Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential.

Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate and whether multicellular clusters of tumor cells possess the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do so as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumors at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells.This article has an associated First Person interview with the first author of the paper.

Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

Background: Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods: Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results: Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. Conclusions: This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. Trial registration: www.clinicaltrials.gov, NCT01343277.

Angiopellosis as an Alternative Mechanism of Cell Extravasation.

Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Stem Cells 2017;35:170-180 Video Highlight: https://youtu.be/i5EI-ZvhBps.

Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies.

BACKGROUND: Resident stem and progenitor cells have been identified in the lung over the last decade, but isolation and culture of these cells remains a challenge. Thus, although these lung stem and progenitor cells provide an ideal source for stem-cell based therapy, mesenchymal stem cells (MSCs) remain the most popular cell therapy product for the treatment of lung diseases. Surgical lung biopsies can be the tissue source but such procedures carry a high risk of mortality. METHODS: In this study we demonstrate that therapeutic lung cells, termed "lung spheroid cells" (LSCs) can be generated from minimally invasive transbronchial lung biopsies using a three-dimensional culture technique. The cells were then characterized by flow cytometry and immunohistochemistry. Angiogenic potential was tested by in-vitro HUVEC tube formation assay. In-vivo bio- distribution of LSCs was examined in athymic nude mice after intravenous delivery. RESULTS: From one lung biopsy, we are able to derive >50 million LSC cells at Passage 2. These cells were characterized by flow cytometry and immunohistochemistry and were shown to represent a mixture of lung stem cells and supporting cells. When introduced systemically into nude mice, LSCs were retained primarily in the lungs for up to 21 days. CONCLUSION: Here, for the first time, we demonstrated that direct culture and expansion of human lung progenitor cells from pulmonary tissues, acquired through a minimally invasive biopsy, is possible and straightforward with a three-dimensional culture technique. These cells could be utilized in long-term expansion of lung progenitor cells and as part of the development of cell-based therapies for the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer.

OBJECTIVE: To determine whether the frequency of cases diagnosed with stage IIIC endometrial cancer is affected by the incorporation of a modified surgical lymph node assessment. METHODS: Since 2008, we have increasingly utilized a modified nodal assessment using an algorithm that incorporates SLN mapping. For this analysis, we identified all cases of newly diagnosed endometrial cancers undergoing a minimally invasive staging procedure not requiring conversion to laparotomy from 1/1/08 to 12/31/10. Procedures were categorized as standard, modified, and hysterectomy only. Differences were based on time period: 2008 (Y1), 2009 (Y2), and 2010 (Y3). Appropriate statistical tests were used. RESULTS: We identified a total of 507 cases. The distribution of cases was 143 (Y1), 190 (Y2), and 174 (Y3). Tumor grade (P=0.05) and high-risk histologies (P=0.8) did not differ during the 3 time periods. A standard staging procedure was performed in the following cases: Y1 (93/143; 65%), Y2 (66/166; 35%), and Y3 (40/164; 23%) (P<0.001). Median operative times were as follows: Y1 (218 min), Y2 (198 min), and Y3 (176.5 min) (P<0.001). The median numbers of total lymph nodes removed among cases with at least 1 node retrieved were: Y1 (20); Y2 (10); Y3 (7) (P<0.001). Cases diagnosed as stage IIIC were as follows: Y1 (10/143; 7%), Y2 (15/166; 7.9%), and Y3 (13/164; 7.5%) (P=1.0). CONCLUSIONS: The incorporation of a modified staging approach utilizing the SLN mapping algorithm reduces the need for standard lymphadenectomy and does not appear to adversely affect the rate of stage IIIC detection.

Multicentre audit of inpatient management of acute exacerbations of chronic obstructive pulmonary disease: comparison with clinical guidelines.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and clinical guidelines for optimised management are available. However, few data assessing concordance with these guidelines are available. We aimed to identify gaps and document variability in clinical practices for COPD admissions. METHODS: Medical records of all admissions over a 3-month period as COPD with non-catastrophic or severe comorbidities or complications at eight acute-care hospitals within the Hunter New England region were retrospectively audited. RESULTS: Mean (SD) length of stay was 6.3 (6.1) days for 221 admissions with mean age of 71 (10), 53% female and 34% current smokers. Spirometry was performed in 34% of admissions with a wide inter-hospital range (4-58%, P < 0.0001): mean FEV1 was 36% (18) predicted. Arterial blood gases were performed on admission in 54% of cases (range 0-85%, P < 0.0001). Parenteral steroids were used in 82% of admissions, antibiotics in 87% and oxygen therapy during admission in 79% (with oxygen prescription in only 3% of these). Bronchodilator therapy was converted from nebuliser to an inhaler device in 51% of cases early in admission at 1.6 (1.7) days. Only 22% of patients were referred to pulmonary rehabilitation (inter-hospital range of 0-50%, P = 0.002). Re-admission within 28 days was higher in rural hospitals compared with metropolitan (27% vs 7%, P < 0.0001). CONCLUSIONS: We identified gaps in best practice service provision associated with wide inter-hospital variations, indicating disparity in access to services throughout the region.

Pedotransfer functions to determine water conducting macroporosity in South African soils.

Macropores play an important role in the rapid transport of water, solutes and pollutants through the soil. Transport through these pores (>0.5 mm) is dominated by gravitational forces (i.e. matrix forces have low impact) resulting in flow rates orders of magnitude higher than rates that would be predicted, posing problems for modelling and understanding water and solute transport through soils. This study aimed to quantify the water conducting macroporosity (WCM) in a range of soils in South Africa and to develop three pedotransfer functions (PTFs) able to predict WCM. Saturated (K(s)) and unsaturated (K30) conductivities were measured in situ on 120 soil profiles using double ring and tension infiltrometers methods. Differences between K(s) and K30 in conjunction with Poiseuille's law and the capillary rise equation were used to calculate WCM. The first two multiple regression functions made use of all available soil properties influencing WCM using a 'best model' and 'backward' analysis approach respectively. The third model used only easily observable soil properties to predict the WCM. The functions were validated using a double-cross method. Results are encouraging with R² values of 0.78, 0.74 and 0.69 for functions 1, 2 and 3 respectively.

Zn(II) binding to Escherichia coli 70S ribosomes.

Escherichia coli 70S ribosomes tightly bind 8 equiv of Zn(II), and EXAFS spectra indicate that Zn(II) may be protein-bound. Ribosomes were incubated with EDTA and Zn(II), and after dialysis, the resulting ribosomes bound 5 and 11 equiv of Zn(II), respectively. EXAFS studies show that the additional Zn(II) in the zinc-supplemented ribosomes binds in part to the phosphate backbone of the ribosome. Lastly, in vitro translation studies demonstrate that EDTA-treated ribosomes do not synthesize an active Zn(II)-bound metalloenzyme, while the as-isolated ribosomes do. These studies demonstrate that the majority of intracellular Zn(II) resides in the ribosome.

Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes.

OBJECTIVE: To compare the incidence of metastatic cancer cells in sentinel lymph nodes (SLN) vs. non-sentinel nodes in patients who had lymphatic mapping for endometrial cancer and to determine the contribution of metastases detected on ultrastaging to the overall nodal metastasis rate. METHODS: All patients who underwent lymphatic mapping for endometrial cancer were reviewed. Cervical injection of blue dye was used in all cases. Sentinel nodes were examined by routine hematoxylin and eosin (H&E), and if negative, by standardized institutional pathology protocol that included additional sections and immunohistochemistry (IHC). RESULTS: Between 09/2005 and 03/2010, 266 patients with endometrial cancer underwent lymphatic mapping. Sentinel node identification was successful in 223 (84%) cases. Positive nodes were diagnosed in 32/266 (12%) patients. Of those, 8/266 patients (3%) had the metastasis detected only by additional section or IHC as part of SLN ultrastaging. Excluding the 8 cases with positive SLN on ultrastaging only, 24/801 (2.99%) SLN and 30/2698 (1.11%) non-SLN were positive for metastatic disease (p=0.0003). CONCLUSION: Using a cervical injection for mapping, metastatic cells from endometrial cancer are three times as likely to be detected in SLN than in the non-sentinel nodes. This finding strongly supports the concept of lymphatic mapping in endometrial cancer to fine tune the nodal dissection topography. By adding SLN mapping to our current surgical staging procedures we may increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. An additional benefit of incorporating pathologic ultrastaging of SLN is the detection of micrometastasis, which may be the only evidence of extrauterine spread.

A nomogram for predicting overall survival of women with endometrial cancer following primary therapy: toward improving individualized cancer care.

OBJECTIVES: Traditionally we have relied mainly on final FIGO stage to estimate overall oncologic outcome in endometrial cancer patients. However, it is well known that other patient factors may play equally important roles in outcome. Our objective was to develop a clinically useful nomogram in the hope of providing a more individualized and accurate estimation of overall survival (OS) following primary therapy. METHODS: Using a prospectively maintained endometrial cancer database, 1735 patients treated between 1993 and 2008 were analyzed. Characteristics known to predict OS were collected. For each patient, points were assigned to each of these 5 variables. A total score was calculated. The association between each predictor and the outcome was assessed by multivariable modeling. The corresponding 3-year OS probabilities were then determined from the nomogram. RESULTS: The median age was 62 years (range, 25-96). Final grade included: G1 (471), G2 (622), G3 (634), and missing (8). Stage included: IA (501), IB (590), IC (141), IIA (36), IIB (75), IIIA (116), IIIB (6), IIIC (135), IVA (7), and IVB (128). Histology included: adenocarcinoma (1376), carcinosarcoma (100), clear cell (62), and serous (197). Median follow-up for survivors was 29.2 months (0-162.2 months). Concordance probability estimator for the nomogram is 0.746+/-0.011. CONCLUSION: We developed a nomogram based on 5 easily available clinical characteristics to predict OS with a high concordance probability. This nomogram incorporates other individualized patient variables beyond FIGO stage to more accurately predict outcome. This new tool may be useful to clinicians in assessing patient risk when deciding on follow-up strategies.

Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis.

No improvement in lung cancer care: the management of lung cancer in 1996 and 2002 in New South Wales.

BACKGROUND: Patterns-of-care studies emphasize significant variation in the management of lung cancer. The aim of the study was to compare the patterns of care for patients diagnosed with lung cancer in 1996 and 2002 within three health areas in New South Wales. METHODS: Treatment data were collected from medical records and treating doctors for the calendar year 1996 and between 1 November 2001 and 31 December 2002. Patients were residents of either south-western Sydney, Hunter or Northern Sydney health areas at the time of diagnosis. chi(2)-tests were used to investigate changes in treatment patterns between the two time periods. An adjusted odds ratio for treatment in 2002 relative to 1996 was calculated using logistic regression. RESULTS: Data were available for 738 and 567 cases in 1996 and 2002, respectively. Cancer-specific therapy was given within 6 months of diagnosis to 62 and 64% of patients, respectively. Adjusting for health area, age, sex, pathology and performance status, the odds ratio (OR) of treatment in 2002 relative to 1996 was 1.03 (95% confidence interval (CI) 0.78-1.35). When stage was included, the odds of treatment in 2002 relative to 1996 for non-small-cell lung cancer (n = 950) was 1.21 (95%CI 0.87-1.68). After adjustment for potential confounders, patients diagnosed with small-cell lung cancer (n = 176) were substantially less likely to receive treatment in 2002 compared with patients diagnosed in 1996 (OR = 0.11; 95%CI 0.04-0.34). CONCLUSION: The odds of receiving treatment in 2002 and 1996 were similar. However, patients diagnosed with small-cell lung cancer in 2002 were significantly less likely to receive treatment. Overall, this study suggests there has been no change in lung cancer care in New South Wales. Further work is required to determine what proportion of persons with lung cancer should receive cancer-specific treatment so that clinical practices can be judged appropriately.

Management of uterine malignancy found incidentally after supracervical hysterectomy or uterine morcellation for presumed benign disease.

Patients who have undergone supracervical hysterectomy or uterine morcellation for presumed benign uterine disease and are found to have malignancy on final pathology represent a management dilemma. Our goal was to analyze our experience and make observations regarding staging, treatment, and outcomes. We performed a retrospective case series of patients referred to our institution with uterine malignancy who previously underwent supracervical hysterectomy or uterine morcellation at the time of original surgery for presumed benign uterine disease. Between January 2000 and March 2006, 17 patients with uterine malignancy were identified. Following initial surgery, 15 (88%) patients had presumed stage I disease and 2 (12%) patients had stage III disease. Two (15%) of 13 patients who underwent completion surgery were upstaged; both had leiomyosarcoma (LMS) originally resected with morcellation. Ten of 11 patients whose stage was confirmed with secondary surgery remain disease free. None of the patients who initially underwent supracervical hysterectomy without morcellation were upstaged by secondary surgery. The median follow-up interval was 30 months (range, 2-90 months). Reoperation for completion surgery and staging is important when uterine malignancy is found incidentally after morcellation or supracervical hysterectomy for presumed benign uterine disease. Approximately 15% of patients will be upstaged by reexploration, particularly those with LMS who underwent morcellation. Patients who undergo completion surgery with restaging and are not upstaged appear to have a good prognosis. Surgical staging is valuable for prognosis and may alter postoperative treatments.

A phase 2 trial of oral imatinib in patients with epithelial ovarian, fallopian tube, or peritoneal carcinoma in second or greater remission.

PURPOSE OF INVESTIGATION: To determine the effect of imatinib on progression-free survival in patients with epithelial ovarian cancer in second or greater complete clinical remission (CCR). METHODS: 35 patients were enrolled between 10/2002 and 1/2005. Eligible patients received imatinib at 400 mg daily orally. RESULTS: One patient withdrew consent, and two patients received protocol therapy in first remission and were excluded. Five patients were removed for possibly related toxicity. No associations were seen between PDGF-R staining and PFS. CONCLUSIONS: Treatment with imatinib for patients with ovarian cancer in second CCR or greater did not prolong the PFS beyond the historical estimate.

Mesenchymal Stem Cell/Red Blood Cell-Inspired Nanoparticle Therapy in Mice with Carbon Tetrachloride-Induced Acute Liver Failure.

Acute liver failure is a critical condition characterized by global hepatocyte death and often time needs a liver transplantation. Such treatment is largely limited by donor organ shortage. Stem cell therapy offers a promising option to patients with acute liver failure. Yet, therapeutic efficacy and feasibility are hindered by delivery route and storage instability of live cell products. We fabricated a nanoparticle that carries the beneficial regenerative factors from mesenchymal stem cells and further coated it with the membranes of red blood cells to increase blood stability. Unlike uncoated nanoparticles, these particles promote liver cell proliferation in vitro and have lower internalization by macrophage cells. After intravenous delivery, these artificial stem cell analogs are able to remain in the liver and mitigate carbon tetrachloride-induced liver failure in a mouse model, as gauged by histology and liver function test. Our technology provides an innovative and off-the-shelf strategy to treat liver failure.

Brain structure and function in patients with ovarian cancer treated with first-line chemotherapy: a pilot study.

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.

Heart Repair Using Nanogel-Encapsulated Human Cardiac Stem Cells in Mice and Pigs with Myocardial Infarction.

Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice. In mice and pigs with acute MI, injection of encapsulated hCSCs preserves cardiac function and reduces scar sizes, whereas injection of hCSCs in saline has an adverse effect on heart healing. In conclusion, thermosensitive nanogels can be used as a stem cell carrier: the porous and convoluted inner structure allows nutrient, oxygen, and secretion diffusion but can prevent the stem cells from being attacked by immune cells.

Safety and Efficacy of Allogeneic Lung Spheroid Cells in a Mismatched Rat Model of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix causing lung distortions and dysfunctions. The prognosis after detection is merely 3-5 years and the only two Food and Drug Administration-approved drugs treat the symptoms, not the disease, and have numerous side effects. Stem cell therapy is a promising treatment strategy for pulmonary fibrosis. Current animal and clinical studies focus on the use of adipose or bone marrow-derived mesenchymal stem cells. We, instead, have established adult lung spheroid cells (LSCs) as an intrinsic source of therapeutic lung stem cells. In the present study, we compared the efficacy and safety of syngeneic and allogeneic LSCs in immuno-competent rats with bleomycin-induced pulmonary inflammation in an effort to mitigate fibrosis development. We found that infusion of allogeneic LSCs reduces the progression of inflammation and fibrotic manifestation and preserves epithelial and endothelial health without eliciting significant immune rejection. Our study sheds light on potential future developments of LSCs as an allogeneic cell therapy for humans with pulmonary fibrosis. Stem Cells Translational Medicine 2017;9:1905-1916.

Lung volume reduction surgery for diffuse emphysema.

BACKGROUND: Lung volume reduction surgery (LVRS) has been re-introduced for treating patients with severe diffuse emphysema. It is a procedure that aims to improve long-term daily functioning, although it is costly and may also be associated with a high risk of mortality. OBJECTIVES: To assemble evidence from randomised controlled trials for the effectiveness of LVRS, and identify optimal surgical techniques. SEARCH STRATEGY: Randomised controlled trials were identified using the Cochrane Airways Group Chronic Obstructive Pulmonary Disease (COPD) register. Searches are current to September 2005. SELECTION CRITERIA: Randomised controlled trials that studied the safety and efficacy of LVRS in patients with diffuse emphysema were included. Studies were excluded if they investigated giant or bullous emphysema. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed trials for inclusion and extracted data. Where possible, data from more than one study were combined using RevMan 4.2 software. MAIN RESULTS: Eight studies (1663 participants) met the entry criteria of the review. One study accounted for 73% of the participants recruited. Study quality was high, although blinding in studies was not possible. Ninety day mortality was significantly greater in all those who underwent LVRS (odds ratio 6.57 (95% CI 3.34 to 12.95), four studies, N = 1415). A subgroup analysis by risk status suggested that there was a subgroup of participants who were consistently at a significant risk of death, although this was only measured in one large study. The ninety day mortality data indicated that death was more likely with LVRS irrespective of risk status identified in one large study. Improvements in lung function, quality of life and exercise capacity were more likely with LVRS than with usual follow-up. AUTHORS' CONCLUSIONS: The evidence summarised in this review is drawn from one large study, and several smaller trials. The findings from the large study indicated that in patients who survive up to three months post-surgery, there were significantly better health status and lung function outcomes in favour of surgery compared with usual medical care. Patients identified post hoc as being of high risk of death from surgery were those with particularly impaired lung function and poor diffusing capacity and/or homogenous emphysema. Further research should address the effect of this intervention on exacerbations and rate of decline in lung function and health status.

Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013.

PURPOSE: Recombinant interferon alfa-2b (rIFNalpha2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFNalpha2b, although the frequency of and the risk factors for developing this toxicity are not well described. The purpose of this study was to identify predictors for the development of severe neuropsychiatric toxicity in CML patients receiving rIFNalpha2b-based therapy. PATIENTS AND METHODS: From a prospective cohort of 91 Philadelphia chromosome-positive, previously untreated, chronic-phase CML patients treated on Cancer and Leukemia Group B (CALGB) 9013, a phase II trial of rIFNalpha2b plus cytarabine, the following were recorded at baseline: age, sex, race, pretreatment history of neurologic or psychiatric diagnosis, spleen size, blood counts, and peripheral blast count. Best response to treatment, rIFNalpha2b cumulative dose, dose duration, and dose-intensity were recorded during follow-up. Severe neuropsychiatric toxicity was defined as grade 3 or 4 events, according to CALGB expanded common toxicity criteria. Univariate and multivariate logistic regression analyses were used to identify variables that were associated with the development of severe neuropsychiatric toxicity. RESULTS: Severe neuropsychiatric toxicity developed in 22 patients (24.0%; 95% confidence interval [CI], 15.2% to 32.8%). Toxicity resolved after withdrawal of treatment in all patients. Five of six patients developed recurrence of symptoms with rechallenge. Twelve (63%) of 19 patients with a pretreatment neurologic or psychiatric diagnosis developed severe neuropsychiatric toxicity, as compared with 10 (14%) of 72 patients without a pretreatment neurologic or psychiatric diagnosis (P =.001), resulting in a relative risk of 4. 55 (95% CI, 2.33 to 8.88) for developing severe neuropsychiatric toxicity. No other variables were independently associated with the development of neuropsychiatric toxicity. CONCLUSION: CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during therapy with rIFNalpha2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFNalpha2b-based therapy.