Ganetespib for small cell lung cancer.

INTRODUCTION: Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC). Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed. Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future.

Continuous-infusion topotecan and erlotinib: a study in topotecan-pretreated ovarian cancer assessing shed collagen epitopes as a marker of invasiveness.

BACKGROUND: Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. METHODS: Topotecan 0.4 mg/m(2) per day was administered by continuous infusion for 9-10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1-10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. RESULTS: Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. FIGURE 1: Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A):: Topotecan and erlotinib. (B):: CA-125 in units/mL. CONCLUSION: Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

Major respiratory adverse events after laparascopic gastric banding surgery for morbid obesity.

BACKGROUND: Laparoscopic adjustable gastric banding surgery has become one of the most common restrictive surgical procedures for treatment of morbid obesity worldwide. Although short-term respiratory complications are well known, long-term data is scarce. We investigated the manifestations of major pulmonary complications showed at least six months after the procedure. METHODS: A retrospective cohort study was conducted at a tertiary university medical center in the five years period of 2006-2010. We included every patient who had had major respiratory complication who needed hospitalization, at least 6 months after laparoscopic adjustable gastric banding procedure. Demographic, pre-operative and post-operative clinical data were collected. We documented respiratory symptoms, results of physical examination, pulmonary function tests, and imaging as well as therapies given and outcome. RESULTS: Out of 2100 patients who underwent LAGB, thirty subjects, mean age of 45.7 (range 29-64) with an equal number of males and females were included. Mean interval between operation and onset of respiratory symptoms was 51.5 months (range 10-150 months). All had dyspeptic complaints which included: regurgitation, fullness after meals, dysphagia and food aspiration with esophageal dilatation. Major respiratory complications included aspiration pneumonia (19) including pulmonary abscess (4) and empyema (2), exacerbation of asthma (3) and hemoptysis (1). Additionally we documented the emergence of chronic diseases such as interstitial lung disease (5) and bronchiectasis (3). One patient developed acute respiratory distress syndrome due to aspiration pneumonia and eventually died in the intensive care unit. The main mode of therapy was deflation of the gastric band. Those who refused to deflate or remove the gastric banding continued to suffer from dyspeptic and respiratory symptoms including recurrent pulmonary abscess. CONCLUSION: Although laparoscopic adjustable gastric banding surgery has few short-term risks and is highly effective at achieving weight reduction, we found an increased risk for major respiratory complications in the long-term period. The obesity epidemic and the increased use of surgical techniques to treat obesity will most likely lead to an increase in the incidence of long-term post-operative respiratory complications. This entity is probably under-reported and needs further research into how to reduce its incidence and morbidity.

Development of patients' decision aid for older women with stage I breast cancer considering radiotherapy after lumpectomy.

PURPOSE: To develop a patient decision aid (PtDA) for older women with Stage I, pathologically node negative, estrogen receptor-positive progesterone receptor-positive breast cancer who are considering adjuvant radiotherapy after lumpectomy and to examine its impact on patients' decision making. METHODS AND MATERIALS: A PtDA was developed and evaluated in three steps according to the Ottawa Decision Support Framework: (1) needs assessment (n = 16); (2) Pilot I to examine PtDA acceptability (n = 12); and (3) Pilot II, a pretest posttest (n = 38) with older women with estrogen receptor-positive progesterone receptor-positive breast cancer after lumpectomy who were receiving adjuvant radiation therapy. Measures included patients' satisfaction with the PtDA, self-reported decisional conflict, level of distress, treatment-related knowledge, and choice predisposition. RESULTS: The PtDA is a booklet that details each adjuvant treatment option's benefits, risks, and side effects tailored to the patient's clinical profile; includes a values clarification exercise; and includes steps to guide patients towards their decision. On the basis of qualitative comments and satisfaction ratings, all women thought that the PtDA was helpful and informative. In comparison with their baseline scores, patients had a statistically significant (p < 0.05) reduction in decisional conflict (adjusted mean difference [AMD], -7.18; 95% confidence interval [CI], -13.50 to 12.59); increased clarity of the benefits and risks (AMD, -10.86; CI, -20.33 to 21.49); and improved general treatment knowledge (AMD, 8.99; CI, 2.88-10.28) after using the PtDA. General trends were also reported in the patients' choice predisposition scores that suggested potential differences in treatment decision after PtDA use. CONCLUSIONS: This study provides evidence that this PtDA may be a helpful educational tool for this group of women. The quality of care for older breast cancer patients may be enhanced by the use of a tailored PtDA to help patients be better informed about their treatment options.

Lung cancer screening--are we there yet?

BACKGROUND: Lung cancer is the most lethal cancer and most cases are the result of cigarette smoking. Although a high risk target population for screening can be defined, and although early stage lung cancer has a much better prognosis than advanced disease, there is still no clear evidence that lung cancer screening decreases mortality. Accordingly, current guidelines suggest that there is no evidence to support routine screening. Although randomized studies in the 1970('s) which used chest x-ray and sputum for screening were clearly negative in the last 20 years more sensitive screening tools such as chest computed tomography have revolutionized the field. However, randomized controlled trials of computed tomography have only recently been launched. AIMS OF THIS REVIEW: Our objectives are to provide the reader with the rationale for screening for lung cancer, to review the older screening studies and their limitations, and to summarize the current knowledge and ongoing trials of lung cancer screening. LITERATURE SEARCH: A literature search using Medline was conducted from 1966 onwards searching for articles with relevant key words such as lung cancer screening chest X - ray low dose computerized tomography cancer screening guideline. When appropriate additional references were found from the bibliographies of identified papers of interest. CONCLUSIONS: Recent uncontrolled multicenter studies of chest computed tomography scans show encouraging results. However, until data from, large properly designed and appropriately analyzed randomized controlled trials which may overcome research biases is available, the benefit of lung cancer screening, if any is still unknown.

Breast cancer-related preferences among women with and without BRCA mutations.

Preference ratings are used to quantify quality of life in analyses used for health care policy making. Subjects indicated how many years of their life expectancy they would trade to avoid BRCA mutations, breast/ovarian cancer, and five preventive measures including prophylactic surgery, annual mammograms, and annual magnetic resonance imaging (MRI). Among 243 respondents, both the 83 women with mutations and the 160 controls rated mammography highest (most favorably), MRI next highest, having a child with a mutation lowest, and ovarian cancer next lowest. Controls rated prophylactic surgery higher than cancer (P < 0.01), but women with mutations did not. In logistic regression, controls were twice as willing as women with mutations to trade time except for screening modalities; younger, lower-income, and non-white women were more willing to trade time than older, higher-income, and white women. Our findings support the use of average-risk individuals' time trade-off preference ratings for health care policy development.

Ontario radiation oncology residents' needs in the first postgraduate year-residents' perspective survey.

PURPOSE: To assess radiation oncology residents' needs and satisfaction in their first postgraduate year (PGY-1) in the province of Ontario. METHODS AND MATERIALS: Of 62 radiation oncology residents, 58 who had completed their PGY-1 and were either enrolled or had graduated in 2006 were invited to participate in a 31-item survey. The questionnaire explored PGY-1 residents' needs and satisfaction in four domains: clinical workload, faculty/learning environment, stress level, and discrimination/harassment. The Fisher's exact and Wilcoxon nonparametric tests were used to determine relationships between covariate items and summary scores. RESULTS: Of 58 eligible residents, 44 (75%) responded. Eighty-four percent of residents felt that their ward and call duties were appropriate. More than 50% of respondents indicated that they often felt isolated from their radiation oncology program. Only 77% agreed that they received adequate feedback, and 40% received sufficient counseling regarding career planning. More than 93% of respondents thought that faculty members had contributed significantly to their learning experience. Approximately 50% of residents experienced excessive stress and inadequate time for leisure or for reading the medical literature. Less than 10% of residents indicated that they had been harassed or experienced discrimination. Eighty-three percent agreed or strongly agreed that their PGY-1 experience had been outstanding. CONCLUSIONS: Most Ontario residents were satisfied with their PGY-1 training program. More counseling by radiation oncology faculty members should be offered to help residents with career planning. The residents might also benefit from more exposure to "radiation oncology" and an introduction to stress management strategies.

Fourteen-year study of hospital admissions for diverticular disease in Ontario.

BACKGROUND: Diverticular disease is one of the most common gastrointestinal conditions affecting the Canadian population, yet very little is known about its epidemiology. OBJECTIVE: The aim of the present study was to measure the rate of hospital admission for diverticular disease by age and sex over a 14-year period in the population of Ontario. PATIENTS AND METHODS: The present study was a retrospective, population-based cohort study of all hospital admissions for diverticular disease from 1988 to 2002. RESULTS: There were 133,875 hospital admissions during the period. Admission rates increased with age, and women were admitted at higher rates than men across all age groups. CONCLUSION: Diverticular disease is an important cause of gastrointestinal morbidity. As the population ages, a rise in the incidence of diverticular disease can be anticipated. Future studies to explain sex difference in admissions are required.