An Audio Jack-Based Electrochemical Impedance Spectroscopy Sensor for Point-of-Care Diagnostics.

Portable and easy-to-use point-of-care (POC) diagnostic devices hold high promise for dramatically improving public health and wellness. In this paper, we present a mobile health (mHealth) immunoassay platform based on audio jack embedded devices, such as smartphones and laptops, that uses electrochemical impedance spectroscopy (EIS) to detect binding of target biomolecules. Compared to other biomolecular detection tools, this platform is intended to be used as a plug-and-play peripheral that reuses existing hardware in the mobile device and does not require an external battery, thereby improving upon its convenience and portability. Experimental data using a passive circuit network to mimic an electrochemical cell demonstrate that the device performs comparably to laboratory grade instrumentation with 0.3% and 0.5° magnitude and phase error, respectively, over a 17 Hz to 17 kHz frequency range. The measured power consumption is 2.5 mW with a dynamic range of 60 dB. This platform was verified by monitoring the real-time formation of a NeutrAvidin self-assembled monolayer (SAM) on a gold electrode demonstrating the potential for POC diagnostics.

Phosphoproteomic network analysis in the sea urchin Strongylocentrotus purpuratus reveals new candidates in egg activation.

Fertilization triggers a dynamic symphony of molecular transformations induced by a rapid rise in intracellular calcium. Most prominent are surface alterations, metabolic activation, cytoskeletal reorganization, and cell-cycle reentry. While the activation process appears to be broadly evolutionarily conserved, and protein phosphorylation is known to play a key role, the signaling networks mediating the response to fertilization are not well described. To address this gap, we performed a time course phosphoproteomic analysis of egg activation in the sea urchin Strongylocentrotus purpuratus, a system that offers biochemical tractability coupled with exquisite synchronicity. By coupling large-scale phosphopeptide enrichment with unbiased quantitative MS, we identified striking changes in global phosphoprotein patterns at 2- and 5-min postfertilization as compared to unfertilized eggs. Overall, we mapped 8796 distinct phosphosite modifications on 2833 phosphoproteins, of which 15% were differentially regulated in early egg activation. Activated kinases were identified by phosphosite mapping, while enrichment analyses revealed conserved signaling cascades not previously associated with egg activation. This work represents the most comprehensive study of signaling associated with egg activation to date, suggesting novel mechanisms that can be experimentally tested and providing a valuable resource for the broader research community. All MS data have been deposited in the ProteomeXchange with identifier PXD002239 (http://proteomecentral.proteomexchange.org/dataset/PXD002239).

Clinical characteristics and early treatment outcomes of follicular lymphoma in young adults.

Follicular lymphoma (FL) in young adults (YA, <40 years old) is uncommon, and the clinical characteristics and outcomes of this group are not well defined. We conducted a retrospective database review of 427 patients with newly diagnosed FL aged 65 years or less registered at Princess Margaret Cancer Centre between 1995 and 2010. YA (n = 61) and those 40-65 (n = 366) were compared with regards to clinical stage at diagnosis, FL International Prognostic Index (FLIPI) score, and the following clinical outcomes: time to second treatment, cause-specific survival (CSS) and overall survival (OS). At diagnosis, stage and FLIPI score were similar, as were the proportion of patients requiring therapy (YA 75% versus older adults 71%). Median follow-up was 8.1 years. Time to second therapy was similar in both age groups (5-year probability 23% YA versus 27% older adults; Gray's P-value = 0.76). Ten-year OS was significantly higher for YA (87% versus older adults 72%; P = 0.029). On multivariate analysis, age <40 years, low FLIPI score and observation as initial management were favourable prognostic factors for OS and CSS. We conclude that YA with FL have a favourable prognosis compared to older patients; whether this reflects competing mortality risks or age-related differences in lymphoma biology warrants further investigation.

Nickel-catalyzed Csp2-Csp3 bond formation by carbon-fluorine activation.

We report herein a general catalytic method for Csp(2)-Csp(3) bond formation through C-F activation. The process uses an inexpensive nickel complex with either diorganozinc or alkylzinc halide reagents, including those with ß-hydrogen atoms. A variety of fluorine substitution patterns and functional groups can be readily incorporated. Sequential reactions involving different precatalysts and coupling partners permit the synthesis of densely functionalized fluorinated building blocks.

Phantom Validation of a Conservation of Activity-Based Partial Volume Correction Method for Arterial Input Function in Dynamic PET Imaging.

Dynamic PET (dPET) imaging can be utilized to perform kinetic modelling of various physiologic processes, which are exploited by the constantly expanding range of targeted radiopharmaceuticals. To date, dPET remains primarily in the research realm due to a number of technical challenges, not least of which is addressing partial volume effects (PVE) in the input function. We propose a series of equations for the correction of PVE in the input function and present the results of a validation study, based on a purpose built phantom. 18F-dPET experiments were performed using the phantom on a set of flow tubes representing large arteries, such as the aorta (1" 2.54 cm ID), down to smaller vessels, such as the iliac arteries and veins (1/4" 0.635 cm ID). When applied to the dPET experimental images, the PVE correction equations were able to successfully correct the image-derived input functions by as much as 59 ± 35% in the presence of background, which resulted in image-derived area under the curve (AUC) values within 8 ± 9% of ground truth AUC. The peak heights were similarly well corrected to within 9 ± 10% of the scaled DCE-CT curves. The same equations were then successfully applied to correct patient input functions in the aorta and internal iliac artery/vein. These straightforward algorithms can be applied to dPET images from any PET-CT scanner to restore the input function back to a more clinically representative value, without the need for high-end Time of Flight systems or Point Spread Function correction algorithms.

A unique variant of a right persistent hypoglossal artery arising from the common carotid artery with complex cardiovascular anomalies in a female neonatal patient.

Persistent primitive hypoglossal artery is a carotid-vertebrobasilar anastomosis, which commonly arises from the internal carotid artery at the level of the C (cervical) 1-3 vertebrae. We describe a unique case of a female infant patient with this anomaly that has an unusually low origin from the distal common carotid artery just below the bifurcation at the level of roughly C5 and supplies the entire vertebrobasilar system. Additional cardiovascular anatomical variations were present: Tetralogy of Fallot and a right-sided aortic arch with mirror image branching. These singular variations are rare in the general population, but even rarer when combined. Awareness of these unusual vascular variants is clinically significant, as they may predispose the patients to early ischemic injury, hemorrhage, aneurysm formation, and can be essential in surgical planning. Therefore, radiographic imaging is of importance in proper diagnosis of such variants.

Gastric duplication cyst mimicking large cystic lymphangioma in an adult: A rare case report and review of the literature.

BACKGROUND: Gastric duplication cysts (GDCs) are a relatively uncommon congenital developmental abnormality, mainly occurring in infants but very rarely in adults. Because of the variability in clinical presentation, it is often quite challenging to diagnose GDCs in adults. We are presenting a case report of an adult diagnosed operatively as having a GDC with a literature review to summarize clinical and imaging features and the treatment selections of GDCs in adults so that doctors could have a comprehensive understanding of this disease and make a precise diagnosis and a suitable therapeutic decision for patients. CASE SUMMARY: A 51-year-old man presented with recurrent epigastric pain and fullness for two years. No significant findings were noted during physical examination and routine blood tests were unremarkable. An abdominal ultrasound revealed a large cyst in the upper left abdominal quadrant. A following contrast-enhanced abdominal computed tomography (CT) scan demonstrated a hypodense cystic lesion between the spleen and stomach. The lesion had scattered calcification in the cyst wall without any significant enhancement. The lesion was initially thought to be a cystic lymphangioma. The patient underwent a surgical resection and intraoperatively it was noted that the lesion was closely adherent to the greater curvature of the stomach. Subsequently, a resection of the gastric mass along with a partial gastrectomy was performed. The patient recovered quickly with a complete symptomatic relief and did not show any further complications during the 8-month follow-up. CONCLUSION: GDCs are quite rare in adults, with a multitude of symptoms, which is quite challenging for precise diagnosis before histological examination. Some imaging techniques involving CT, magnetic resonance imaging, and endoscopic ultrasound could provide valuable morphological features for differential diagnosis.

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

Low Incidence of Esophageal Toxicity After Lung Stereotactic Body Radiation Therapy: Are Current Esophageal Dose Constraints Too Conservative?

PURPOSE: To explore and quantify the relationship between esophageal dose and toxicity in the setting of lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: This analysis was conducted on the basis of a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54 Gy/3 fractions, 48 Gy/4 fractions alternate days, or 60 Gy/8 fractions daily. Toxicity was prospectively graded using Common Terminology Criteria for Adverse Events version 3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiation therapy dose, in 2-Gy-equivalent dose, using an α/ß ratio of 3 Gy in the linear-quadratic model. RESULTS: A total of 632 patients were analyzed. The median follow-up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute grade ≥1 esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n = 21). The median (range) esophageal doses were 11.8 Gy (0.2-48.2 Gy), 10.34 Gy (0.17-44.5 Gy), and 9.63 Gy (0.08-43 Gy) for Dmax, D1cc, and D2cc, respectively. A 15% risk of esophageal toxicity was associated with a 2-Gy-equivalent dose of Dmax 141.6 Gy, D1cc 123.61 Gy, and D2cc 117.6 Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity, and the remainder had grade 2 or lower toxicity. CONCLUSIONS: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumors, may provide more accurate dose-toxicity parameters.

Outcome following radiotherapy for head and neck basal cell carcinoma with 'aggressive' features.

OBJECTIVES: The literature demonstrates that 'aggressive' head-and-neck basal cell carcinomas (HN-BCC) have a higher than expected relapse rate with unfavorable outcomes. We report outcomes following definitive (dRT) or post-operative radiotherapy (PORT) for these tumors. METHODS: We reviewed all HN-BCC patients with 'aggressive' features (primary lesions diameter >10mm, >2 recurrences, or extra-cutaneous extension), treated with megavoltage dRT or PORT between 1998 and 2013. Loco-regional control (LRC) and relapse-free survival (RFS) were estimated using the competing risk method, and overall survival (OS) by Kaplan-Meier method. Univariable analysis explored factors associated with relapse. RESULTS: A total of 108 histologically confirmed 'aggressive' HN-BCC patients were identified, including 38 (35%) presenting de novo and 70 (65%) treated for recurrence (rBCC). dRT was offered to 72 (66.7%) patients and PORT to 36 (33.3%). Median follow-up was 3.5years. Actuarial 3-year LRC, RFS, and OS were 87% (95% confidence interval: 77-92), 82% (72-89), and 87% (80-94), respectively. LRC rates for dRT and PORT were similar [hazard ratio (HR) 0.61 (0.17-2.23), p=0.46]. Factors associated with higher risk of relapse were: rBCC [HR 7.96 (1.03-61.71), p=0.047], 'H-zone' (mid face, eyes, and ears) location [HR 3.13 (1.07-9.19), p=0.04], tumor size [HR 1.32 (1.08-1.6), p=0.006], nodal involvement [HR 3.68 (1.11-12.2), p=0.03] and stage [HR 3.13 (1.19-8.26), p=0.02]. CONCLUSION: RT is an effective treatment for 'aggressive' HN-BCC when used as a definitive modality or as PORT. Non-surgical management with definitive radiotherapy provides an alternative effective option if surgery is not used.

Primary spinal epidural lymphoma: patients' profile, outcome, and prognostic factors: a multicenter Rare Cancer Network study.

PURPOSE: To assess the clinical profile, treatment outcome, and prognostic factors in primary spinal epidural lymphoma (PSEL). METHODS AND MATERIALS: Between 1982 and 2002, 52 consecutive patients with PSEL were treated in nine institutions of the Rare Cancer Network. Forty-eight patients had an Ann Arbor stage IE and four had a stage IIE. Forty-eight patients underwent decompressive laminectomy, all received radiotherapy (RT) with (n = 32) or without chemotherapy (n = 20). Median RT dose was 36 Gy (range, 6-50 Gy). RESULTS: Six (11%) patients progressed locally and 22 (42%) had a systemic relapse. At last follow-up, 28 patients were alive and 24 had died. The 5-year overall survival, disease-free survival, and local control were 69%, 57%, and 88%, respectively. In univariate analyses, favorable prognostic factors were younger age and complete neurologic response. Multivariate analysis showed that combined modality treatment, RT volume, total dose more than 36 Gy, tumor resection, and complete neurologic response were favorable prognostic factors. CONCLUSIONS: Primary spinal epidural lymphoma has distinct clinical features and outcome, with a relatively good prognosis. After therapy, local control is excellent and systemic relapse occurs in less than half the cases. Combined modality treatment appears to be superior to RT alone.

Outcome of hyperfractionated radiotherapy in chemotherapy-resistant non-Hodgkin's lymphoma.

PURPOSE: Patients with chemotherapy-resistant lymphoma have rapidly progressive disease and a poor prognosis. Local symptoms are treated with radiotherapy (RT) for local control. We have reviewed local control and toxicity in patients treated with hyperfractionated accelerated RT. METHODS AND MATERIALS: A total of 34 patients received hyperfractionated RT between 1997 and 2003. The radiation dose was 39.9-40.5 Gy in 30 fractions. The median treatment time was 22 days with twice-daily involved-field RT. The median follow-up was 4.4 years. Response was assessed <3 months after RT and was classified as a complete response, a complete response-unconfirmed, a partial response, or no response. Local control was defined as maintenance of local complete response, complete response-unconfirmed, or lack of local progression with a partial response. Recurrence or progression outside the RT volume was regarded as distant disease. RESULTS: The median age was 53 years; 20 patients were men and 14 were women. The initial diagnosis was Stage I-II in 56% and Stage III-IV in 44%. The disease bulk was > or =10 cm in 35% (n = 12). The histologic features at diagnosis were follicular in 11 (Grade 1 in 4, Grade 2 in 3, and Grade 3 in 4), diffuse large B-cell in 14, peripheral T-cell lymphoma in 2, Burkitt-like in 1, mantle cell in 2, natural killer cell in 2, plasmacytoma/lymphoma in 1, and T-cell lymphoblastic in 1. The initial treatment was chemotherapy in 32 patients (94%); 71% were refractory to initial chemotherapy and 29% developed a relapse after an initial response. The RT response was complete in 24% (n = 8), complete, unconfirmed in 26% (n = 9), partial in 47% (n = 16), and none in 3% (n = 1). The local control rate was 73% at 1, 2, and 3 years. Grade 1 dermatitis was the most common side effect. CONCLUSION: Hyperfractionated RT provided good local control and was well tolerated. This encouraging result requires additional study with comparison to conventional fractionation regimens.

Detection of Hepatitis C core antibody by dual-affinity yeast chimera and smartphone-based electrochemical sensing.

Yeast cell lines were genetically engineered to display Hepatitis C virus (HCV) core antigen linked to gold binding peptide (GBP) as a dual-affinity biobrick chimera. These multifunctional yeast cells adhere to the gold sensor surface while simultaneously acting as a "renewable" capture reagent for anti-HCV core antibody. This streamlined functionalization and detection strategy removes the need for traditional purification and immobilization techniques. With this biobrick construct, both optical and electrochemical immunoassays were developed. The optical immunoassays demonstrated detection of anti-HCV core antibody down to 12.3pM concentrations while the electrochemical assay demonstrated higher binding constants and dynamic range. The electrochemical format and a custom, low-cost smartphone-based potentiostat ($20 USD) yielded comparable results to assays performed on a state-of-the-art electrochemical workstation. We propose this combination of synthetic biology and scalable, point-of-care sensing has potential to provide low-cost, cutting edge diagnostic capability for many pathogens in a variety of settings.

Phase II Study of Concurrent Pemetrexed, Cisplatin, and Radiation Therapy for Stage IIIA/B Unresectable Non-Small Cell Lung Cancer.

INTRODUCTION: Concurrent thoracic radiation and platinum-based chemotherapy is the standard of care for treatment of unresectable stage IIIA-IIIB non-small-cell lung cancer (NSCLC), but the optimal drug regimen has not been established. PATIENTS AND METHODS: In the present single-arm phase II trial, patients with previously untreated, unresectable stage IIIA-IIIB NSCLC (all histologic types) were treated with pemetrexed-cisplatin (500 mg/m(2) intravenously on days 1 and 22, 20 mg/m(2) intravenously on days 1-5 and days 22-26) concurrent with radiotherapy (61-66 Gy in 31-35 fractions), followed by 2 cycles of consolidation pemetrexed-cisplatin (75 mg(2)) therapy. The primary endpoint was the 1-year overall survival (OS) rate. The study treatment was considered active if the 1-year OS rate was ≥ 70%. RESULTS: A total of 39 patients, including 6 from the previous phase I trial who had been treated at the recommended phase II dose, were eligible for analysis. The most common drug-related grade 3 to 4 adverse events during the concurrent phase were hematologic and 5.1% of patients experienced grade 3 esophagitis. The response rate was 45.9% (17 of 37 patients), with no complete responses. The 1-, 2-, and 3-year OS survival rates were 79.5%, 56.4%, and 46.2%, respectively. The median OS, time to progressive disease, and progression-free survival was 30.3, 13.7, and 11.8 months, respectively. CONCLUSION: Full-dose cisplatin and pemetrexed can be administered concurrently with conventional doses of thoracic radiation. The median and 1-year OS rates were favorable compared with published clinical trials in this setting. The regimen was tolerable, and the toxicity profile was consistent with the known toxicity profiles of pemetrexed, cisplatin, and radiation.

A single institution experience of extranodal natural killer/T cell lymphoma of nasal type.

Extranodal natural killer/T cell lymphoma (ENKTL) nasal type is a rare form of non-Hodgkin lymphoma that is more commonly seen in Asia and Latin America than in North America or Europe. The purpose of this study was to determine the treatment outcomes with a combined modality approach and whether treatment outcomes varied according to ethnicity in patients with ENKTL, nasal type in Toronto, Canada. Patients presenting with ENKTL, nasal type, between 1994 and 2011 were retrospectively reviewed. Patient characteristics, including the patient's ethnic origin, treatment details and outcomes were recorded and analyzed for significant differences between Asian and Caucasian patients. A total of 34 patients were identified: 16 Asian, 16 Caucasian, one Aboriginal and one Hispanic. All patients had nasal cavity involvement. The majority had localized disease: stage I (n = 22), stage II (n = 6); and stage IV in six patients. Combined radiotherapy (RT) and chemotherapy was intended for 32 of the 34 patients, with two receiving RT alone. Median RT dose was 45 Gy (range: 35-50.4 Gy). Response to initial treatment was observed in 44% of patients. Two-year disease-free survival was 17.8% (Asian patients: 18.8%, Caucasians: 20%, p = 0.82), and overall survival 39.2% (Asian patients: 30%, Caucasians: 42%, p = 0.52). There were no significant differences in clinical outcomes in terms of patient ethnicity. A combined modality approach (with cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] chemotherapy administered initially) is of limited effectiveness. We have now adopted the use of RT as the initial treatment approach, followed by multiagent chemotherapy.

Classification and Reporting of Late Radiographic Changes After Lung Stereotactic Body Radiotherapy: Proposing a New System.

UNLABELLED: Radiation-induced parenchymal lung changes after stereotactic body radiotherapy are common, and can obscure the primary tumor site. In this study we propose a structured radiographic reporting tool for characterization of these changes, pilot its feasibility in a group of radiation oncologists, and test the interrater agreement. We could demonstrate the applicability of the scale, with a fair to moderate agreement. BACKGROUND: The purpose of the study was to design and pilot a synoptic scale for characterization of late radiographic changes after lung stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: A participatory design process involving 6 radiation oncologists and 2 thoracic radiologists was used in the scale's design. Seventy-seven early-stage non-small-cell lung cancer patients who were treated with SBRT were included, and after treatment their serial computed tomography (CT) images were scored by 6 radiation oncologists. Gwet's First-order Agreement Coefficient (AC1) and a leave-one-out (LOO) analysis was used to assess interrater reliability and variability among raters, respectively. RESULTS: The scale reports on 5 independent categories including "tumor in primary site," "tumor in involved lobe," "consolidation," "volume loss," and "ground-glass or interstitial changes." At each time point, each category is reported as "increased," "stable," "decreased," "obscured," or "not present," compared with the previous. The total number of rated images for the pilot ranged from 450 at 6 months to 84 at 48 months. The primary tumor site was scored as obscured in 38% to 40% of ratings from 12 months onward; 3% to 5% of primary tumors were scored as "increased." Consolidation, volume loss, and ground-glass or interstitial changes were increasingly marked as "stable" with time. At 24 months, AC1 was 0.28 (LOO, 0.22-0.42), 0.47 (LOO, 0.39-0.72), 0.45 (LOO, 0.42-0.50), 0.21 (LOO, 0.15-0.26), and 0.25 (LOO, 0.20-0.38) for the 5 categories listed, respectively. CONCLUSION: In a population of clinicians, this scale could be implemented to characterize evolving lung changes after SBRT, and had fair to moderate interrater agreement. Obscured tumor site is a common challenge of follow-up CT imaging, and new imaging techniques should be explored. This scale provides a tool for communicating changes after SBRT.

Impact of chest wall and lung invasion on outcome of stage I-II Hodgkin's lymphoma after combined modality therapy.

PURPOSE: To examine the impact of extranodal chest wall and lung invasion on the prognosis of patients with clinical Stage I-II Hodgkin's lymphoma treated with combined modality therapy. MATERIALS AND METHODS: The outcome of 324 patients with clinical Stage I-II Hodgkin's lymphoma treated with combined modality therapy between 1981 and 1996 was analyzed. Twenty-two patients had chest wall invasion and 40 had invasion of lung parenchyma. The chemotherapy regimens used were ABVD in 182 patients (56%), MOPP/ABV(D) in 45 (14%), MOPP in 86 (27%), and other chemotherapy regimens in 11 patients (3%). This was followed by mantle/mediastinal radiotherapy (RT) in 163 patients (50%), extended-field RT in 135 patients (42%), and infradiaphragmatic RT in 26 patients (8%). The impact of chest wall and lung invasion on local relapse, disease-free survival, cause-specific survival, and overall survival was examined. RESULTS: After a median follow-up of 8.3 years, the 5-year cause-specific and overall survival rate of the entire cohort was 93% and 90%, respectively. Compared with patients with no extranodal involvement, patients with chest wall invasion had significantly worse local control (89% vs. 68%, p = 0.005), disease-free survival (84% vs. 59%, p = 0.016), and cause-specific survival (94% vs. 86%, p = 0.009). Overall survival was also worse among patients with chest wall invasion, but not significantly so (90% vs. 82%, p = 0.10). Among the 16 patients with chest wall invasion but without lung invasion, 7 progressed during treatment or relapsed, 6 with local failure (crude relapse rate 44%, 95% confidence interval [CI] 19-68%), and 5 died (crude death rate 31%, 95% CI 9-54%). After adjusting for other significant prognostic factors, patients with chest wall invasion had significantly worse local control (hazard ratio 2.8, 95% CI 1.2-6.3), disease-free survival (hazard ratio 2.3, 95% CI 1.1-4.8), and cause-specific survival (hazard ratio 2.8, 95% CI 1.1-6.8). Lung invasion was not significantly associated with any of the outcomes assessed. CONCLUSIONS: Chest wall invasion is an adverse prognostic factor among clinical Stage I-II Hodgkin's lymphoma patients treated with combined modality therapy, although we did not find a worse outcome for patients with lung invasion. Efforts to reduce treatment intensity in these patients should be undertaken with caution, recognizing their increased risk of local relapse.

Nickel-catalyzed selective defluorination to generate partially fluorinated biaryls.

A Ni-catalyzed, chemoselective cross-coupling reaction of polyfluoroarenes under mild reaction conditions is reported. A variety of fluorine-containing biaryls are synthesized in good-to-excellent yields. A wide range of substitution patterns and functional groups are tolerated.

The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development.

Normophosphatemic familial tumoral calcinosis (NFTC) is caused by mutations in the SAMD9 gene. This gene is absent in mouse, while there is a murine paralog, Samd9-like (Samd9L). To clarify the relationships between SAMD9 and SAMD9L, we investigated the transcriptional regulation and expression pattern of mouse Samd9L. An ∼1.5-kb mouse Samd9L promoter fragment was cloned, and a series of 5' deletion constructs were linked to a luciferase reporter gene. All constructs showed significant activity in transfected epithelial cells and mouse fibroblasts, and the presence of regulatory cis-elements as close as 87 bp upstream of the transcription start site was identified. Ras-responsive element binding protein 1 (Rreb-1) was identified in this region by protein-DNA binding array. The expression of Samd9L was upregulated by calcitonin, and this was preceded by a significant increase in the expression of Rreb-1 mRNA. Quantitative real-time PCR analysis of Samd9L revealed near-ubiquitous expression, with the highest level in the kidney. Tissue-specific expression was also confirmed both by in situ ß-gal staining and quantitative enzymatic activity assay in a transgenic Samd9L(+/-) mouse in which the LacZ gene replaced exon 2 in the Samd9L gene. These findings assist in understanding the regulation of Samd9L in the context of its paralogous gene, SAMD9, which harbors mutations in NFTC.

Phase I trial of radiation with concurrent and consolidation pemetrexed and cisplatin in patients with unresectable stage IIIA/B non-small-cell lung cancer.

PURPOSE: To evaluate the feasibility and safety of concurrent pemetrexed/cisplatin/thoracic radiotherapy followed by consolidation pemetrexed/cisplatin for unresectable Stage IIIA/B non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligible patients with <5% weight loss and good performance status received two cycles of pemetrexed (300, 400, or 500 mg/m(2) on Days 1 and 22 for Dose Levels 1, 2, and 3/4, respectively) and cisplatin (25 mg/m(2) Days 1-3 for Dose Levels 1-3; 20 mg/m(2) Days 1-5 for Dose Level 4) concurrent with thoracic radiation (61-66 Gy in 31-35 fractions). Consolidation consisted of two cycles of pemetrexed/cisplatin (500 mg/m(2), 75 mg/m(2)) 21 days apart, after concurrent therapy. RESULTS: Between January 2006 and October 2007, 16 patients entered the study. Median follow-up was 17.2 months. No dose-limiting toxicities were observed. Median radiation dose was 64 Gy (range, 45-66 Gy). Rates of significant Grade 3/4 hematologic toxicity were 38% and 7%, respectively. One patient experienced Grade 3 acute esophagitis, and 2 experienced late (Grade 3) esophageal stricture, successfully managed with dilation. One patient experienced Grade 3 pneumonitis. The overall response rate was 88%. One-year overall survival was 81%. CONCLUSIONS: Full systemic dose pemetrexed seems to be safe with full-dose cisplatin and thoracic radiation in Stage IIIA/B NSCLC. Pemetrexed is the first third-generation cytotoxic agent tolerable at full dose in this setting. A Phase II study evaluating Dose Level 4 is ongoing.