Armando J. Huaringa

Outcome of bone marrow transplantation patients requiring mechanical ventilation.

Objective: To identify outcome predictors in bone marrow transplantation (BMT) patients admitted to the intensive care unit (ICU) of The University of Texas M. D. Anderson Cancer Center who required endotracheal intubation and mechanical ventilation. Design: Retrospective, comparative study. Setting: A 16‐bed medical intensive care unit in a university teaching cancer center. Patients: The records of 60 consecutive BMT patients who developed respiratory failure requiring mechanical ventilation were reviewed. Interventions: None. Measurements and Main Results: The most frequent complication leading to respiratory failure was pneumonia (41%) followed by diffuse alveolar hemorrhage (37%). Eighteen percent of the patients were extubated and discharged from the ICU, but only 5% were alive at 6 months. Graft vs. host disease was a predictor of a poor outcome (p < .05). Breast cancer as an underlying disease and pulmonary edema as a complication were favorable predictive factors (p < .05). Five of 26 patients with diffuse alveolar hemorrhage and four of 33 patients with pneumonia survived. We found no relationship between survival and age, gender, BMT type, or Acute Physiology and Chronic Health Evaluation II score. Prolonged mechanical ventilation (≥15 days) and late development of respiratory failure (>30 days after BMT) were associated with poor prognosis. Conclusions: The ICU survival rate of BMT patients who developed pulmonary complications and required mechanical ventilation was 18%. Prognostic factors were described identifying patients with a substantial survival rate as well as those in whom mechanical ventilation was futile.

Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced pulmonary malignancies

Purpose: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. Experimental Design: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 μg/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. Results: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 μg/kg/day. At 20.0 μg/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. Conclusions: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient’s plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 μg/kg/day (equivalent to 0.5 mg/m2/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.

Bronchoalveolar lavage in the diagnosis of pulmonary complications of bone marrow transplant patients

Bronchoalveolar lavage (BAL) has proved valuable in the diagnosis of pulmonary complications in immunosuppressed patients. We evaluated the diagnostic yield of BAL in pulmonary complications in bone marrow transplantation (BMT) recipients. We reviewed sequentially the records of 89 patients during an 18-month period. BAL was diagnostic in 42 patients (47%). The most common pulmonary complication diagnosed by BAL was diffuse alveolar hemorrhage (n = 15); followed by bacterial pneumonia (n = 10), respiratory syncytial virus (n = 8), aspergillosis (n = 6), Pneumocystis carinii pneumonia (n = 5), cytomegalovirus (CMV) (n = 4), and others (n = 4). The final diagnoses in the BAL non-diagnostic group were: bacterial pneumonia (n = 6), CMV (n = 6), idiopathic pneumonia syndrome (n = 5), cancer recurrence (n = 4), cardiogenic pulmonary edema (n = 4), and others (n = 9). We conclude that BAL is a useful diagnostic tool in BMT-related pulmonary complications. Bone Marrow Transplantation (2000) 25, 975–979.

Feasibility, phase I, and pharmacological study of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced malignancies in the lungs.

Topoisomerase-I inhibitors have the capability to eradicate human tumors in xenograft models. Therefore human cancer cells are extremely sensitive to camptothecin.1 Camptothecin analogues are nevertheless not curative in clinical settings probably because of poor distribution of the camptothecin lactone to the tumor cells growing in humans. We hypothesized that a modification of the formulation and a systemic delivery that avoids first pass in the liver may increase the therapeutic index. Aerosol delivery of liposomal 9-nitrocamptothecin (L-9NC) may possibly delay the opening of the lactone ring through liposomation. We plan to demonstrate that delivery through aerosolization of fine particles is associated with systemic absorption2 and perhaps with sustained levels of closed ring 9-nitrocamptothecin (9NC). Animal data (nude mice) show minimal toxicity and no weight loss, with substantial antitumor activity at reduced doses against breast, lung, and colon cancer xenografts.3 The objective of this study is to determine the feasibility and safety of administering L-9NC by aerosolization for five consecutive days per week.

Abstract 1426: Cyclooxygenase-2 (COX-2) utilizes Jun N-terminal kinases to induce invasion but not tamoxifen resistance in MCF-7 breast cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Elevated Cyclooxygenase-2 (COX-2) expression in breast tumors had been associated with a lower survival rate in patients with Estrogen Receptor α (ERα)-positive tumors. We propose that COX-2 reduces survival rate in breast cancer patients with ERα-positive tumors because COX-2 decreases tamoxifen sensitivity and increases invasive activity of breast cancer cells. We demonstrated that transfection of the COX-2 gene in the tamoxifen-sensitive, ERα-positive MCF-7 breast cancer cell line decreased the cells’ sensitivity to tamoxifen by about 5-fold, and increased their invasive activity by about 3-fold. Furthermore, we demonstrated that COX-2 utilizes PGE2 to activate Protein Kinase C (PKC) to induce these tumorigeneic effects. However, which downstream factors are recruited by the COX-2/PGE2/PKC pathway to induce tamoxifen resistance and breast cancer cell invasion are not known. Here we report that COX-2 increases the phosphorylation of Jun N-terminal kinase (JNK), but not that of extracellular signal regulated kinases (ERK1,2), p38 mitogen activated protein kinase, or Akt. Inhibition of JNK by a chemical inhibitor or siRNA led to decreased COX-2-mediated invasion. Yet, JNK inhibition did not affect COX-2-mediated tamoxifen resistance. We propose that JNK is a promising target to block invasion in patients whose tumors are ERα-positive and present high levels of COX-2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1426. doi:10.1158/1538-7445.AM2011-1426