Disrupted Neural Synchrony Mediates the Relationship between White Matter Integrity and Cognitive Performance in Older Adults.

Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. Electroencephalography was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value. Specifically, better preservation of the inferior fronto-occipital fasciculus in older individuals drives faster task-related modulations of alpha and gamma long-range phase-locking value between the inferior frontal gyrus and occipital lobe and lower local phase-amplitude coupling in occipital lobes, which in turn drives better cognitive control performance. Our results help delineate the role of individual variability of white matter microstructure in dynamic synchrony and cognitive performance during normal aging.

American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.

BACKGROUND: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. METHODS: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. RESULTS: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings. CONCLUSIONS: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sß0 (HbSß0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSß0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Autologous and Allogeneic Skin Cell Grafts in the Treatment of Severely Burned Patients: Retrospective Clinical Study.

BACKGROUND: Transplantation of skin cells (keratinocytes and fibroblasts) cultured in vitro is a method of choice for the treatment of severe and extensive burns in patients with a deficit of donor sites for free split-thickness skin grafts, and when the grave medical condition of the patient excludes the possibility of an operation under general anesthetic. Appropriate amounts of keratinocytes and/or fibroblasts cultured in vitro are grafted as a suspension in platelet-leukocyte-rich gel directly on the prepared acceptor site. Approximately 3 weeks are needed for autologous cell culture to grow. Allogeneic cells are obtained from patients who died before their own autologous cell transplantation. Therefore allogeneic cells are considered as ready to use product. The aim of the study was to evaluate the efficiency of in vitro cultured autologous/allogeneic skin cell grafts in the treatment of burns. MATERIALS AND METHODS: In this study a group of 68 patients hospitalized in the Dr Stanislaw Sakiel Centre for Burn Treatment in Siemianowice Slaskie and treated with in vitro cultured skin cells suspended in platelet-leukocyte-rich gel were analyzed. RESULTS: Autologous/allogeneic keratinocytes and fibroblasts transplantation hastens wound closure. CONCLUSION: A major factor in burn treatment is early application of skin cells, so allogeneic cells are more appropriate, because these cells are an on-shelf product. It is especially important in groups of patients with third-degree burn greater than 40%. Allogeneic cells application does not increase hospitalization length in comparison to autologous cells, meaning usage of allogeneic cells in burns treatment is as efficient as autologous cells.

Experience in Using Fetal Membranes: The Present and New Perspectives.

INTRODUCTION: The placenta is an accessible source of tissues for transplantation. Placental transplants have been used in wound treatment because of the basic function of the placenta and its nutritious properties and structure. PATIENTS AND METHODS: The aim of this work is to present the clinical usage of fetal membranes, including human amnion, on the basis of the burn treatment center's experience. The clinical use of amnion and different types of placental transplants are described. The initial results of research work within the MEDPIG project are presented regarding the application of placenta from transgenic pigs as a source of tissues for transplantation. RESULTS: From August 2011 to March 2017, 252,592 cm2 of biostatic human amnion transplants were prepared in our tissue bank. During this period they were transplanted to 528 patients, including 10 patients with Lyell syndrome. Initial studies were conducted in which placentas were collected from 5 transgenic pigs and 27,426 cm2 of amniotic grafts were prepared from them. DISCUSSION: The authors' own experience as well as the literature confirm the extraordinary efficiency of transplants prepared from placental tissues, especially from the amniotic membrane. CONCLUSIONS: The clinical effects confirm the effectiveness of using human amnion in wound treatment. Amniotic transplant is a new treatment standard in toxic epidermal necrolysis TEN (Lyell's syndrome), which has found confirmation in very good clinical outcomes. The collected placentas from transgenic animals enabled the preparation of significantly more grafts than in the case of human material, which is a great advantage of this source of placenta over human tissues.

Infections in the tissue material and their impact on the loss of transplants in the Laboratory of in vitro Cell and Tissue Culture with Tissue Bank in the years 2011-2015.

Radiation sterilization eliminates microbiological infections but causes the degradation of the cell factor. The negative result of microbiological examination for tissue transplants is one of the conditions for approval for distribution in patients. The study attempts to verify impact of the presence of microbes onto material for transplant loss. In the 2011-2015 period, we analyzed 293 donors of skin and amnion. Microbiological sampling was performed. The total of 21 strains of bacteria, molds and fungi was identified in collected tissue. The widest spectrum of strains was found in skin (17), followed by amnia (8). The total number of positive findings was 147 and was again highest in skin (129), while the number of positive findings in amnia was 18 only. The general percentage of fungal infections was very low. The presence of fungal strains was only observed in allogeneic skin (2%). Large number of microorganisms isolated from the skin before sterilization was observed, so it seems impossible to use allogeneic intravital skin. However, the intravital application of allogeneic amnion obtained from cesarean section remains to be considered.

Lithographically fabricated silicon microreactor for in situ characterization of heterogeneous catalysts­Enabling correlative characterization techniques.

We report on a new modular setup on a silicon-based microreactor designed for correlative spectroscopic, scattering, and analytic on-line gas investigations for in situ studies of heterogeneous catalysts. The silicon microreactor allows a combination of synchrotron radiation based techniques (e.g., X-ray diffraction and X-ray absorption spectroscopy) as well as infrared thermography and Raman spectroscopy. Catalytic performance can be determined simultaneously by on-line product analysis using mass spectrometry. We present the design of the reactor, the experimental setup, and as a first example for an in situ study, the catalytic partial oxidation of methane showing the applicability of this reactor for in situ studies.

FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet.

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

Association of hearing impairment with brain volume changes in older adults.

Hearing impairment in older adults is independently associated in longitudinal studies with accelerated cognitive decline and incident dementia, and in cross-sectional studies, with reduced volumes in the auditory cortex. Whether peripheral hearing impairment is associated with accelerated rates of brain atrophy is unclear. We analyzed brain volume measurements from magnetic resonance brain scans of individuals with normal hearing versus hearing impairment (speech-frequency pure tone average>25 dB) followed in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging for a mean of 6.4 years after the baseline scan (n=126, age 56-86 years). Brain volume measurements were performed with semi-automated region-of-interest (ROI) algorithms, and brain volume trajectories were analyzed with mixed-effect regression models adjusted for demographic and cardiovascular factors. We found that individuals with hearing impairment (n=51) compared to those with normal hearing (n=75) had accelerated volume declines in whole brain and regional volumes in the right temporal lobe (superior, middle, and inferior temporal gyri, parahippocampus, p<.05). These results were robust to adjustment for multiple confounders and were consistent with voxel-based analyses, which also implicated right greater than left temporal regions. These findings demonstrate that peripheral hearing impairment is independently associated with accelerated brain atrophy in whole brain and regional volumes concentrated in the right temporal lobe. Further studies investigating the mechanistic basis of the observed associations are needed.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB.

OBJECTIVE: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia. METHOD: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. RESULTS: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. CONCLUSIONS: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Stability Of Default-Mode Network Activity In The Aging Brain.

Activity attributed to the default-mode occurs during the resting state and is thought to represent self-referential and other intrinsic processes. Although activity in default-associated regions changes across the lifespan, little is known about the stability of default-mode activity in the healthy aging brain. We investigated changes in rest-specific activity across an 8 year period in older participants in the Baltimore Longitudinal Study of Aging (BLSA) neuroimaging study. Comparison of resting-state and recognition memory PET regional cerebral blood flow conditions from baseline and 8-year follow-up shows relative stability of rest-specific activity over time in medial frontal/anterior cingulate, hippocampal and posterior cingulate regions commonly associated with the default-mode. In contrast, prefrontal, parahippocampal and occipital cortical regions, which are not typically associated with default-mode activity, show changes over time Overall, activity in the major components of the default-mode network remains stable in healthy older individuals, a finding which may assist in identifying factors that discriminate between normal and pathological aging.

Longitudinal pattern of regional brain volume change differentiates normal aging from MCI.

BACKGROUND: Neuroimaging measures have potential as surrogate markers of disease through identification of consistent features that occur prior to clinical symptoms. Despite numerous investigations, especially in relation to the transition to clinical impairment, the regional pattern of brain changes in clinically normal older adults has not been established. We predict that the regions that show early pathologic changes in association with Alzheimer disease will show accelerated volume loss in mild cognitive impairment (MCI) compared to normal aging. METHODS: Through the Baltimore Longitudinal Study of Aging, we prospectively evaluated 138 nondemented individuals (age 64-86 years) annually for up to 10 consecutive years. Eighteen participants were diagnosed with MCI over the course of the study. Mixed-effects regression was used to compare regional brain volume trajectories of clinically normal individuals to those with MCI based on a total of 1,017 observations. RESULTS: All investigated volumes declined with normal aging (p < 0.05). Accelerated change with age was observed for ventricular CSF (vCSF), frontal gray matter, superior, middle, and medial frontal, and superior parietal regions (p < or = 0.04). The MCI group showed accelerated changes compared to normal controls in whole brain volume, vCSF, temporal gray matter, and orbitofrontal and temporal association cortices, including the hippocampus (p < or = 0.04). CONCLUSION: Although age-related regional volume loss is apparent and widespread in nondemented individuals, mild cognitive impairment is associated with a unique pattern of structural vulnerability reflected in differential volume loss in specific regions. Early identification of patterns of abnormality is of fundamental importance for detecting disease onset and tracking progression.

II. Temporal patterns of longitudinal change in aging brain function.

Time-dependent changes in brain activity were assessed in a group of older adults who maintained good physical and cognitive health at years 1, 3, 5, 7, and 9 of the Baltimore Longitudinal Study of Aging neuroimaging study. Each year, these participants underwent PET scans during rest and delayed verbal and figural recognition memory conditions. While memory performance remained stable over the 8 years, both generalized and modality-specific patterns of time-dependent changes in regional cerebral blood flow (rCBF) were found. Many brain regions showed steady, progressive changes in rCBF over the 8 years while others maintained rCBF for a number of years before showing incremental declines or increases in activity. These temporal patterns of change were observed in many regions of the brain, particularly in the frontal and temporal lobes, suggesting that there are distinctive patterns of age-related functional decline and compensatory activity over time. The precise patterns of regional involvement and the temporal dynamics of rCBF change within specific regions vary based on cognitive processing demands.

I. Longitudinal changes in aging brain function.

Changes in brain activity over time were evaluated in a group of older adults in the Baltimore Longitudinal Study of Aging who maintained good physical and cognitive health. Participants underwent PET scans during rest and delayed verbal and figural recognition memory performance at year 1 baseline and at year 9. While memory performance remained stable over the 8 years, longitudinal changes in regional cerebral blood flow were observed within each scan condition. Further analyses revealed distinctive patterns of change related specifically to verbal or figural recognition, as well as longitudinal changes common to all scan conditions. These findings demonstrate that the older brain undergoes functional reorganization with increasing age in healthy, cognitively stable individuals. In view of the stable memory performance, the task-dependent results suggest that age-related changes in brain activity help maintain cognitive function with advancing age.

Serum uric acid and brain ischemia in normal elderly adults.

BACKGROUND: Uric acid (UA) has antioxidant properties yet when elevated is associated with vascular disease and stroke. Further, even high normal UA is associated with increased risk of mild cognitive dysfunction in elderly adults. METHOD: In this cross-sectional, observational study, we examined the relationship between serum UA and aggregate volume of white matter hyperintense (WMH) signals observed on proton density and T2-weighted brain MR images in a community sample of 177 adults ages 20 to 92. Using logistic regression, we tested whether participants with UA concentrations in the highest quartile of the sample--but still normal--would have increased WMH volumes. RESULTS: Compared with those with low to moderate levels, participants with high normal serum UA were more likely to fall in the highest quartile of WMH volume. The odds ratios (95% CIs) of increased WMH were 2.6 (1.2 to 5.4) for total, 2.5 (1.2 to 5.1) for periventricular, and 2.8 (1.4 to 5.9) for subcortical WMH volume. After controlling for age, sex, race, education, body mass, hypertension, and diabetes, the multivariate-adjusted odds of large total and subcortical WMH volumes remained elevated. Finally, high normal UA increased the odds of having excessive ischemic burden four- to fivefold in adults ages 60 and older. CONCLUSIONS: These findings demonstrate that mildly elevated serum uric acid is associated with increased burden of cerebral ischemic pathology, particularly in older adults. We outline the potential pathogenesis of this association. A clinical trial of antihyperuricemic medication to treat or prevent chronic brain ischemia might be warranted.

Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study.

BACKGROUND: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1-4) every 21 days for up to six courses. RESULTS: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths. CONCLUSIONS: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

Brain activation during encoding and recognition of verbal and figural information in older adults.

Positron emission tomography (PET) patterns of cerebral blood flow associated with verbal and figural memory are described in relation to their value as functional probes for studying longitudinal changes that occur in the aging brain. Relative to a matching control task, verbal and figural encoding increase blood flow in prefrontal cortex (PFC), anterior cingulate, insular, lateral and medial temporal, occipital cortex and the cerebellum. Additionally, medial temporal regions exhibited greater activity during figural encoding relative to verbal encoding. During recognition, blood flow increases in prefrontal, cingulate, insular, and lateral temporal and Broca's areas. Analysis of hemispheric asymmetry reveals that the prefrontal cortex exhibits regionally dependent results. Prefrontal region BA 10 demonstrates more bilateral activation during encoding and retrieval, whereas BA 46 shows right greater than left activation during both encoding and retrieval. Overall, the two tasks activate diverse regions within the frontal, temporal and occipital lobes of the brain, including areas that show age-related structural changes, proving their usefulness in the longitudinal assessment of brain function in the elderly.

Autoimmunity to the M(r) 32,000 subunit of replication protein A in breast cancer.

PURPOSE: We sought to identify autoantigens recognized by antibodies in breast cancer patient sera with potential diagnostic or prognostic significance. EXPERIMENTAL DESIGN: Serum from a female breast cancer patient exhibiting a high titer antinuclear antibody was used to screen a HeLa cDNA expression library, leading to the cloning of a cDNA for the M(r) 32,000 subunit of replication protein A (RPA32). RPA32 expression and localization were assayed in autologous tumor by monoclonal antibody staining. A specific ELISA using recombinant protein was used to screen sera from 801 breast cancer patients and 65 controls. RESULTS: A relationship between anti-replication protein A (RPA) antibodies and the ductal breast carcinoma of the proband was suggested by overexpression and aberrant localization of RPA32 in tumor cells as compared with surrounding normal ductal tissue and by the presence of anti-RPA32 antibodies before the diagnosis. The prevalence of anti-RPA32 antibodies was significantly higher (P < 0.01) among breast cancer patients (87 of 801 patients) than among noncancer controls (0 of 65 controls). Similarly, anti-RPA32 antibodies were present in 4 of 39 patients with intraductal in situ carcinoma. No associations were found between anti-RPA antibodies and survival, occurrence of a second tumor, metastases, or antibodies to p53. Reactivity to RPA32 also was detected in sera from 3 of 47 patients with other cancers. CONCLUSIONS: In view of the central role of RPA in DNA replication, recombination, and repair, we suggest that autoimmunity to RPA32 may reflect molecular changes involved in the process of tumorigenesis. The finding of antibodies to RPA32 before diagnosis and their prevalence in in situ carcinoma suggest that they are potentially useful markers of early disease.

Inverse T(2) contrast at 1.5 Tesla between gray matter and white matter in the occipital lobe of normal adult human brain.

T(2) of cortical gray matter is generally assumed to be longer than that of white matter. It is shown here that this is not the case in the occipital lobe, but that this effect is often obscured at lower resolution and concealed in standard T(2)-weighted images. Using a high-resolution (1 x 1.3 x 2 mm(3)) segmented EPI Carr-Purcell-Meiboom-Gill sequence, T(2) relaxation times of the brain were measured at 1.5 T for eight healthy adult volunteers. The average T(2) values of cortical gray and white matter were found to be 88 +/- 2 and 84 +/- 3 msec in the frontal lobe, 84 +/- 2 and 83 +/- 3 msec in the parietal lobe, and 79 +/- 1 and 87 +/- 3 msec in the occipital lobe, respectively. This unexpected occipital T(2) contrast between gray and white matter is attributed to regional differences in iron concentration.

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer.

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1; vincristine 1 mg/m2 on day 8; and ifosfamide 1.2 gm/m2 on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.

Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160).

OBJECTIVE: The rate of complete resection (50%) and the 5-year survival (30%) for non-small cell lung carcinomas of the superior sulcus have not changed for 40 years. Recently, combined modality therapy has improved outcome in other subsets of locally advanced non-small cell lung carcinoma. This trial tested the feasibility of induction chemoradiation and surgical resection in non-small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival. METHODS: Patients with mediastinoscopy-negative T3-4 N0-1 superior sulcus non-small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation. Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later. All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis. RESULTS: From April 1995 to September 1999, 111 eligible patients (77 men, 34 women) were entered in the study, including 80 (72.1%) with T3 and 31 with T4 tumors. Induction therapy was completed as planned in 102 (92%) patients. There were 3 treatment-related deaths (2.7%). Cytopenia was the main grade 3 to 4 toxicity. Of 95 patients eligible for surgery, 83 underwent thoracotomy, 2 (2.4%) died postoperatively, and 76 (92%) had a complete resection. Fifty-four (65%) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease. The 2-year survival was 55% for all eligible patients and 70% for patients who had a complete resection. To date, survival is not significantly influenced by patient sex, T status, or pathologic response. CONCLUSIONS: (1) This combined modality treatment is feasible in a multi-institutional setting; (2) the pathologic complete response rates were high; and (3) resectability and overall survival were improved compared with historical experience, especially for T4 tumors, which usually have a grim prognosis.