Jean Santamauro

Phase II Trial of Saracatinib (AZD0530), an Oral SRC-inhibitor for the Treatment of Patients with Hormone Receptor-negative Metastatic Breast Cancer

BACKGROUND SRC activation is associated with cell migration, proliferation, and metastasis. Saracatinib is an oral tyrosine kinase inhibitor (TKI) selective for SRC. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER)(-) and progesterone receptor (PR)(-) metastatic breast cancer (MBC). PATIENTS AND METHODS Patients who had undergone ≤ 1 previous chemotherapy regimen for measurable ER(-) and PR(-) MBC received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 months. Secondary endpoints included toxicity and progression-free survival (PFS). Levels of circulating tumor cells (CTCs) in response to therapy were measured over time. RESULTS Nine patients were treated on study. After a median of 2 cycles (range 1-3), no patient had achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12-109 days).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient acquired potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from the study. Common adverse events included fatigue, elevated liver enzymes, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency. CONCLUSIONS These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER(-)/PR(-) MBC.

Organizing Pneumonia as a Side Effect of Ipilimumab Treatment of Melanoma

Ipilimumab is one of the newly developed human monoclonal antibodies used in the treatment of metastatic melanoma. Its primary mechanism of action is a specific blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a T-cell receptor responsible for inhibition of lymphocyte activation. By blocking CTLA-4, ipilimumab enhances immune responses against tumor cells, but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect. In this report, we describe the case of a 58-year-old woman with metastatic melanoma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough. Extensive workup revealed organizing pneumonia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolution of her pulmonary disease. To our knowledge, this is the first report of pulmonary toxicity caused by ipilimumab, which manifested on pathology as organizing pneumonia.

PNEUMOCYSTIS CARINII PNEUMONIA

Pneumocystis carinii pneumonia (PCP) remains an important complication of AIDS. Advances have been made in establishing the taxonomy of the organism but the life cycle of the organism and pathogenetic mechanisms of disease remain obscure. In HIV patients the incidence of PCP has decreased because of widespread use of prophylaxis and survival of those with PCP has improved with use of adjunctive corticosteroid therapy. Less toxic drug therapies are still needed as well as better noninvasive diagnostic techniques.

Fatal respiratory failure associated with treatment of prostate cancer using docetaxel and estramustine

Chemotherapy that targets microtubular trafficking induces responses in most patients with prostate cancer. One regimen under investigation is the combination of docetaxel and estramustine. We report on 2 patients with androgen-independent disease who received continuous weekly docetaxel and estramustine and who died of irreversible respiratory failure. The clinical, pathologic, and radiographic data support drug toxicity as the likely etiology. Inclusive of these patients, only 17 cases (10 fatal) of acute pulmonary toxicity using docetaxel have been reported, despite its wide use. We recommend that patients receiving weekly docetaxel, with or without estramustine, have frequent treatment breaks and be evaluated with computed tomography of the chest every 8 weeks.

The lung in the immunocompromised host: diagnostic methods.

Accessible online at: www.karger.com/journals/res Previous articles in this series: 1. Nicod LP: Pulmonary defence mechanisms. Respiration 1999;66:2–11. 2. Baughman RP: The lung in the immunocompromised patient. Infectious complications, part I. Respiration 1999;66:95–109. 3. Tamm M: The lung in the immunocompromised patient. Infectious complications, part 2. Respiration 1999;66:199–207. 4. Cadranel J, Naccache JM, Wislez M, Mayaud C: Pulmonary malignancies in the immunocompromised patient. Respiration 1999;66:289–309. 5. Crawford S: Non-infectious lung diseases in the immunocompromised host. Respiration 1999;66:385–395. Over the past several decades, the number of immunosuppressed patients has become larger and the spectrum of illnesses has broadened and become more complex. Because the lung is a target organ for disease, the types of pulmonary disorders that affect the immunocompromised host (ICH) have also increased. Perhaps no other patient population presents with such a variety of infectious and noninfectious pathologic processes. Often these patients pose significant medical challenges because of difficulties associated with making a specific pulmonary diagnosis. Here we review the armamentarium of procedures available for making pulmonary diagnoses, with emphasis on the specific yield and risk associated with each procedure.

A Sleep Medicine Curriculum for Pulmonary and Pulmonary / Critical Care Fellowship Programs – A Multi-Society Expert Panel Report

BACKGROUND: Pulmonary medicine specialists find themselves responsible for the diagnosis and management of patients with sleep disorders. Despite the increasing prevalence of many of these conditions, many sleep medicine fellowship training slots go unfilled, leading to a growing gap between the volume of patients seeking care for sleep abnormalities and the number of physicians formally trained to manage them. To address this need, we convened a multisociety panel to develop a list of curricular recommendations related to sleep medicine for pulmonary fellowship training programs. METHODS: Surveys of pulmonary and pulmonary/critical care fellowship program directors and recent graduates of these programs were performed to assess the current state of sleep medicine education in pulmonary training, as well as the current scope of practice of pulmonary specialists. These data were used to inform a modified Delphi process focused on developing curricular recommendations relevant to sleep medicine. RESULTS: Surveys confirmed that pulmonary medicine specialists are often responsible for the diagnosis and treatment of a number of sleep conditions, including several that are not traditionally considered related to respiratory medicine. Through five rounds of voting, the panel crafted a list of 52 curricular competencies relevant to sleep medicine for recommended inclusion in pulmonary training programs. CONCLUSIONS: Practicing pulmonary specialists require a broad knowledge of sleep medicine to provide appropriate care to patients they will be expected to manage. Training program directors may use the list of competencies as a framework to ensure adequate mastery of important content by graduating fellows.