoms before diagnosis was 18 months. Tumors presented in the trunk in 44% of patients, the lower extremity in 31%, and the upper extremity in 25%. Median follow-up time was 45 months. At least one local recurrence was experienced by 69% of patients. Metastases to regional lymph nodes during the course of the disease developed in 44% of patients and to the lungs in 44%. Median survival was 88.8 months, with a 66% 5-year survival rate. Pulmonary metastasis was correlated with decreased survival. Conclusions: A delay in diagnosis of epithelioid sarcoma is common. Epithelioid sarcoma differs from other sarcoma subtypes in propensity for nodal spread and local recurrence. Careful follow-up evaluating local recurrence, nodal spread, and pulmonary metastases is warranted.

Nonoperative Management of Tracheal Laceration During Endotracheal Intubation

Tracheal laceration is a rare but potentially devastating complication of endotracheal intubation. Traditional management of intubation-related tracheal laceration is operative. Nonoperative management of a woman noted to have a tracheal laceration during intubation is described. Criteria by which nonoperative treatment can be considered are outlined.

Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines

Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.

Isolated lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma

OBJECTIVE Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated. METHODS TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. PHARMACOKINETICS STUDY: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats received an intravenous injection of 5 x 10(6) methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted. RESULTS TOXICITY Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg. PHARMACOKINETICS Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002). EFFICACY Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 +/- 10) than in the groups receiving intravenous melphalan (60 +/- 21) or buffered hetastarch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, respectively). CONCLUSION Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.

Establishment of an Experimental Intrapulmonary Tumor Nodule Model

BACKGROUND A pulmonary tumor model is necessary to study the biology and therapy of lung cancer. Methods to establish a solitary intrapulmonary nodule are not well defined. Two methods for solitary intrapulmonary tumor nodule development in the Fischer rat are described. METHODS Methylcholanthrene-induced sarcoma cell suspensions were introduced into lung parenchyma of Fischer rats via limited thoracotomy and lung puncture, or instilled into a distal airway after tracheal puncture and catheterization. Intrapulmonary tumor location, implantation mortality, procedure length, and animal survival were recorded. RESULTS Single pulmonary nodules developed at the implanted position in 100% (n = 320) and 95% (62/65) of animals after direct injection into the pulmonary parenchyma or via tracheal puncture and instillation. Operative mortality was 2% and 5% via lung or tracheal implantation, respectively. Less than 5 minutes was required for each implantation. Mean survival time was 24 +/- 2 and 26 +/- 6 days after lung or tracheal implantation in animals allowed to survive until tumor-induced death. CONCLUSIONS These easily performed, reproducible methods of establishing solitary intrapulmonary tumors are useful tools for lung cancer research.

Sequential Bilateral Isolated Lung Perfusion in the Rat: An Experimental Model

BACKGROUND A model of isolated single-lung perfusion in the rat has been established in our laboratory to study the chemotherapeutic treatment of pulmonary metastases. A sequential bilateral isolated lung perfusion model was designed to investigate the feasibility of staged perfusions in the rat. METHODS Twenty-four Fischer rats were randomized into three experimental groups of 8 rats each. All rats underwent left isolated lung perfusion. One, 2, or 3 weeks later, the rats in groups I, II, and III, respectively, underwent contralateral (right) perfusion. Five control animals (group IV) underwent sequential bilateral sham thoracotomies 1 week apart. Arterial blood gas analysis was performed 1 week after the second operation in the rats in groups I and IV. RESULTS All animals survived the first operation, with 100% (8/8), 75% (6/8), and 100% (8/8) of the animals in perfusion groups I, II, and III, respectively, surviving the second operation. All control animals (group IV) survived the second sham thoracotomy. Arterial blood gas analysis did not show a significant difference in the oxygen or carbon dioxide partial pressure or the pH between group I and IV (p = 0.32, 0.96, and 0.76, respectively). CONCLUSIONS Our experiments demonstrate that sequential bilateral isolated lung perfusion is safe in and well tolerated by the rat. This model can be used to investigate the safety and efficacy of staged perfusions with chemotherapeutic agents in the treatment of bilateral pulmonary metastases in the rat.