Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-ß1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation.

The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase-4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease.

Swarm Learning for decentralized and confidential clinical machine learning.

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.

Effect of Targeting Mean Arterial Pressure During Cardiopulmonary Bypass by Monitoring Cerebral Autoregulation on Postsurgical Delirium Among Older Patients: A Nested Randomized Clinical Trial.

Importance: Delirium occurs in up to 52% of patients after cardiac surgery and may result from changes in cerebral perfusion. Using intraoperative cerebral autoregulation monitoring to individualize and optimize cerebral perfusion may be a useful strategy to reduce the incidence of delirium after cardiac surgery. Objective: To determine whether targeting mean arterial pressure during cardiopulmonary bypass (CPB) using cerebral autoregulation monitoring reduces the incidence of delirium compared with usual care. Design, Setting, and Participants: This randomized clinical trial nested within a larger trial enrolled patients older than 55 years who underwent nonemergency cardiac surgery at a single US academic medical center between October 11, 2012, and May 10, 2016, and had a high risk for neurologic complications. Patients, physicians, and outcome assessors were masked to the assigned intervention. A total of 2764 patients were screened, and 199 were eligible for analysis in this study. Intervention: In the intervention group, the patient's lower limit of cerebral autoregulation was identified during surgery before CPB. On CPB, the patient's mean arterial pressure was targeted to be greater than that patient's lower limit of autoregulation. In the control group, mean arterial pressure targets were determined according to institutional practice. Main Outcomes and Measures: The main outcome was any incidence of delirium on postoperative days 1 through 4, as adjudicated by a consensus expert panel. Results: Among the 199 participants in this study, mean (SD) age was 70.3 (7.5) years and 150 (75.4%) were male. One hundred sixty-two (81.4%) were white, 26 (13.1%) were black, and 11 (5.5%) were of other race. Of 103 patients randomized to usual care, 94 were analyzed, and of 102 patients randomized to the intervention 105 were analyzed. Excluding 5 patients with coma, delirium occurred in 48 of the 91 patients (53%) in the usual care group compared with 39 of the 103 patients (38%) in the intervention group (P = .04). The odds of delirium were reduced by 45% in patients randomized to the autoregulation group (odds ratio, 0.55; 95% CI, 0.31-0.97; P = .04). Conclusions and Relevance: The results of this study suggest that optimizing mean arterial pressure to be greater than the individual patient's lower limit of cerebral autoregulation during CPB may reduce the incidence of delirium after cardiac surgery, but further study is needed. Trial Registration: ClinicalTrials.gov identifier: NCT00981474.

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies.

The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin.

Differentiation of inflammatory macrophages from monocytes is characterized by an orderly integration of epigenetic and transcriptional regulatory mechanisms guided by lineage-determining transcription factors such as PU.1. Further activation of macrophages leads to a stimulus- or microenvironment-specific signal integration with subsequent transcriptional control established by the action of tissue- or signal-associated transcription factors. Here, we assess four histone modifications during human macrophage activation and integrate this information with the gene expression data from 28 different macrophage activation conditions in combination with GM-CSF. Bioinformatically, for inflammatory macrophages we define a unique network of transcriptional and epigenetic regulators (TRs), which was characterized by accessible promoters independent of the activation signal. In contrast to the general accessibility of promoters of TRs, mRNA expression of central TRs belonging to the TR network displayed stimulus-specific expression patterns, indicating a second level of transcriptional regulation beyond epigenetic chromatin changes. In contrast, stringent integration of epigenetic and transcriptional regulation was observed in networks of TRs established from somatic tissues and tissue macrophages. In these networks, clusters of TRs with permissive histone marks were associated with high gene expression whereas clusters with repressive chromatin marks were associated with absent gene expression. Collectively, these results support that macrophage activation during inflammation in contrast to lineage determination is mainly regulated transcriptionally by a pre-defined TR network.

High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review.

BACKGROUND: A subset of undifferentiated small round cell sarcomas (USRCSs) is currently being recognized as emerging entities with unique gene fusions: CIC-DUX4 (the area of focus in this article), BCOR-CCNB3, or CIC-FOXO4 gene fusions. CIC-DUX4 and CIC-FOXO4 fusions have been reported in soft tissue tumors, while BCOR-CCNB3 fusion with an X chromosomal inversion was described in both bone and soft tissue tumors. CIC-DUX4 fusion can either harbor t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13), while t(4;19)(q35;q13.1) is reported more commonly. CASE REPORT: The aim of this study is to share a new case report of a 36-year-old woman who had a rapidly growing mass in her right upper thigh, which was found to be an undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion was confirmed by cytogenetic testing. Combined modality treatment with surgery, radiation, and chemotherapy was used and achieved a good response. A review of the literature of the reported cases with CIC-DUX4 fusions including both t(4;19) and t(10;19) translocations revealed a total of 44 cases reported. Out of these 44 cases, 33 showed t(4;19)(q35;q13.1) translocation compared to 11 cases with t(10;19)(q26.3;q13). CONCLUSIONS: Undifferentiated small round cell sarcomas are aggressive tumors. Their treatment includes surgery, chemotherapy, and radiation. Resistance to chemotherapy is common. Lung and brain are common sites of metastasis, with associated poor prognosis. Generally, median survival is less than 2 years. Newer techniques have been developed recently which helped identify a subset of previously unclassifiable sarcomas, with promising prognostic value.

Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220.

BACKGROUND: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. METHODS: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility. RESULTS: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. CONCLUSIONS: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.

High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.

High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.

Duration and magnitude of blood pressure below cerebral autoregulation threshold during cardiopulmonary bypass is associated with major morbidity and operative mortality.

OBJECTIVES: Optimizing blood pressure using near-infrared spectroscopy monitoring has been suggested to ensure organ perfusion during cardiac surgery. Near-infrared spectroscopy is a reliable surrogate for cerebral blood flow in clinical cerebral autoregulation monitoring and might provide an earlier warning of malperfusion than indicators of cerebral ischemia. We hypothesized that blood pressure below the limits of cerebral autoregulation during cardiopulmonary bypass would be associated with major morbidity and operative mortality after cardiac surgery. METHODS: Autoregulation was monitored during cardiopulmonary bypass in 450 patients undergoing coronary artery bypass grafting and/or valve surgery. A continuous, moving Pearson's correlation coefficient was calculated between the arterial pressure and low-frequency near-infrared spectroscopy signals and displayed continuously during surgery using a laptop computer. The area under the curve of the product of the duration and magnitude of blood pressure below the limits of autoregulation was compared between patients with and without major morbidity (eg, stroke, renal failure, mechanical lung ventilation >48 hours, inotrope use >24 hours, or intra-aortic balloon pump insertion) or operative mortality. RESULTS: Of the 450 patients, 83 experienced major morbidity or operative mortality. The area under the curve of the product of the duration and magnitude of blood pressure below the limits of autoregulation was independently associated with major morbidity or operative mortality after cardiac surgery (odds ratio, 1.36; 95% confidence interval, 1.08-1.71; P = .008). CONCLUSIONS: Blood pressure management during cardiopulmonary bypass using physiologic endpoints such as cerebral autoregulation monitoring might provide a method of optimizing organ perfusion and improving patient outcomes from cardiac surgery.

Cerebral blood flow autoregulation is preserved after hypothermic circulatory arrest.

BACKGROUND: Patients undergoing aortic operations with hypothermic circulatory arrest (HCA) may require prolonged rewarming, a maneuver associated with impaired cerebral blood flow (CBF) autoregulation. The purpose of this study was to determine the effects of HCA on CBF autoregulation with a validated method based on near-infrared spectroscopy. METHODS: Regional cerebral oxygen saturation (rSco2) was monitored in 25 patients undergoing aortic reconstructive operations. HCA was used in 13 patients. Autoregulation was measured continuously during the operation by calculating the linear correlation coefficient between low-frequency changes in rSco2 and mean arterial pressure (MAP), generating the variable cerebral oximetry index (COx). When CBF autoregulation is functional, COx is near 0, because CBF and MAP are not correlated, but approaches 1 when autoregulation is impaired (ie, CBF is pressure passive). On the basis of prior studies, impaired autoregulation was defined as COx exceeding 0.3. RESULTS: COx did not differ between HCA and non-HCA groups before cardiopulmonary bypass or during the cooling phase of the operation, although the lower limit of autoregulation tended to be lower in patients before HCA (p = 0.053). During patient rewarming, COx was lower in the HCA group (p = 0.045), and abnormal COx was less frequent (31% vs 75%, p = 0.047) compared with the non-HCA group. CONCLUSIONS: During aortic reconstructive operations, CBF autoregulation is preserved during the cooling phase of the procedure in patients undergoing HCA. Perfusion maneuvers associated with HCA may be protective against impaired autoregulation during rewarming compared with the non-HCA group.

Multicenter trial of EC145 in advanced, folate-receptor positive adenocarcinoma of the lung.

BACKGROUND: EC145 is a novel folate-receptor targeted agent consisting of a folate molecule linked to a vinca alkaloid. EC20 is a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo. The objective of this study was to determine the activity of EC145 in patients with chemotherapy refractory lung adenocarcinoma, whose tumors expressed the FR as determined by EC20 imaging. METHODS: Patients with advanced adenocarcinoma of the lung, Eastern Cooperative Oncology Group performance status 0 to 2, normal organ function, those who had progressed after at least two prior cytotoxic regimens, and with EC 20 uptake in at least one index lesion were eligible. The primary objective of the study was the ability to receive four or more cycles of therapy. RESULTS: Sixty patients were screened and 43 patients were enrolled. Eleven patients (26%) received more than four cycles (95% confidence interval [CI] 14%, 41%), and one patient had partial response (response rate (RR) = 2.3%, 95% CI 0%, 12%). Patients in whom all target tumor lesions expressed FR by EC 20 scans had a trend toward superior results in terms of clinical benefit response (50% versus 14.3 %; p = 0.10) and survival (47.2 weeks versus 14.9 weeks [HR = 0.539, p = 0.101]) compared with those in whom at least one but not all target lesions were positive for FR (FR+). CONCLUSION: EC145 demonstrated clinical activity with a good toxicity profile in this population. Uniform uptake of EC20 may predict activity of EC145 and be useful for prospective selection of patients in future trials.

Baseline cardiovascular risk predicts subsequent changes in resting brain function.

BACKGROUND AND PURPOSE: The Framingham Heart Study group cardiovascular disease risk profile (FCRP) score was used to assess the relationship between baseline cardiovascular risk and subsequent changes in resting state cerebral blood flow (CBF) in cognitively normal older participants from the Baltimore Longitudinal Study of Aging. METHODS: Ninty-seven cognitively normal participants underwent annual resting-state positron emission tomography scans at baseline and over a period of up to 8 years (mean interval, 7.4 years). Images quantifying voxel-wise longitudinal rates of CBF change were calculated and used to examine the relationship between baseline FCRP score and changes over time in regional CBF. Individual components of the FCRP score (age, cholesterol, blood pressure, smoking status, and type 2 diabetes) were also correlated with changes in regional CBF to examine the independent contributions of each component to the overall pattern of change. RESULTS: Higher baseline FCRP scores were associated with accelerated longitudinal decline in CBF in orbitofrontal, medial frontal/anterior cingulate, insular, precuneus, and brain stem regions. Of the components that comprise the FCRP score, higher diastolic blood pressure and diabetes were associated independently with greater decline in the medial frontal/anterior cingulate and insular regions, respectively. CONCLUSIONS: Baseline cardiovascular risk factors are associated with greater rates of decline in resting state regional brain function. The regions showing accelerated decline participate in higher-order cognitive processes and are also vulnerable to age-related neuropathology. These results, in conjunction with other studies, encourage early treatment of cardiovascular risk factors in older individuals.

Subjective report of word-finding and memory deficits in normal aging and dementia.

OBJECTIVE: Compare subjective reports of both memory and word-finding deficits to clinical diagnosis and objective neuropsychological testing. BACKGROUND: With the increasing number of aging individuals with cognitive impairments, effective screening measures would improve the likelihood of detection. Subjective reports of symptoms are typically obtained in clinical settings, yet the validity of these reports is relatively unknown. METHODS: Clinical screening for dementia was carried out at an Alzheimer disease center. Dichotomous ratings for memory and word-finding/language problems were given by patients and neurologists. These ratings were compared with 13 neuropsychological measures of word-finding/language and episodic memory. RESULTS: Ratings of memory by both patients and neurologists correlated well with standard neuropsychological measures of memory. However, both the patients' and physicians' ratings of word-finding/language impairments had notably less of a correlation with the relevant neuropsychological measures of word-finding/language. CONCLUSION: Compared with ratings of memory, similar assessments of word-finding/language difficulties were relatively inaccurate, and thus poor predictors of impairment. It is imperative to develop effective screening methods that will help reveal cognitive impairments, as this issue will almost certainly become more pressing given the projected increase in the number of aging individuals and those with dementia.

Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-Kit-positive, extensive-stage small-cell lung cancer.

BACKGROUND: The prognosis for patients with extensive-stage small-cell lung cancer remains poor. This trial was designed to evaluate irinotecan/cisplatin plus maintenance imatinib in patients with c-Kit-positive disease (the transmembrane receptor c-Kit is the product of the c-KIT protooncogene). PATIENTS AND METHODS: Immunohistochemistry for c-Kit was performed before enrollment. Treatment consisted of irinotecan 65 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 on day 1 and every 21 days for 4 cycles. Imatinib was administered at 400 mg twice a day until progression or unacceptable toxicity occurred. RESULTS: Fourteen patients were enrolled. Slow accrual led to early study termination. Six patients did not begin treatment with imatinib because of disease progression, persistent toxicity, or referral for radiation therapy. Eight patients had a partial response with irinotecan/cisplatin and received imatinib. The median number of weeks on imatinib was 6.1 (range, 4.1-25.1 weeks). Reasons for imatinib discontinuation included disease progression (n = 7) and persistent neutropenia (n = 1). No objective responses to imatinib were evident, but 3 patients (21%) exhibited stable disease for 12, 15, and 25 weeks. The median progression-free survival was 4.3 months (95% CI, 2.9-4.8 months). The median overall survival was 7.8 months (95% CI, 5.7-10.0 months). The irinotecan/cisplatin regimen was well tolerated (grade 1/2 neutropenia, 29%; anemia, 43%; thrombocytopenia, 14%; and diarrhea, 29%), except in 1 patient with grade 3 vomiting. Imatinib toxicity included grade 1/2 nausea in 50% of the patients, peripheral edema in 75% of the patients, grade 3 fatigue in 13% of the patients, and neutropenia in 13% of the patients. CONCLUSION: Despite the selection of tumors expressing c-Kit, imatinib did not appear to delay disease progression after response to chemotherapy. However, this trial was underpowered because of its early termination. Although disease stability with imatinib was evident in 3 patients and the therapy was well tolerated, this approach does not appear to warrant further clinical study.

Incidental findings on brain magnetic resonance imaging of children with sickle cell disease.

OBJECTIVE: We describe the prevalence and range of incidental intracranial abnormalities identified through MRI of the brain in a large group of children screened for a clinical trial. METHODS: We included 953 children between 5 and 14 years of age who were screened with MRI of the brain for the Silent Infarct Transfusion Trial. All had sickle cell anemia or sickle beta-null thalassemia. MRI scans were interpreted by 3 neuroradiologists. MRI scans reported to have any abnormality were reviewed by 2 study neuroradiologists. Incidental findings were classified into 4 categories, that is, no, routine, urgent, or immediate referral recommended. Cerebral infarctions and vascular lesions were not considered incidental and were excluded. RESULTS: We identified 63 children (6.6% [95% confidence interval: 5.1%-8.4%]) with 68 incidental intracranial MRI findings. Findings were classified as urgent in 6 cases (0.6%), routine in 25 cases (2.6%), and no referral required in 32 cases (3.4%). No children required immediate referral. Two children with urgent findings underwent surgery in the subsequent 6 months. CONCLUSION: In this large cohort of children, incidental intracranial findings were identified for 6.6%, with potentially serious or urgent findings for 0.6%.

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer.

BACKGROUND: Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. METHODS: Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). RESULTS: Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 µg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 µg/ml and 0.05 +/- 0.07 µg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 µg/ml, with no correlation between salivary and plasma drug levels. CONCLUSIONS: Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.

Silent Cerebral Infarct Transfusion (SIT) trial imaging core: application of novel imaging information technology for rapid and central review of MRI of the brain.

The Silent Cerebral Infarct Multicenter Transfusion (SIT) Trial is a multi-institutional intervention trial in which children with silent cerebral infarcts are randomized to receive either blood transfusion therapy or observation (standard care) for 36 months. The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States, Canada, UK, and France. Each child undergoes a screening magnetic resonance imaging (MRI) of the brain to detect the presence of silent cerebral infarct-like lesions, a pre-randomization (baseline) MRI and exit MRI to determine if there are new or enlarged cerebral infarcts, using a designated, prospective imaging protocol. The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging. Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers. Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infarct-like lesions. Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center. The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days. This novel strategy was designed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures. The technology, process, and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements.

Phase II study of celecoxib and docetaxel in non-small cell lung cancer (NSCLC) patients with progression after platinum-based therapy.

INTRODUCTION: To evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy. METHODS: Patients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate. RESULTS: Twenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0-25%) and the 6-month survival rate was 59% (95% CI 37-80%). Median survival time was 6.9 months (95% CI, 2.8-15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15-57%) and 1% (95% CI, 0-10%), respectively. The most frequent grade > or =3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial. CONCLUSIONS: The addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel.

Phase II study of docetaxel and celecoxib, a cyclooxygenase-2 inhibitor, in elderly or poor performance status (PS2) patients with advanced non-small cell lung cancer.

INTRODUCTION: The utility of two-drug chemotherapy regimens in elderly or performance status (PS 2) patients with advanced non-small cell lung cancer (NSCLC) remains to be established. Preclinical studies suggested that celecoxib, a Cyclooxygenase-2 inhibitor, has antitumor activity in NSCLC and can enhance the activity of chemotherapy drugs. We conducted a phase II study to evaluate the efficacy of the combination of weekly docetaxel and celecoxib in advanced NSCLC patients, who were either elderly (> or =70 years) or PS2. METHODS: Patients with stage IIIB (with pleural effusion) or IV NSCLC who were > or =70 years and had a PS of 0-2 or patients of any age with a PS of 2 were included. Patients should have been off any nonsteroidal anti-inflammatory drug for 30 continuous days before study enrollment. Patients were treated with weekly docetaxel 36 mg/m i.v. on days 1, 8, 15 of a 28 day cycle and Celecoxib 400 mg po twice daily. Disease assessment was performed after every two cycles. The study design required 39 patients. RESULTS: Study was terminated after 34 patients were enrolled due to safety concerns regarding celecoxib. Thirty patients were evaluable. The response rate was 15%. The median progression free survival and median survival were 2.3 months and 5.0 months, respectively. The median survival of patients > or =70 years old with a PS of 0-1 was 8.3 months and the median survival of PS2 patients was 2.8 months. The combination was well tolerated with fatigue as the most common adverse effect. Two patients developed arterial thrombotic events. CONCLUSION: In these 'special populations' of patients with advanced NSCLC, the addition of celecoxib to docetaxel did not seem to improve the outcome compared with single agent docetaxel.