Science.gov

Sample records for alk positive patients

  1. Anti-ALK Antibodies in Patients with ALK-Positive Malignancies Not Expressing NPM-ALK

    PubMed Central

    Damm-Welk, Christine; Siddiqi, Faraz; Fischer, Matthias; Hero, Barbara; Narayanan, Vignesh; Camidge, David Ross; Harris, Michael; Burke, Amos; Lehrnbecher, Thomas; Pulford, Karen; Oschlies, Ilske; Siebert, Reiner; Turner, Suzanne; Woessmann, Wilhelm

    2016-01-01

    Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK-negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK. PMID:27471553

  2. Effectiveness of crizotinib in a patient with ALK IHC-positive/FISH-negative metastatic lung adenocarcinoma.

    PubMed

    Rosoux, A; Pauwels, P; Duplaquet, F; D'Haene, N; Weynand, B; Delos, M; Menon, R; Heukamp, L C; Thunnissen, E; Ocak, S

    2016-08-01

    We report a case of crizotinib effectiveness in a heavily pretreated patient with a metastatic NSCLC initially considered IHC-positive and FISH-negative for ALK rearrangement. After repeated analyses of tumor samples, borderline ALK FISH-positivity (18.5% positive cells) was demonstrated. PMID:27393517

  3. Total Body Metabolic Tumor Response in ALK Positive Non-Small Cell Lung Cancer Patients Treated with ALK Inhibition

    PubMed Central

    Koole, Michel J. B.; Bongaerts, Alphons H. H.; Pruim, Jan; Groen, Harry J. M.

    2016-01-01

    Background In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and survival. CT measurement of the tumor may insufficiently reflect the actual tumor load changes during targeted therapy with crizotinib. We explored whether 18F-FDG PET measured metabolic changes are different from CT based changes and studied the impact of these changes on disease progression. Methods 18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed according to the 1999 EORTC recommendations and PERCIST criteria. Agreement was assessed using McNemars test. During follow-up, patients received additional PET/CT during crizotinib treatment and second generation ALK inhibition. We assessed whether PET was able to detect progression earlier then CT. Results In this exploratory study 15 patients were analyzed who were treated with crizotinib. There was a good agreement in the applicability of CT and 18F-FDG PET/CT using the EORTC recommendations. During first line crizotinib and subsequent second line ALK inhibitors, PET was able to detect progression earlier then CT in 10/22 (45%) events of progression and in the others disease progression was detected simultaneously. Conclusion In advanced ALK positive NSCLC PET was able to detect progressive disease earlier than with CT in nearly half of the assessments while both imaging tests performed similar in the others. PMID:27137772

  4. Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer.

    PubMed

    Landi, Lorenza; Cappuzzo, Federico

    2016-02-01

    Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting. PMID:26582431

  5. A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib.

    PubMed

    Kodityal, Sandeep; Elvin, Julia A; Squillace, Rachel; Agarwal, Nikita; Miller, Vincent A; Ali, Siraj M; Klempner, Samuel J; Ou, Sai-Hong Ignatius

    2016-02-01

    The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib. PMID:26775591

  6. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

    PubMed Central

    Melosky, B.; Agulnik, J.; Albadine, R.; Banerji, S.; Bebb, D.G.; Bethune, D.; Blais, N.; Butts, C.; Cheema, P.; Cheung, P.; Cohen, V.; Deschenes, J.; Ionescu, D.N.; Juergens, R.; Kamel-Reid, S.; Laurie, S.A.; Liu, G.; Morzycki, W.; Tsao, M.S.; Xu, Z.; Hirsh, V.

    2016-01-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  7. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

    PubMed

    Melosky, B; Agulnik, J; Albadine, R; Banerji, S; Bebb, D G; Bethune, D; Blais, N; Butts, C; Cheema, P; Cheung, P; Cohen, V; Deschenes, J; Ionescu, D N; Juergens, R; Kamel-Reid, S; Laurie, S A; Liu, G; Morzycki, W; Tsao, M S; Xu, Z; Hirsh, V

    2016-06-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  8. Rationale for co-targeting IGF-1R and ALK in ALK fusion positive lung cancer

    PubMed Central

    Lovly, Christine M.; McDonald, Nerina T.; Chen, Heidi; Ortiz-Cuaran, Sandra; Heukamp, Lukas C.; Yan, Yingjun; Florin, Alexandra; Ozretić, Luka; Lim, Diana; Wang, Lu; Chen, Zhao; Chen, Xi; Lu, Pengcheng; Paik, Paul K.; Shen, Ronglai; Jin, Hailing; Buettner, Reinhard; Ansén, Sascha; Perner, Sven; Brockmann, Michael; Bos, Marc; Wolf, Jürgen; Gardizi, Masyar; Wright, Gavin M.; Solomon, Benjamin; Russell, Prudence A.; Rogers, Toni-Maree; Suehara, Yoshiyuki; Red-Brewer, Monica; Tieu, Rudy; de Stanchina, Elisa; Wang, Qingguo; Zhao, Zhongming; Johnson, David H.; Horn, Leora; Wong, Kwok-Kin; Thomas, Roman K.; Ladanyi, Marc; Pao, William

    2014-01-01

    The ALK tyrosine kinase inhibitor (TKI), crizotinib, shows significant activity in patients whose lung cancers harbor ALK fusions but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the intriguing clinical observation of a patient with ALK fusion+ lung cancer who had an ‘exceptional response’ to an IGF-1R antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor, IRS-1, and IRS-1 knockdown enhances the anti-tumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK/IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, IGF-1R/IRS-1 levels are increased in biopsy samples from patients progressing on crizotinib therapy. Collectively, these data support a role for the IGF-1R/IRS-1 pathway in both ALK TKI-sensitive and TKI-resistant states and provide biological rationale for further clinical development of dual ALK/IGF-1R inhibitors. PMID:25173427

  9. Alectinib for choroidal metastasis in a patient with crizotinib-resistant ALK rearranged positive non-small cell lung cancer.

    PubMed

    Okuma, Yusuke; Tanaka, Yuichiro; Kamei, Tina; Hosomi, Yukio; Okamura, Tatsuru

    2015-01-01

    Choroidal metastasis is rare in cancer patients. Small molecules of molecular targeted agents for lung cancer with actionable mutations were reported to be palliated for symptoms caused by choroidal metastasis. Visual disturbance by choroidal metastasis significantly decreases quality of life during the patient's remaining lifespan; therefore, radiotherapy or laser photocoagulation is proposed with consensus. However, improvement in survival with matched molecular targeted agents for oncogenic driver mutations reminds us to also be concerned with late treatment toxicities. A 30-year-old female patient previously treated with crizotinib harboring ALK rearranged non-small cell lung cancer complained of visual disturbance, fever, and bone pains undergoing anti-PD-1 antibody treatment. A decreased proportion of ALK fusion was demonstrated by fluorescence in situ hybridization in liver metastasis compared to the primary site in a chemo-naïve state. She was diagnosed with low vision, choroidal metastasis and retinal detachment. Therefore, she started alectinib treatment and both her ocular and systemic symptoms were palliated in a week. Later, she temporarily discontinued alectinib because of skin rash although the choroidal metastasis and retinal detachment resolved and she regained low vision completely at 2 weeks. She obtained partial response with alectinib for more than 5 months after recovering from skin rash. PMID:26082648

  10. Peptides derived from the dependence receptor ALK are proapoptotic for ALK-positive tumors

    PubMed Central

    Aubry, A; Galiacy, S; Ceccato, L; Marchand, C; Tricoire, C; Lopez, F; Bremner, R; Racaud-Sultan, C; Monsarrat, B; Malecaze, F; Allouche, M

    2015-01-01

    ALK is a receptor tyrosine kinase with an oncogenic role in various types of human malignancies. Despite constitutive activation of the kinase through gene alterations, such as chromosomal translocation, gene amplification or mutation, treatments with kinase inhibitors invariably lead to the development of resistance. Aiming to develop new tools for ALK targeting, we took advantage of our previous demonstration identifying ALK as a dependence receptor, implying that in the absence of ligand the kinase-inactive ALK triggers or enhances apoptosis. Here, we synthesized peptides mimicking the proapoptotic domain of ALK and investigated their biological effects on tumor cells. We found that an ALK-derived peptide of 36 amino acids (P36) was cytotoxic for ALK-positive anaplastic large-cell lymphoma and neuroblastoma cell lines. In contrast, ALK-negative tumor cells and normal peripheral blood mononuclear cells were insensitive to P36. The cytotoxic effect was due to caspase-dependent apoptosis and required N-myristoylation of the peptide. Two P36-derived shorter peptides as well as a cyclic peptide also induced apoptosis. Surface plasmon resonance and mass spectrometry analysis of P36-interacting proteins from two responsive cell lines, Cost lymphoma and SH-SY5Y neuroblastoma, uncovered partners that could involve p53-dependent signaling and pre-mRNA splicing. Furthermore, siRNA-mediated knockdown of p53 rescued these cells from P36-induced apoptosis. Finally, we observed that a treatment combining P36 with the ALK-specific inhibitor crizotinib resulted in additive cytotoxicity. Therefore, ALK-derived peptides could represent a novel targeted therapy for ALK-positive tumors. PMID:25950466

  11. Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer

    PubMed Central

    Schaefer, Eric S; Baik, Christina

    2016-01-01

    Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg

  12. Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.

    PubMed

    Schaefer, Eric S; Baik, Christina

    2016-01-01

    Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%-7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg

  13. Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study)

    PubMed Central

    Takeuchi, K.; Togashi, Y.; Kamihara, Y.; Fukuyama, T.; Yoshioka, H.; Inoue, A.; Katsuki, H.; Kiura, K.; Nakagawa, K.; Seto, T.; Maemondo, M.; Hida, T.; Harada, M.; Ohe, Y.; Nogami, N.; Yamamoto, N.; Nishio, M.; Tamura, T.

    2016-01-01

    Background Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. Patients and methods In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. Result ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Conclusions Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. Registration number JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center). PMID:26487585

  14. ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern.

    PubMed

    Sakamoto, Kana; Nakasone, Hideki; Togashi, Yuki; Sakata, Seiji; Tsuyama, Naoko; Baba, Satoko; Dobashi, Akito; Asaka, Reimi; Tsai, Chien-Chen; Chuang, Shih-Sung; Izutsu, Koji; Kanda, Yoshinobu; Takeuchi, Kengo

    2016-04-01

    Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+LBCL) is a rare, aggressive B-cell lymphoma with ALK fusion genes. Histopathologically, the ALK immunohistochemical staining pattern is suggestive of the fusion partner of ALK. Here, we examined an ALK+LBCL case showing a unique diffuse cytoplasmic ALK staining pattern and identified EML4-ALK, which has not previously been reported in ALK+LBCL. Furthermore, to clarify whether the prognosis differs depending on the staining pattern, we reviewed 112 previously reported cases, and analyzed immunohistochemical markers and clinical data stratified by the staining pattern. We found that ALK staining can be classified into a granular cytoplasmic staining (GCS) or a non-GCS patterns. Sixty-four adult cases for which both the ALK staining pattern and survival time were reported were further analyzed for survival trends. The non-GCS pattern was significantly associated with inferior overall survival (P = 0.031). This difference remained significant after adjusting for age and clinical stage (hazard ratio 5.08, 95 % CI 1.88-13.7, P = 0.0013). Given that the ALK immunohistochemical staining pattern is associated with the ALK fusion partner, the present results suggest that the prognosis for ALK+LBCL differs depending on the ALK fusion partner. PMID:26781614

  15. Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer.

    PubMed

    Isozaki, Hideko; Takigawa, Nagio; Kiura, Katsuyuki

    2015-01-01

    The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene. PMID:25941796

  16. Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer

    PubMed Central

    Isozaki, Hideko; Takigawa, Nagio; Kiura, Katsuyuki

    2015-01-01

    The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene. PMID:25941796

  17. Detection of tumor ALK status in neuroblastoma patients using peripheral blood.

    PubMed

    Combaret, Valérie; Iacono, Isabelle; Bellini, Angela; Bréjon, Stéphanie; Bernard, Virginie; Marabelle, Aurélien; Coze, Carole; Pierron, Gaelle; Lapouble, Eve; Schleiermacher, Gudrun; Blay, Jean Yves

    2015-04-01

    New protocols based on ALK-targeted therapy by crizotinib or other ALK-targeting molecules have opened for the treatment of patients with neuroblastoma (NB) if their tumors showed mutation and/or amplification of the ALK gene. However, tumor samples are not always available for analysis of ALK mutational status in particular at relapse. Here, we evaluated the ALK mutational status of NB samples by analysis of circulating DNA, using the droplet digital PCR (ddPCR) system. ddPCR assays was developed for the detection of ALK mutations at F1174 and R1275 hotspots found in NB tumors and was applied for the analysis of circulating DNA obtained from 200 μL of serum or plasma samples collected from 114 patients with NB. The mutations F1174L (exon 23 position 3520, T>C and position 3522, C>A) and the mutation R1275Q (exon 25 position 3824, G>A) were detected in circulating DNA. The sensitivity of our test was 100%, 85%, and 92%, respectively, and the specificity was 100%, 91%, and 98%, respectively. In conclusion, the assay that we have developed offers a reliable, noninvasive blood test to assess ALK mutational status at F1174 and R1275 hotspots and should help clinicians to identify patients showing an ALK mutation in particular when no tumor tissue is available. PMID:25653133

  18. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer

    PubMed Central

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors. PMID:25414829

  19. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors. PMID:25414829

  20. Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

    PubMed Central

    Desquesnes, Aurore; Le Gonidec, Sophie; AlSaati, Talal; Beau, Isabelle; Lamant, Laurence; Meggetto, Fabienne; Espinos, Estelle; Codogno, Patrice; Brousset, Pierre; Giuriato, Sylvie

    2015-01-01

    Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients. PMID:26338968

  1. Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib

    PubMed Central

    El-Osta, Hazem; Shackelford, Rodney

    2015-01-01

    The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%–7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib–ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naïve and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy. PMID:26622190

  2. Initial Diagnosis of ALK-Positive Non-Small-Cell Lung Cancer Based on Analysis of ALK Status Utilizing Droplet Digital PCR.

    PubMed

    Lund, H Louise; Hughesman, Curtis B; Fakhfakh, Kareem; McNeil, Kelly; Clemens, Shahira; Hocken, Kimberly; Pettersson, Ryan; Karsan, Aly; Foster, Leonard J; Haynes, Charles

    2016-05-01

    We describe a novel droplet digital PCR (ddPCR) assay capable of detecting genomic alterations associated with inversion translocations. It is applied here to detection of rearrangements in the anaplastic lymphoma kinase (ALK) gene associated with ALK-positive non-small-cell lung cancer (NSCLC). NSCLC patients may carry a nonreciprocal translocation on human chromosome 2, in which synchronized double stranded breaks (DSB) within the echinoderm microtubule-associated protein-like 4 (EML4) gene and ALK lead to an inversion of genetic material that forms the non-natural gene fusion EML4-ALK encoding a constitutively active tyrosine kinase that is associated with 3 to 7% of all NSCLCs. Detection of ALK rearrangements is currently achieved in clinics through direct visualization via a fluorescent in situ hybridization (FISH) assay, which can detect those rearrangements to a limit of detection (LOD) of ca. 15%. We show that the ddPCR assay presented here provides a LOD of 0.25% at lower cost and with faster turnaround times. PMID:27043019

  3. Prospective screening for ALK: clinical features and outcome according to ALK status.

    PubMed

    Fallet, Vincent; Cadranel, Jacques; Doubre, Hélène; Toper, Cécile; Monnet, Isabelle; Chinet, Thierry; Oliviero, Gérard; Foulon, Guillaume; De Cremoux, Hubert; Vieira, Thibault; Antoine, Martine; Wislez, Marie

    2014-05-01

    The aim of this study was to analyse the clinico-pathological characteristics and outcomes of a cohort of French patients who were prospectively screened for Anaplastic Lymphoma Kinase (ALK) rearrangement. One hundred and sixteen consecutive patients screened for ALK rearrangement to be recruited into a crizotinib registration trial were included from eight French centres. ALK rearrangement was detected by fluorescence in situ hybridization. Seventeen patients (14.6%) were positive for ALK. ALK+ patients were younger (p = 0.049) and more likely to be males (p=0.032), non- or light-smokers (p = 0.048) and without underlying respiratory disease (p=0.025) compared to ALK- patients. Thyroid-transcription factor-1 expression was present in all ALK+ tumours. ALK+ tumours tended to have lymph node and brain metastases. In multivariate analyses, gender, smoking history and N stage were independently associated with ALK status. Median overall survival (OS) was not reached for ALK+ patients and was significantly longer than for ALK- patients (hazard ratio for death for ALK- patients 2.98; 95% CI [1.29-6.90], p=0.01). French ALK+ patients present a specific phenotype. ALK rearrangement should be determined to improve OS with an effective targeted therapy. PMID:24589437

  4. The role of the ALK receptor in cancer biology.

    PubMed

    Hallberg, B; Palmer, R H

    2016-09-01

    A vast array of oncogenic variants has been identified for anaplastic lymphoma kinase (ALK). Therefore, there is a need to better understand the role of ALK in cancer biology in order to optimise treatment strategies. This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements. A wide variety of ALK fusions, in which the kinase domain of ALK and the amino-terminal portion of various protein partners are fused, occur in cancer, with echinoderm microtubule-associated protein-like 4 (EML4)-ALK being the most prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusion proteins can mediate different signalling outputs, depending on properties such as subcellular localisation and protein stability. The ALK fusions found in tumours lack spatial and temporal regulation, which can also affect dimerisation and substrate specificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and ceritinib, are currently approved in Europe for use in ALK-positive NSCLC and several others are in development. These ALK TKIs bind slightly differently within the ATP-binding pocket of the ALK kinase domain and are associated with the emergence of different resistance mutation patterns during therapy. This emphasises the need to tailor the sequence of ALK TKIs according to the ALK signature of each patient. Research into the oncogenic functions of ALK, and fast paced development of ALK inhibitors, has substantially improved outcomes for patients with ALK-positive NSCLC. Limited data are available surrounding the physiological ligand-stimulated activation of ALK signalling and further research is needed. Understanding the role of ALK in tumour biology is key to further optimising therapeutic strategies for ALK-positive

  5. ALK-positive inflammatory myofibroblastic tumor harboring ALK gene rearrangement, occurring after allogeneic stem cell transplant in an adult male.

    PubMed

    Vroobel, Katherine; Judson, Ian; Dainton, Melissa; McCormick, Alison; Fisher, Cyril; Thway, Khin

    2016-08-01

    Inflammatory myofibroblastic tumor arose as a defined neoplasm from the disparate group of tumors (both neoplastic and inflammatory) originally described as inflammatory pseudotumors. The morphologic features are well described, and 50-60% of cases are associated with fusions of the anaplastic lymphoma kinase (ALK) gene. We describe an inflammatory myofibroblastic tumor in the lower abdominal wall of an adult male, which occurred 88days after he received an allogeneic stem cell transplant for T-lymphoblastic lymphoma, and which was positive for ALK immunohistochemistry and showed ALK gene rearrangement by fluorescence in situ hybridization. Two other cases are reported in the post-stem cell transplant setting, but both occurred in children and did not have molecular analysis performed. The etiology remains unclear, but may be due to immune dysregulation caused by any combination of prior chemotherapy, radiotherapy and immune suppression. These neoplasms should be considered as a rare consequence of allogeneic stem cell transplantation and referral to a specialist sarcoma center for further management may be required. PMID:27155927

  6. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  7. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

    PubMed

    Metro, Giulio; Lunardi, Gianluigi; Bennati, Chiara; Chiarini, Pietro; Sperduti, Isabella; Ricciuti, Biagio; Marcomigni, Luca; Costa, Cinzia; Crinò, Lucio; Floridi, Piero; Gori, Stefania; Chiari, Rita

    2016-09-01

    In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS. PMID:27324494

  8. Native and rearranged ALK copy number and rearranged cell count in NSCLC: Implications for ALK inhibitor therapy

    PubMed Central

    Camidge, D. Ross; Skokan, Margaret; Kiatsimkul, Porntip; Helfrich, Barbara; Lu, Xian; Barón, Anna E.; Schulte, Nathan; Maxson, DeLee; Aisner, Dara L.; Franklin, Wilbur A.; Doebele, Robert C.; Varella-Garcia, Marileila

    2013-01-01

    Background Anaplastic Lymphoma Kinase positive (ALK+) non-small cell lung cancer (NSCLC) responds to ALK inhibitors. Clinically, ≥ 15% cells showing rearrangements by break-apart FISH classify tumors as positive. Increases in native and rearranged ALK copy number also occur. Methods 1426 NSCLC clinical specimens (174 ALK+ and 1252 ALK negative), and 24 ALK negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH. Results Clinical specimens with 0–9%, 10–15%, 16–30%, 31–50% and >50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Increased native ALK copy number (≥3 copies/cell in ≥40% cells) was detected in 19% of ALK+ and 62% of ALK negative tumors. In ALK negative tumors, abundant focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in ~6% of tumors. Mean native ALK copy number ranged from 2.1–6.9 in cell lines and was not correlated with crizotinib sensitivity (IC50s 0.34–2.8 uM) (r=0.279, p=0.1764). Neither native, nor rearranged ALK copy number, nor percentage cells positive correlated with extra-central nervous system progression free survivalin ALK+ patients on crizotinib. Conclusions 8.5% of cases are below the established positivity threshold by ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. However, rare complex patterns of increased native ALK in patients should be studied further as atypical rearrangements contained within these may otherwise be missed. PMID:24022839

  9. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment. PMID:27133743

  10. ALK ambiguous-positive non-small cell lung cancers are tumors challenged by diagnostic and therapeutic issues.

    PubMed

    Uguen, Arnaud; Andrieu-Key, Sophie; Vergne, Florence; Descourt, Renaud; Quéré, Gilles; Quintin-Roué, Isabelle; Key, Stéphane; Guéguen, Paul; Talagas, Matthieu; De Braekeleer, Marc; Marcorelles, Pascale

    2016-09-01

    Searching for ALK rearrangements using the approved fluorescent in situ hybridization (FISH) test and complementary immunohistochemistry (IHC) has become the rule to treat patients with advanced non‑small cell lung cancer (NSCLC) with anti‑ALK targeted therapy. The concordance between the two techniques is reported to be strong but imperfect. We report our experience with cases of ALK‑rearranged lung adenocarcinomas pointing out particularly ambiguous cases. FISH and IHC data on ALK but also c‑MET IHC as well as EGFR and KRAS mutation screening are considered, together with response to crizotinib treatment. We classified the 55 FISH ALK‑rearranged tumors into two groups according to the FISH and IHC results: a concordant FISH+IHC+ group (31 tumors) and an ambiguous group (24 tumors). These tumors were considered as 'ambiguous' ALK‑positive due to negative (21 tumors) or non‑contributive (3 tumors) IHC. In addition, the percentage of FISH-positive nuclei was between 15 and 20% in 17 tumors belonging to one or the other group (now called borderline tumors). We discuss the accuracy of the different tests with intent to determine whether ambiguous and borderline tumors are real positive ALK‑rearranged tumors. To conclude, ambiguous ALK‑positive lung cancers are challenging tumors with diagnosis and therapeutic issues that can justify parallel FISH, IHC and molecular screening strategy. PMID:27460205

  11. A novel Patient Derived Tumorgraft model with TRAF1-ALK Anaplastic Large Cell Lymphoma translocation

    PubMed Central

    Abate, Francesco; Todaro, Maria; van der Krogt, Jo-Anne; Boi, Michela; Landra, Indira; Machiorlatti, Rodolfo; Tabbo’, Fabrizio; Messana, Katia; Barreca, Antonella; Novero, Domenico; Gaudiano, Marcello; Aliberti, Sabrina; Di Giacomo, Filomena; Tousseyn, Thomas; Lasorsa, Elena; Crescenzo, Ramona; Bessone, Luca; Ficarra, Elisa; Acquaviva, Andrea; Rinaldi, Andrea; Ponzoni, Maurilio; Longo, Dario Livio; Aime, Silvio; Cheng, Mangeng; Ruggeri, Bruce; Piccaluga, Pier Paolo; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Pera-Gresely, Benet; Cerchietti, Leandro; Iqbal, Javeed; Chan, Wing C; Shultz, Leonard D.; Kwee, Ivo; Piva, Roberto; Wlodarska, Iwona; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Although Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human Patient Derived Tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies. PMID:25533804

  12. The analysis of ALK gene rearrangement by fluorescence in situ hybridization in non-small cell lung cancer patients

    PubMed Central

    Krawczyk, Paweł Adam; Ramlau, Rodryg Adam; Szumiło, Justyna; Kozielski, Jerzy; Kalinka-Warzocha, Ewa; Bryl, Maciej; Knopik-Dąbrowicz, Alina; Spychalski, Łukasz; Szczęsna, Aleksandra; Rydzik, Ewelina; Milanowski, Janusz

    2013-01-01

    Introduction ALK gene rearrangement is observed in a small subset (3–7%) of non-small cell lung cancer (NSCLC) patients. The efficacy of crizotinib was shown in lung cancer patients harbouring ALK rearrangement. Nowadays, the analysis of ALK gene rearrangement is added to molecular examination of predictive factors. Aim of the study The frequency of ALK gene rearrangement as well as the type of its irregularity was analysed by fluorescence in situ hybridisation (FISH) in tissue samples from NSCLC patients. Material and methods The ALK gene rearrangement was analysed in 71 samples including 53 histological and 18 cytological samples. The analysis could be performed in 56 cases (78.87%), significantly more frequently in histological than in cytological materials. The encountered problem with ALK rearrangement diagnosis resulted from the scarcity of tumour cells in cytological samples, high background fluorescence noises and fragmentation of cell nuclei. Results The normal ALK copy number without gene rearrangement was observed in 26 (36.62%) patients ALK gene polysomy without gene rearrangement was observed in 25 (35.21%) samples while in 3 (4.23%) samples ALK gene amplification was found. ALK gene rearrangement was observed in 2 (2.82%) samples from males, while in the first case the rearrangement coexisted with ALK amplification. In the second case, signet-ring tumour cells were found during histopathological examination and this patient was successfully treated with crizotinib with partial remission lasting 16 months. Conclusions FISH is a useful technique for ALK gene rearrangement analysis which allows us to specify the type of gene irregularities. ALK gene examination could be performed in histological as well as cytological (cellblocks) samples, but obtaining a reliable result in cytological samples depends on the cellularity of examined materials. PMID:24592134

  13. Fluorescence in situ hybridization analysis of the ALK gene in 2,045 non-small cell lung cancer patients from North-Western Spain (Galicia)

    PubMed Central

    Sánchez-Ares, María; Cameselle-Teijeiro, José M.; Vázquez-Estévez, Sergio; Lázaro-Quintela, Martín; Vázquez-Boquete, Ángel; Afonso-Afonso, Francisco J.; Casal-Rubio, Joaquín; González-Piñeiro, Ana L.; Rico-Rodríguez, Yolanda; Fírvida-Pérez, José L.; Ruíz-Bañobre, Juan; Couso, Elena; Santomé, Lucía; Pérez-Becerra, Raquel; García-Campelo, Rosario; Amenedo, Margarita; Azpitarte-Raposeiras, Cristina; Antúnez, José; Abdulkader, Ihab

    2016-01-01

    Identification of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is a standard diagnostic test in patients with advanced non-small cell lung cancer (NSCLC). The current study describes the experience of ALK rearrangement detection of a referral center in the public health care system of Galicia in North-Western Spain. The fluorescence in situ hybridization (FISH) patterns of the ALK gene and the clinical and pathological features of these patients are reported. This study is also of interest for comparative purposes due to the relative geographical isolation of the area, which could have contributed to particular genetic features. A total of 2,045 tissue samples from NSCLC patients were collected between October 2010 and July 2015 and tested for ALK rearrangements by FISH. Examination of 1,686 paraffin-embedded tissue specimens and 395 cytological samples (306 cell block preparations and 53 cytological smears) was conducted, and any associations between the FISH results and clinicopathological features were assessed. The rate of successful evaluation was marginally higher in tissue samples than in cytological samples (92.9% vs. 84.1%); this difference was not significant. ALK rearrangements were identified in 82 patients(4%): 65 (79.3%) in tissue specimens, 15 (18.3%) in cell block samples and 2 (2.4%) in cytological smears. This genetic translocation appeared to be associated with a non-smoking history, younger age, female gender, stage IV and adenocarcinoma histological type. The findings demonstrate that ALK evaluation by FISH is feasible in tissue and cytological samples. The clinical and pathological features of the ALK-positive series of patients are similar to those previously reported in the literature. PMID:27446444

  14. Management of Brain Metastases in ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Rusthoven, Chad G; Doebele, Robert C

    2016-08-20

    The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 54-year-old man with a former 15-pack-year smoking history presents with cough and dyspnea. Initial work-up with imaging demonstrates a right suprahilar mass measuring 4.7 cm as well as several enlarged hilar and ipsilateral mediastinal lymph nodes. Bronchoscopy with biopsy reveals adenocarcinoma consistent with a lung primary. Staging with positron emission tomography/computed tomography (PET/CT) reidentifies the primary mass and lymph nodes and shows several PET-avid bone metastases. Brain magnetic resonance imaging (MRI) demonstrates a 1.6-cm right parietal mass with mild vasogenic edema and four additional brain metastases measuring 4 to 9 mm in size. Molecular testing is positive for an anaplastic lymphoma kinase (ALK) gene rearrangement using fluorescence in situ hybridization and negative for EGFR, ROS1, RET, BRAF, KRAS, and other oncogenes. The patient denies any neurologic symptoms and has no significant findings on neurologic exam. He is referred to you for management options for newly diagnosed stage IV (T2aN2M1b) lung adenocarcinoma. PMID:27298405

  15. Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib.

    PubMed

    Fujita, Shiro; Masago, Katsuhiro; Katakami, Nobuyuki; Yatabe, Yasushi

    2016-06-01

    We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment. PMID:26751586

  16. Patterns of response to crizotinib in recurrent glioblastoma according to ALK and MET molecular profile in two patients.

    PubMed

    Le Rhun, Emilie; Chamberlain, Marc C; Zairi, Fahed; Delmaire, Christine; Idbaih, Ahmed; Renaud, Florence; Maurage, Claude Alain; Grégoire, Valérie

    2015-01-01

    Two patients with an unmethylated MGMT promoter and IDH1 (R132H) wild-type recurrent glioblastoma were treated with crizotinib. Prolonged stabilization of the disease (17 months) was achieved in the first case. Interestingly, anaplastic lymphoma kinase (ALK) expression and c-MET protein overexpression was observed. Conversely, no response to crizotinib was obtained in the second case with MET protein overexpression and c-MET amplification but no ALK expression or ALK gene amplification. These case studies suggest that novel targeted ALK inhibitors may provide relevant clinical benefit in selected cases in which driver mutations are demonstrable. PMID:26498130

  17. High concordance of ALK rearrangement between primary tumor and paired metastatic lymph node in patients with lung adenocarcinoma

    PubMed Central

    Hou, Likun; Ren, Shengxiang; Su, Bo; Zhang, Liping; Wu, Wei; Zhang, Wei; Dong, Zhengwei; Huang, Yan

    2016-01-01

    Background Lung cancer has heterogeneous features. It remains unclear whether ALK rearrangement was distributed heterogeneously in tumor from different anatomic sites. To address this issue, we investigate the concordance of ALK rearrangement between primary tumors and paired metastatic lymph nodes in pulmonary adenocarcinoma patients. Methods From Sep 2013 to May 2014, resectable lung adenocarcinoma patients with EGFR wildtype and paired metastatic lymph nodes from Tongji University affiliated Shanghai pulmonary hospital were selected into this study. An auto-mated Ventana ALK with clone D5F3 antibody immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detected ALK rearrangement. Discordant cases between IHC and RT-PCR were further validated by fluorescence in situ hybridization (FISH). Results A total of 101 patients were enrolled into this study with a median age of 60 years old (range, 35–78 years). ALK rearrangement was found in 20 primary lesions, while in 18 paired metastatic lymph nodes. ALK rearrangement was more frequently happened in younger (P<0.001), Nonsmokers (P=0.012), high-stage disease (P=0.021) and predominantly solid growth pattern (P=0.024). The concordance rate between primary tumor and paired metastatic lymph nodes was 98%. Two patients with ALK rearrangement on primary tumor didn’t show ALK gene fusion on paired metastatic lymph nodes. Sixty-eight cases had more than two stations of metastatic lymph nodes. ALK rearrangement in the different station of metastatic lymph nodes of the same patient was consistent. Conclusions High concordant rate of ALK rearrangement between primary tumors and paired metastatic lymph nodes were found in this study. The authors concluded that specimens from metastatic lesions and primary tumors are equally suitable for detection ALK rearrangement. PMID:27293826

  18. Drastic initial response and subsequent response to two ALK inhibitors in a patient with a highly aggressive ALK-rearranged inflammatory myofibroblastic tumor arising in the pleural cavity.

    PubMed

    Ono, Akira; Murakami, Haruyasu; Serizawa, Masakuni; Wakuda, Kazushige; Kenmotsu, Hirotsugu; Naito, Tateaki; Taira, Tetsuhiko; Koh, Yasuhiro; Ohde, Yasuhisa; Nakajima, Takashi; Endo, Masahiro; Takahashi, Toshiaki

    2016-09-01

    A 57-year-old male current smoker was diagnosed with an aggressive variant of ALK-rearranged inflammatory myofibroblastic tumor (IMT) arising in the pleural cavity. First line treatment with ASP3026 was initiated at a dose of 125mg once daily. A follow-up CT scan revealed drastic regression of the pleural lesion. After disease progression with ASP3026 treatment, LDK378 (ceritinib) was initiated at a dose of 750mg once daily. A follow-up CT scan revealed a second drastic regression of the pleural lesion. Furthermore, it is noteworthy that this case represents the use of serum hyaluronan levels to assist in monitoring of treatment efficacy in an IMT. Herein, we present the first case of a patient with a highly aggressive ALK-rearranged IMT arising in the pleural cavity, who showed both initial and subsequent drastic response to two ALK inhibitors while being monitored for serum hyaluronan. PMID:27565932

  19. New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib

    PubMed Central

    Rothschild, Sacha I

    2016-01-01

    Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%–8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective. PMID:27217763

  20. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

    PubMed

    Guan, J; Tucker, E R; Wan, H; Chand, D; Danielson, L S; Ruuth, K; El Wakil, A; Witek, B; Jamin, Y; Umapathy, G; Robinson, S P; Johnson, T W; Smeal, T; Martinsson, T; Chesler, L; Palmer, R H; Hallberg, B

    2016-09-01

    The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients. PMID:27483357

  1. ALK-positive anaplastic large cell lymphoma with soft tissue involvement in a young woman

    PubMed Central

    Gao, Kehai; Li, Hongtao; Huang, Caihong; Li, Huazhuang; Fang, Jun; Tian, Chen

    2016-01-01

    Introduction Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma that has strong expression of CD30. ALCL can sometimes involve the bone marrow, and in advanced stages, it can produce destructive extranodal lesions. But anaplastic large cell lymphoma kinase (ALK)+ ALCL with soft tissue involvement is very rare. Case report A 35-year-old woman presented with waist pain for over 1 month. The biopsy of soft tissue lesions showed that these cells were positive for ALK-1, CD30, TIA-1, GranzymeB, CD4, CD8, and Ki67 (90%+) and negative for CD3, CD5, CD20, CD10, cytokeratin (CK), TdT, HMB-45, epithelial membrane antigen (EMA), and pan-CK, which identified ALCL. After six cycles of Hyper-CVAD/MA regimen, she achieved partial remission. Three months later, she died due to disease progression. Conclusion This case illustrates the unusual presentation of ALCL in soft tissue with a bad response to chemotherapy. Because of the tendency for rapid progression, ALCL in young adults with extra-nodal lesions are often treated with high-grade chemotherapy, such as Hyper-CVAD/MA. PMID:27445489

  2. Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation.

    PubMed

    Busam, Klaus J; Vilain, Ricardo E; Lum, Trina; Busam, Jonathan A; Hollmann, Travis J; Saw, Robyn P M; Coit, Daniel C; Scolyer, Richard A; Wiesner, Thomas

    2016-06-01

    A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in nonspitzoid primary and metastatic cutaneous melanomas. ALK immunohistochemistry was performed on 603 melanomas (303 primary and 300 metastatic tumors) from 600 patients. ALK immunohistochemistry expression was identified in 7 primary and 9 metastatic tumors. In 5 of 7 primary tumors and in 6 of 9 metastatic lesions, the majority of tumor cells were immunoreactive for ALK. In the other 2 primary and 3 metastatic lesions, positive staining was identified in less than half of the tumor cells. ALK positivity was found in the presence or absence of BRAF or NRAS mutations. In contrast to prior observations with ALK-positive Spitz tumors, none of the ALK-positive melanomas harbored a translocation. Instead, the ALK-positive melanomas predominantly expressed the recently described ALK isoform, ALK, which lacks the extracellular and transmembrane domains of wild-type ALK, consists primarily of the intracellular tyrosine kinase domain, and originates from an alternative transcriptional initiation site within the ALK gene. The findings are clinically relevant as patients with metastatic melanoma who have ALK expression may potentially benefit from treatment with ALK kinase inhibitors. PMID:26872010

  3. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening

    PubMed Central

    Wang, Kai; Kim, Sun Young; Jang, Jiryeon; Kim, Seung Tae; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Lee, Jiyun; Lee, Woo Yong; Park, Yoon Ah; Huh, Jung Wook; Yun, Seong Hyeon; Do, In-Gu; Kim, Seok Hyung; Balasubramanian, Sohail; Stephens, Philip J.; Ross, Jeffrey S.; Li, Gang Gary; Hornby, Zachary; Ali, Siraj M.; Miller, Vincent A.; Kim, Kyoung-Mee; Ou, Sai-Hong Ignatius

    2015-01-01

    Purpose Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. Results Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. Conclusions ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors. PMID:26172300

  4. Moving molecularly directed therapies to the first-line in ALK-positive lung cancer: crizotinib is just the beginning.

    PubMed

    Klempner, Samuel J; Raufi, Alexander; Ou, Sai-Hong Ignatius

    2015-10-01

    The increasing appreciation of oncogenic driver alterations in non-small cell lung cancer (NSCLC) has resulted in a rapid expansion of therapeutic compounds. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations are the prototypical examples and have driven the paradigm shift in NSCLC management. Early phase studies in previously treated ALK+ patients demonstrated activity and recently Solomon et al. confirmed the superiority of crizotinib over chemotherapy in first line treatment. The phase III PROFILE 1014 represents the culmination of the rapid development of crizotinib and provides lessons for future generation ALK inhibitors and other molecularly directed therapies in NSCLC. Important considerations for second and third generation inhibitors include the ability to overcome known resistance mechanisms, CNS activity, improvement in side effect profile, and safety in possible combination strategies. PMID:26629439

  5. A novel molecular variant of the chimeric NPM-ALK transcript in Ki-1 positive large cell lymphoma

    SciTech Connect

    Ladanyi, M.

    1994-09-01

    The breakpoints of the t(2;5)(p23;q35), reported to be present in 30-40% of Ki-1 positive large cell lymphoma (Ki-1 LCL), have recently been cloned. They involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase polymerase chain reaction (RT-PCR) using NPM and ALK primers detects a consistent fusion product in Ki-1 cases with the translocation. We performed NPM-ALK RT-PCR on 16 cases of Ki-1 LCL, of which 13 had informative cytogenetics. Amplifiable template was confirmed in all samples by RT-PCR using {beta}-actin primers. Ten cases showed the expected 177 base pair (bp) RT-PCR product indicative of the translocation, including all 6 cases with cytogenetic evidence of the t(2;5) and 3 cases without 5q35 abnormalities. One additional case, which had uninformative cytogenetics, showed only a novel 144 bp RT-PCR product. Sequencing of this PCR product showed an in-frame junction of NPM to ALK, 20 bp distal to the usual NPM junction site and 53 bp distal to usual ALK junction site. The predicted chimeric protein is thus shorter by 11 amino acids, but the putative ALK catalytic domain remains intact. This case was a histologically typical anaplastic Ki-1 LCL which showed a clonal rearrangement of the T-cell receptor {beta} gene. The functional significance of this molecular variant and its relation to the exon structure of both genes require further study. The overall incidence of the translocation in this series, about 70%, is higher than suspected from cytogenetic analysis alone.

  6. A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

    PubMed

    Abate, F; Todaro, M; van der Krogt, J-A; Boi, M; Landra, I; Machiorlatti, R; Tabbò, F; Messana, K; Abele, C; Barreca, A; Novero, D; Gaudiano, M; Aliberti, S; Di Giacomo, F; Tousseyn, T; Lasorsa, E; Crescenzo, R; Bessone, L; Ficarra, E; Acquaviva, A; Rinaldi, A; Ponzoni, M; Longo, D L; Aime, S; Cheng, M; Ruggeri, B; Piccaluga, P P; Pileri, S; Tiacci, E; Falini, B; Pera-Gresely, B; Cerchietti, L; Iqbal, J; Chan, W C; Shultz, L D; Kwee, I; Piva, R; Wlodarska, I; Rabadan, R; Bertoni, F; Inghirami, G

    2015-06-01

    Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies. PMID:25533804

  7. Detection of EML4-ALK fusion gene and features associated with EGFR mutations in Chinese patients with non-small-cell lung cancer

    PubMed Central

    Wen, Miaomiao; Wang, Xuejiao; Sun, Ying; Xia, Jinghua; Fan, Liangbo; Xing, Hao; Zhang, Zhipei; Li, Xiaofei

    2016-01-01

    Purpose Echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) and epidermal growth factor receptor (EGFR) define specific molecular subsets of lung cancer with distinct clinical features. We aimed at revealing the clinical features of EML4-ALK fusion gene and EGFR mutation in non-small-cell lung cancer (NSCLC). Methods We enrolled 694 Chinese patients with NSCLC for analysis. EML4-ALK fusion gene was analyzed by real-time polymerase chain reaction, and EGFR mutations were analyzed by amplified refractory mutation system. Results Among the 694 patients, 60 (8.65%) patients had EML4-ALK fusions. In continuity correction χ2 test analysis, EML4-ALK fusion gene was correlated with sex, age, smoking status, and histology, but no significant association was observed between EML4-ALK fusion gene and clinical stage. A total of 147 (21.18%) patients had EGFR mutations. In concordance with previous reports, EGFR mutation was correlated with age, smoking status, histology, and clinical stage, whereas patient age was not significantly associated with EGFR mutation. Meanwhile, to our surprise, six (0.86%) patients had coexisting EML4-ALK fusions and EGFR mutations. Conclusion EML4-ALK fusion gene defines a new molecular subset in patients with NSCLC. Six patients who harbored both EML4-ALK fusion genes and EGFR mutations were identified in our study. The EGFR mutations and the EML4-ALK fusion genes are coexistent. PMID:27103824

  8. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

    PubMed Central

    Lindeman, Neal I.; Cagle, Philip T.; Beasley, Mary Beth; Chitale, Dhananjay Arun; Dacic, Sanja; Giaccone, Giuseppe; Jenkins, Robert Brian; Kwiatkowski, David J.; Saldivar, Juan-Sebastian; Squire, Jeremy; Thunnissen, Erik; Ladanyi, Marc

    2014-01-01

    Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert

  9. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

    PubMed Central

    Lindeman, Neal I.; Cagle, Philip T.; Beasley, Mary Beth; Chitale, Dhananjay Arun; Dacic, Sanja; Giaccone, Giuseppe; Jenkins, Robert Brian; Kwiatkowski, David J.; Saldivar, Juan-Sebastian; Squire, Jeremy; Thunnissen, Erik; Ladanyi, Marc

    2014-01-01

    Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed

  10. Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma

    SciTech Connect

    Xu, Fei; Li, Hongling; Sun, Yong

    2014-11-28

    Highlights: • First reported Axl is co-expressed with ALK in neuroblastoma tissues and cell lines. • Axl activation promotes cell growth and impairs the efficiency of ALK inhibitor. • Further found silence of Axl leads to increased sensitivity to ALK inhibitors. • Axl inhibitor promotes the efficiency of targeted therapy in vitro and in vivo. • Axl activation should be considered in the clinical application of ALK inhibitors. - Abstract: Neuroblastoma (NB) patients harboring mutated ALK can be expected to potentially benefit from targeted therapy based on ALK tyrosine kinase inhibitor (TKI), such as crizotinib and ceritinib. However, the effect of the treatment varies with different individuals, although with the same genic changes. Axl receptor tyrosine kinase is expressed in a variety of human cancers, but little data are reported in NB, particularly in which carrying mutated ALK. In this study, we focus on the roles of Axl in ALK-mutated NB for investigating rational therapeutic strategy. We found that Axl is expressed in ALK-positive NB tissues and cell lines, and could be effectively activated by its ligand GAS6. Ligand-dependent Axl activation obviously rescued crizotinib-mediated suppression of cell proliferation in ALK-mutated NB cells. Genetic inhibition of Axl with specific small interfering RNA markedly increased the sensitivity of cells to ALK-TKIs. Furthermore, a small-molecule inhibitor of Axl significantly enhanced ALK-targeted therapy, as an increased frequency of apoptosis was observed in NB cells co-expressing ALK and Axl. Taken together, our results demonstrated that activation of Axl could lead to insensitivity to ALK inhibitors, and dual inhibition of ALK and Axl might be a potential therapeutic strategy against ALK-mutated NB.

  11. Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins

    SciTech Connect

    Kang, Chung Hyo; Yun, Jeong In; Lee, Kwangho; Lee, Chong Ock; Lee, Heung Kyoung; Yun, Chang-Soo; Hwang, Jong Yeon; Cho, Sung Yun; Jung, Heejung; Kim, Pilho; Ha, Jae Du; Jeon, Jeong Hee; Choi, Sang Un; Jeong, Hye Gwang; Kim, Hyoung Rae; Park, Chi Hoon

    2015-08-28

    Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151-L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15–20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants. - Highlights: • We synthesized KRCA-0008 derivatives having trifluoromethyl instead of chloride. • KRCA-0080 shows superior activity against several ALK mutants to KRCA-0008. • Cellular assays show our ALK inhibitors suppress only EML4-ALK positive cells. • Our ALK inhibitors induce G1/S arrest to lead apoptosis in H3122 cells. • KRCA-0080 has superior in vivo efficacy to crizotinib and KRCA-0008 by 15–20%.

  12. Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions.

    PubMed

    Cameron, Laird; Solomon, Benjamin

    2015-07-01

    Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC. PMID:26076736

  13. Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

    PubMed

    Dudnik, Elizabeth; Siegal, Tali; Zach, Leor; Allen, Aaron M; Flex, Dov; Yust-Katz, Shlomit; Limon, Dror; Hirsch, Fred R; Peled, Nir

    2016-04-01

    Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred. PMID:26677785

  14. ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.

    PubMed

    Ueda, T; Nakata, Y; Yamasaki, N; Oda, H; Sentani, K; Kanai, A; Onishi, N; Ikeda, K; Sera, Y; Honda, Z-I; Tanaka, K; Sata, M; Ogawa, S; Yasui, W; Saya, H; Takita, J; Honda, H

    2016-08-25

    Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK(R1275Q), an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK(R1275Q) knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK(R1275Q) globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK(R1275Q)/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK(R1275Q)-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK(R1275Q)/MYCN mice. These results collectively indicate that ALK(R1275Q) confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK(R1275Q)/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK(R1275Q)-positive tumors. PMID:26829053

  15. ALK-Positive Inflammatory Myofibroblastic Tumor of the Nipple During Pregnancy-An Unusual Presentation of a Rare Disease.

    PubMed

    Kovács, Anikó; Máthé, Gyöngyvér; Mattsson, Jan; Stenman, Göran; Kindblom, Lars-Gunnar

    2015-01-01

    Inflammatory myofibroblastic tumors (IMT) is a benign to low-grade malignant neoplasm most commonly occurring in the viscera and soft tissues of children and young adults. Involvement of the breast is very rare. This report presents the first case of IMT of the nipple and highlights the histologic features and differential diagnosis at this unusual anatomical site. The patient was a 31-years-old pregnant woman with a palpable mass at the upper half of the left nipple. The lesion appeared after breastfeeding of her first child and increased in size during her second pregnancy. A conservative, incomplete surgical excision was performed in the 24th week of the second pregnancy. The residual tumor subsequently underwent spontaneous regression. There was no evidence of disease 5 years after surgery. FISH and immunohistochemical analyses revealed rearrangement and overexpression of the ALK gene, a typical feature of both pulmonary and extrapulmonary IMT. PMID:25772857

  16. Is ALK-gene rearrangement overlooked in primary gastrointestinal T-cell lymphomas? About two cases.

    PubMed

    Mneimneh, Wadad S; Vyas, Shikhar Gautam; Cheng, Liang; Cummings, Oscar W; Czader, Magdalena

    2015-12-01

    A 41-year-old male patient with a history of ankylosing spondylitis and Crohn disease, treated with immunomodulators and disease-modifying drugs, was diagnosed with a primary intestinal T-cell lymphoma that followed a 7.5-year-course. This transmural proliferation lacked cytological characteristics of anaplastic large cell lymphoma (ALCL), and was CD8-positive, and CD30- and anaplastic lymphoma kinase (ALK)-negative by immunohistochemistry (IHC). However, ALK-gene rearrangement (ALK-gr) was detected by fluorescence in situ hybridization (FISH) in both initial and persistent disease. The possibility of indolent T-cell lymphoproliferative disease of the gastrointestinal tract with atypical features (transmural involvement) related to ALK-gr was suggested. A previous case of aggressive 'enteropathy-associated ALCL' in the context of celiac disease was recently reported, which also lacked anaplastic morphology, and where CD30 and ALK expression was incidentally demonstrated by IHC, and ALK-gr subsequently confirmed by FISH. These two recent cases represent two distinct rare entities pertaining to the group of primary intestinal T-cell lymphomas, and they both show unexpected ALK-gr. This suggests that ALK-gr has been overlooked in the group of primary intestinal T-cell lymphomas. Performing IHC and FISH tests for ALK-gr in primary gastrointestinal T-cell lymphomas might be of importance, particularly with the advancement of targeted therapy that could impact treatment and prognosis. PMID:26531107

  17. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer

    PubMed Central

    Amatu, Alessio; Somaschini, Alessio; Cerea, Giulio; Bosotti, Roberta; Valtorta, Emanuele; Buonandi, Pasquale; Marrapese, Giovanna; Veronese, Silvio; Luo, David; Hornby, Zachary; Multani, Pratik; Murphy, Danielle; Shoemaker, Robert; Lauricella, Calogero; Giannetta, Laura; Maiolani, Martina; Vanzulli, Angelo; Ardini, Elena; Galvani, Arturo; Isacchi, Antonella; Sartore-Bianchi, Andrea; Siena, Salvatore

    2015-01-01

    Background: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. Methods: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. Results: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1–35 of CAD with exons 20–29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. Conclusions: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC. PMID:26633560

  18. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

    PubMed Central

    Facchinetti, Francesco; Di Maio, Massimo; Graziano, Paolo; Bria, Emilio; Rossi, Giulio; Novello, Silvia

    2016-01-01

    Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient. PMID:27413712

  19. The neuroblastoma associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK translocated cancers

    PubMed Central

    Sasaki, Takaaki; Okuda, Katsuhiro; Zheng, Wei; Butrynski, James; Capelletti, Marzia; Wang, Liping; Gray, Nathanael S.; Wilner, Keith; Christensen, James G.; Demetri, George; Shapiro, Geoffrey I.; Rodig, Scott J.; Eck, Michael J.; Jänne, Pasi A.

    2011-01-01

    The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harbouring a RANBP2-ALK translocation who progressed while crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, or the HSP90 inhibitor 17-AAG are both effective in models harbouring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers. PMID:21030459

  20. Intact or broken-apart RNA: an alternative concept for ALK fusion screening in non-small cell lung cancer (NSCLC).

    PubMed

    Kotoula, Vassiliki; Bobos, Mattheos; Vassilakopoulou, Maria; Tsolaki, Eleftheria; Chrisafi, Sofia; Psyrri, Amanda; Lazaridis, George; Papadopoulou, Kyriaki; Efstratiou, Ioannis; Michail-Strantzia, Catherine; Debelenko, Larisa V; Kosmidis, Paris; Fountzilas, George

    2015-01-01

    Anaplastic lymphoma kinase (ALK) break-apart fluorescent in situ hybridization (FISH) is currently used in diagnostics for the selection of non-small cell lung cancer (NSCLC) patients to receive crizotinib. We evaluated ALK status in NSCLC with a novel ALK mRNA test based on the break-apart FISH concept, which we called break-apart transcript (BAT) test. ALK5' and ALK3' transcript patterns were established with qPCR for ALK-expressing controls including fusion-negative neuroblastomas, as well as fusion-positive anaplastic large cell lymphomas and NSCLC. The BAT test was evaluated on 271 RNA samples from routinely processed paraffin NSCLC tissues. Test results were compared with ALK FISH (n=121), immunohistochemical (IHC) analysis (n=86), and automated quantitative analysis (AQUA, n=83). On the basis of the nonoverlapping ALK BAT patterns in ALK-expressing controls (P<0.0001), 8/174 adenocarcinomas (4.6%) among 259 informative NSCLC were predicted as fusion positive. Overall concordance for paired method results was high (94.1% to 98.8%) but mainly concerned negative prediction because of the limited availability of positive-matched cases. Tumors with 100% cytoplasmic IHC staining of any intensity (n=3) were positive for AQUA, FISH, and BAT test; tumors with lower IHC positivity and different staining patterns were AQUA-negative. Upon multiple reevaluations, ALK gene status was considered as originally misinterpreted by FISH in 3/121 cases (2.5%). Tumors with >4 ALK gene copies were associated with longer overall survival upon first-line chemotherapy. In conclusion, application of the ALK BAT test on routinely processed NSCLC tissues yields the same fusion partner independent information as ALK break-apart FISH but is more robust and cost-effective. The BAT concept may be considered for the development of further drug-predictive translocation tests. PMID:25153496

  1. Two novel ALK mutations mediate acquired resistance to the next generation ALK inhibitor alectinib

    PubMed Central

    Katayama, Ryohei; Friboulet, Luc; Koike, Sumie; Lockerman, Elizabeth L.; Khan, Tahsin M.; Gainor, Justin F.; Iafrate, A. John; Takeuchi, Kengo; Taiji, Makoto; Okuno, Yasushi; Fujita, Naoya; Engelman, Jeffrey A.; Shaw, Alice T.

    2014-01-01

    Purpose The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged NSCLC. Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. Experimental Design We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity-relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. Results We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. Conclusions We have identified two novel ALK mutations arising after alectinib exposure which are sensitive to other next generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. PMID:25228534

  2. Droplet Digital PCR for Absolute Quantification of EML4-ALK Gene Rearrangement in Lung Adenocarcinoma.

    PubMed

    Wang, Qiushi; Yang, Xin; He, Yong; Ma, Qiang; Lin, Li; Fu, Ping; Xiao, Hualiang

    2015-09-01

    Crizotinib treatment significantly prolongs progression-free survival, increases response rates, and improves the quality of life in patients with ALK-positive non-small-cell lung cancer. Droplet Digital PCR (ddPCR), a recently developed technique with high sensitivity and specificity, was used in this study to evaluate the association between the abundance of ALK rearrangements and crizotinib effectiveness. FFPE tissues were obtained from 103 consecutive patients with lung adenocarcinoma. Fluorescent in situ hybridization (FISH) and ddPCR were performed. The results revealed that 14 (13.6%) of the 103 patients were positive by dual-color, break-apart FISH. Three variants (1, 2, and 3) of the EML4-ALK gene rearrangements were detected. Thirteen of 14 ALK-positive cases identified by FISH were confirmed by ddPCR (four with variant 1, two with variant 2, and seven with variant 3). The case missed by ddPCR was identified as KIF5B-ALK gene rearrangement by PCR-based direct sequencing. Sixteen patients were detected with low copy numbers of EML4-ALK gene rearrangement, which failed to meet the positive cutoff point of FISH. Two of them responded well to crizotinib after unsuccessful chemotherapy. Our study indicates that ddPCR can be used as a molecular analytical tool to accurately measure the EML4-ALK rearrangement copy numbers in FFPE samples of lung adenocarcinoma patients. PMID:26142544

  3. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients.

    PubMed

    Gambacorti Passerini, Carlo; Farina, Francesca; Stasia, Alessandra; Redaelli, Sara; Ceccon, Monica; Mologni, Luca; Messa, Cristina; Guerra, Luca; Giudici, Giovanni; Sala, Elena; Mussolin, Lara; Deeren, Dries; King, Michael H; Steurer, Michael; Ordemann, Rainer; Cohen, Amos M; Grube, Matthias; Bernard, Lea; Chiriano, Gianpaolo; Antolini, Laura; Piazza, Rocco

    2014-02-01

    Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile. PMID:24491302

  4. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

    PubMed Central

    Song, Zilan; Wang, Meining; Zhang, Ao

    2015-01-01

    The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID:26579422

  5. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors

    PubMed Central

    Sasaki, Takaaki; Koivunen, Jussi; Ogino, Atsuko; Yanagita, Masahiko; Nikiforow, Sarah; Zheng, Wei; Lathan, Christopher; Marcoux, J. Paul; Du, Jinyan; Okuda, Katsuhiro; Capelletti, Marzia; Shimamura, Takeshi; Ercan, Dalia; Stumpfova, Magda; Xiao, Yun; Weremowicz, Stanislawa; Butaney, Mohit; Heon, Stephanie; Wilner, Keith; Christensen, James G.; Eck, Michel J.; Wong, Kwok-Kin; Lindeman, Neal; Gray, Nathanael S.; Rodig, Scott J.; Jänne, Pasi A.

    2011-01-01

    Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from, a crizotinib treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076), and from studying a resistant version of the ALK TKI (TAE684) sensitive H3122 cell line. The crizotinib resistant DFCI076 cell line, harboured a unique L1152R ALK secondary mutation, and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent co-activation of epidermal growth factor receptor (EGFR) signalling. In contrast, the TAE684 resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harboured co-activation of EGFR signalling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naïve NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signalling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients. PMID:21791641

  6. Fluorescence In Situ Hybridization, Immunohistochemistry, and Next-Generation Sequencing for Detection of EML4-ALK Rearrangement in Lung Cancer

    PubMed Central

    Pekar-Zlotin, Marina; Hirsch, Fred R.; Soussan-Gutman, Lior; Ilouze, Maya; Dvir, Addie; Boyle, Theresa; Wynes, Murry; Miller, Vincent A.; Lipson, Doron; Palmer, Gary A.; Ali, Siraj M.; Dekel, Shlomi; Brenner, Ronen; Bunn, Paul A.

    2015-01-01

    Background. The U.S. Food and Drug Administration-approved method for detecting EML4-ALK rearrangement is fluorescence in situ hybridization (FISH); however, data supporting the use of immunohistochemistry (IHC) for that purpose are accumulating. Previous studies that compared FISH and IHC considered FISH the gold standard, but none compared data with the results of next-generation sequencing (NGS) analysis. Materials and Methods. We studied FISH and IHC (D5F3 antibody) systematically for EML4-ALK rearrangement in 51 lung adenocarcinoma patients, followed by NGS in case of discordance. Results. Of 51 patients, 4 were positive with FISH (7.8%), and 8 were positive with IHC (15.7%). Three were positive with both. NGS confirmed that four of the five patients who were positive with IHC and negative with FISH were positive for ALK. Two were treated by crizotinib, with progression-free survival of 18 and 6 months. Considering NGS as the most accurate test, the sensitivity and specificity were 42.9% and 97.7%, respectively, for FISH and 100% and 97.7%, respectively, for IHC. Conclusion. The FISH-based method of detecting EML4-ALK rearrangement in lung cancer may miss a significant number of patients who could benefit from targeted ALK therapy. Screening for EML4-ALK rearrangement by IHC should be strongly considered, and NGS is recommended in borderline cases. Two patients who were negative with FISH and positive with IHC were treated with crizotinib and responded to therapy. PMID:25721120

  7. Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs.

    PubMed

    Li, Jianzong; Liu, Wei; Luo, Hao; Bao, Jinku

    2016-09-01

    Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified. PMID:27585676

  8. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

    PubMed Central

    Koivunen, Jussi P.; Mermel, Craig; Zejnullahu, Kreshnik; Murphy, Carly; Lifshits, Eugene; Holmes, Alison J.; Choi, Hwan Geun; Kim, Jhingook; Chiang, Derek; Thomas, Roman; Lee, Jinseon; Richards, William G.; Sugarbaker, David J.; Ducko, Christopher; Lindeman, Neal; Marcoux, J. Paul; Engelman, Jeffrey A.; Gray, Nathanael S.; Lee, Charles; Meyerson, Matthew; Jänne, Pasi A.

    2011-01-01

    Purpose The EML4-ALK fusion gene has been detected in ~7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLCs and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK containing cell lines in vitro and in vivo. Experimental Design We screened 305 primary NSCLCs (both US (n=138) and Korean (n=167) patients) and 83 NSCLC cell lines using RT-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results We detected 4 different variants, including two novel variants, of EML4-ALK using RT-PCR in 8/305 tumors (3%) and in 3/83 (3.6%) NSCLC cell lines. All EML4-ALK containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (< 10 pack years) cigarette smokers compared to current/former smokers (6% vs. 1%; p=0.049). TAE684 inhibited the growth of 1 of 3 (H3122) EML4-ALK containing cell lines in vitro and in vivo, inhibited Akt phosphorylation and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to co-activation of EGFR and ERBB2. The combination of TAE684 and CL-387,785 (EGFR/ERBB2 kinase inhibitor), inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions EML4-ALK is found in the minority of NSCLCs. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK. PMID:18594010

  9. ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression.

    PubMed

    Ou, Sai-Hong; Milliken, Jeffrey C; Azada, Michele C; Miller, Vincent A; Ali, Siraj M; Klempner, Samuel J

    2016-01-01

    Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. Both tumor samples had essentially the same genomic profile by comprehensive genomic profiling otherwise. This is the first patient report that demonstrates ALK F1174V mutation is sensitive to alectinib and further confirms missense acquired ALK I1171 mutation is resistant to alectinib. Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations. PMID:26464158

  10. Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer

    PubMed Central

    Yun, Jae Won; Lee, Hyun-Woo; Kim, DeokGeun; Ji, Yongick; Kim, Duk-Hwan; Park, Woong-Yang; Shin, Hyun-Tae; Kim, Kyoung-Mee; Ahn, Myung-Ju; Park, Keunchil; Sun, Jong-Mu

    2015-01-01

    The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5’ fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target

  11. Successful treatment of hepatic oligometastases with stereotactic ablative radiotherapy and radiofrequency ablation in an anaplastic lymphoma kinase fusion-positive lung cancer patient.

    PubMed

    Weber, Britta; Liu, Mitchell; Sobkin, Paul; Morris, Stephan W; Hout, David; van der Westhuizen, Nicholas; Tonseth, R Petter; Saltman, David L

    2016-03-01

    Local ablative therapy with stereotactic ablative radiotherapy may improve survival in oncogene-addicted lung cancer patients with extracranial oligometastatic disease treated with targeted therapies. There is limited data on the use of radiofrequency ablation (RFA) in this same setting. We present a case of an anaplastic lymphoma kinase (ALK)-positive lung cancer patient with hepatic oligometastatic progression who was successfully treated with both stereotactic ablative radiation and RFA while continuing with an ALK inhibitor. PMID:27087977

  12. Bilateral breast adenocarcinomas with EML4–ALK fusion in a patient with multiple metastases successfully treated with crizotinib: is lung the primary site?

    PubMed Central

    Liu, Chao; Ding, Lijuan; Sun, Bing; Wu, Shikai

    2016-01-01

    Breast metastases from non-mammary cancers are rare, especially when they appear synchronously. Clinically, it is vitally important to accurately diagnose these patients, as this will directly influence their treatment and survival. We present a very rare and complex case of bilateral breast adenocarcinomas with an EML4–ALK fusion, which was diagnosed as bilateral breast metastases of non-small-cell lung cancer by immunohistochemistry and comprehensive genomic investigation. The patient was successfully treated with an ALK inhibitor (crizotinib); symptoms improved quickly after initiation of crizotinib therapy, and a partial response was observed after 3 months. The experience of diagnosis and treatment of this case indicates the importance and necessity of genomic investigations in such patients, and suggests that we need to consider the rare possibility of this kind of metastasis in order to provide optimal treatment. PMID:27366096

  13. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib

    PubMed Central

    Mahuad, Carolina Valeria; Repáraz, María de los Ángeles Vicente; Zerga, Marta E.; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-01-01

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy.

  14. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib.

    PubMed

    Mahuad, Carolina Valeria; Repáraz, María de Los Ángeles Vicente; Zerga, Marta E; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-06-28

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  15. SUMOylation Confers Posttranslational Stability on NPM-ALK Oncogenic Protein.

    PubMed

    Vishwamitra, Deeksha; Curry, Choladda V; Shi, Ping; Alkan, Serhan; Amin, Hesham M

    2015-09-01

    Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+) T-cell lymphoma is an aggressive form of cancer that commonly affects children and adolescents. The expression of NPM-ALK chimeric oncogene results from the chromosomal translocation t(2;5)(p23;q35) that causes the fusion of the ALK and NPM genes. This translocation generates the NPM-ALK protein tyrosine kinase that forms the constitutively activated NPM-ALK/NPM-ALK homodimers. In addition, NPM-ALK is structurally associated with wild-type NPM to form NPM/NPM-ALK heterodimers, which can translocate to the nucleus. The mechanisms that sustain the stability of NPM-ALK are not fully understood. SUMOylation is a posttranslational modification that is characterized by the reversible conjugation of small ubiquitin-like modifiers (SUMOs) with target proteins. SUMO competes with ubiquitin for substrate binding and therefore, SUMOylation is believed to protect target proteins from proteasomal degradation. Moreover, SUMOylation contributes to the subcellular distribution of target proteins. Herein, we found that the SUMOylation pathway is deregulated in NPM-ALK+ T-cell lymphoma cell lines and primary lymphoma tumors from patients. We also identified Lys24 and Lys32 within the NPM domain as the sites where NPM-ALK conjugates with SUMO-1 and SUMO-3. Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation. One possible mechanism for the SENP1-mediated decrease in NPM-ALK levels was the increase in NPM-ALK association with ubiquitin, which facilitates its degradation. Our findings propose a model in which aberrancies in SUMOylation contribute to the pathogenesis of NPM-ALK+ T-cell lymphoma. Unraveling such pathogenic mechanisms may lead to devising novel strategies to eliminate this aggressive neoplasm. PMID:26476082

  16. Detection of EML4-ALK in Lung Adenocarcinoma Using Pleural Effusion with FISH, IHC, and RT-PCR Methods

    PubMed Central

    Zhou, Xiaodie; Song, Yong; Zhou, Xiaojun; Yu, Like; Wang, Jiandong

    2015-01-01

    Anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) gene rearrangements occur in approximately 5% of non-small-cell lung cancers (NSCLC), leading to the overexpression of anaplastic lymphoma kinase and predicting a response to the targeted inhibitor, crizotinib. Malignant pleural effusion occurs in most patients with advanced lung cancer, especially adenocarcinoma, and tissue samples are not always available from these patients. We attempted to clarify the feasibility of detecting the EML4-ALK fusion gene in pleural effusion cells using different methods. We obtained 66 samples of pleural effusion from NSCLC patients. The pleural effusion fluid was centrifuged, and the cellular components obtained were formalin fixed and paraffin embedded. The EML4-ALK fusion gene status was determined with fluorescent in situ hybridization (FISH), reverse transcription—polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). EML4-ALK was detected in three of 66 patient samples (4.5%) with RT-PCR. When the RT-PCR data were used as the standard, one false positive and one false negative samples were identified with IHC; and one false negative sample was identified with FISH. These results suggest that a block of pleural effusion cells can be used to detect the EML4-ALK fusion gene. IHC had good sensitivity, but low specificity. FISH had low sensitivity, but high specificity. RT-PCR is a good candidate method for detecting EML4-ALK in blocks of pleural effusion cells from lung cancer patients. PMID:25785456

  17. Alectinib-Induced Alopecia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

    PubMed Central

    Koizumi, Tomonobu; Fukushima, Toshirou; Gomi, Daisuke; Kobayashi, Takashi; Sekiguchi, Nodoka; Sakamoto, Akiyuki; Sasaki, Shigeru; Mamiya, Keiko

    2016-01-01

    Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents. PMID:27194980

  18. Comprehensive histologic analysis of ALK-rearranged lung carcinomas.

    PubMed

    Yoshida, Akihiko; Tsuta, Koji; Nakamura, Harumi; Kohno, Takashi; Takahashi, Fumiaki; Asamura, Hisao; Sekine, Ikuo; Fukayama, Masashi; Shibata, Tatsuhiro; Furuta, Koh; Tsuda, Hitoshi

    2011-08-01

    A subset (1% to 5%) of non-small-cell lung carcinomas harbors the EML4-ALK fusion gene. Data from previous studies on the histomorphology of ALK-rearranged lung cancer are inconsistent, and the specific histologic parameters that characterize this subset and how accurately such parameters predict underlying ALK abnormality remain uncertain. To answer these questions, we performed a comprehensive histologic analysis of 54 surgically resected, extensively sampled ALK-rearranged lung carcinomas and compared them with 100 consecutive resections of ALK-wild-type lung cancers. All 54 cases showed at least a focal adenocarcinoma component, and 3 and 2 cases had additional squamous and sarcomatoid differentiation, respectively. Solid or acinar growth pattern, cribriform structure, presence of mucous cells (signet-ring cells or goblet cells), abundant extracellular mucus, lack of lepidic growth, and lack of significant nuclear pleomorphism were more common in ALK-positive cancers. Two recognizable constellations of findings, a solid signet-ring cell pattern and a mucinous cribriform pattern, were present at least focally in the majority (78%) of ALK-positive tumors, but were rare (1%) in ALK-negative tumors. Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement. Characteristic histologies were present both in primary sites and in metastases. Thus, histologic findings may help to identify cases for ALK testing. However, none of the histologic parameters were completely sensitive or specific to ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies. ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear. PMID:21753699

  19. Rapid and dramatic response to alectinib in an anaplastic lymphoma kinase rearranged non-small-cell lung cancer patient who is critically ill.

    PubMed

    Yoshida, Tatsuya; Hida, Toyoaki; Yatabe, Yasushi

    2016-07-01

    Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response. The present case is the first reported case of rapid and marked response to alectinib in ALK-positive NSCLC patients who had poor PS and severe organ dysfunction, such as disseminated intravascular coagulation. Further investigation of the safety and efficacy of ALK-TKI for ALK-positive NSCLC patients who are critically ill is warranted. PMID:26938871

  20. Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.

    PubMed

    Isozaki, Hideko; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Ochi, Nobuaki; Yasugi, Masayuki; Ninomiya, Takashi; Yamane, Hiromichi; Hotta, Katsuyuki; Sakai, Katsuya; Matsumoto, Kunio; Hosokawa, Shinobu; Bessho, Akihiro; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2016-03-15

    Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. PMID:26719536

  1. Anaplastic Lymphoma Kinase (ALK) Signaling in Lung Cancer.

    PubMed

    Ou, Sai-Hong Ignatius; Shirai, Keisuke

    2016-01-01

    Chromosomal rearrangement in the anaplastic lymphoma kinase (ALK) gene was identified as an oncogenic driver in non-small cell lung cancer (NSCLC) in 2007. A multi-targeted ALK/ROS1/MET inhibitor, crizotinib, targeting this activated tyrosine kinase has led to significant clinical benefit including tumor shrinkage and prolonged survival without disease progression and has been approved by US FDA since 2011 for the treatment of advanced ALK-rearranged NSCLC (Ou et al. Oncologist 17:1351-1375, 2012). Knowledge gained from treating ALK-rearranged NSCLC patients including the presenting clinicopathologic characteristics, methods of detecting ALK-rearranged NSCLC, pattern of relapse and acquired resistance mechanisms while on crizotinib, and the clinical activities of more potent ALK inhibitors has led us to a detailed and ever expanding knowledge of the ALK signaling pathway in lung cancer but also raising many more questions that remained to be answered in the future. This book chapter will provide a concise summary of the importance of ALK signaling pathway in lung cancer. Understanding the ALK signaling pathway in lung cancer will likely provide the roadmap to the management of major epithelial malignancies driven by receptor tyrosine kinase rearrangement. PMID:26667344

  2. Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs.

    PubMed

    Bayliss, Richard; Choi, Jene; Fennell, Dean A; Fry, Andrew M; Richards, Mark W

    2016-03-01

    A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90. PMID:26755435

  3. Molecular Characterization of Inflammatory Myofibroblastic Tumors with Frequent ALK and ROS1 Fusions and Rare Novel RET Gene Rearrangement

    PubMed Central

    Antonescu, Cristina R; Suurmeijer, Albert JH; Zhang, Lei; Sung, Yun-Shao; Jungbluth, Achim A; Travis, William D; Al-Ahmadie, Hikmat; Fletcher, Christopher DM; Alaggio, Rita

    2015-01-01

    Approximately 50% of conventional IMTs harbor ALK gene rearrangement and overexpress ALK. Recently gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in one patient PDGFRB. However, it remains uncertain if the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1 and RET by FISH. Additionally, next generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1 rearranged IMTs, all except one presenting in children, mainly in the lung and intra-abdominal and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 IHC. Two of the cases showed TFG-ROS1 fusions. Interestingly, one adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) of IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly 90% of fusion negative IMT were seen in adults, while >90% of pediatric IMT showed gene rearrangements.EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in

  4. The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

    PubMed Central

    Manshouri, Roxsan; Shi, Ping; Amin, Hesham M.

    2014-01-01

    NPM-ALK+ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK+ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK+ solid tumors. However, NPM-ALK+ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK+ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK+ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK+ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK+ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials. PMID:25026277

  5. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma

    PubMed Central

    Cazes, Alex; Lopez-Delisle, Lucille; Tsarovina, Konstantina; Pierre-Eugène, Cécile; De Preter, Katleen; Peuchmaur, Michel; Nicolas, André; Provost, Claire; Louis-Brennetot, Caroline; Daveau, Romain; Kumps, Candy; Cascone, Ilaria; Schleiermacher, Gudrun; Prignon, Aurélie; Speleman, Frank; Rohrer, Hermann; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2014-01-01

    Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma. PMID:24811913

  6. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts.

    PubMed

    Scarfò, Irene; Pellegrino, Elisa; Mereu, Elisabetta; Kwee, Ivo; Agnelli, Luca; Bergaggio, Elisa; Garaffo, Giulia; Vitale, Nicoletta; Caputo, Manuel; Machiorlatti, Rodolfo; Circosta, Paola; Abate, Francesco; Barreca, Antonella; Novero, Domenico; Mathew, Susan; Rinaldi, Andrea; Tiacci, Enrico; Serra, Sara; Deaglio, Silvia; Neri, Antonino; Falini, Brunangelo; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio; Piva, Roberto

    2016-01-14

    Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions. PMID:26463425

  7. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to 1st and 2nd generation ALK inhibitors in pre-clinical models

    PubMed Central

    Zou, Helen Y.; Friboulet, Luc; Kodack, David P.; Engstrom, Lars D.; Li, Qiuhua; West, Melissa; Tang, Ruth W.; Wang, Hui; Tsaparikos, Konstantinos; Wang, Jinwei; Timofeevski, Sergei; Katayama, Ryohei; Dinh, Dac M.; Lam, Hieu; Lam, Justine L.; Yamazaki, Shinji; Hu, Wenyue; Patel, Bhushankumar; Bezwada, Divya; Frias, Rosa L.; Lifshits, Eugene; Mahmood, Sidra; Gainor, Justin F.; Affolter, Timothy; Lappin, Patrick B.; Gukasyan, Hovhannes; Lee, Nathan; Deng, Shibing; Jain, Rakesh K; Johnson, Ted W.; Shaw, Alice T.; Fantin, Valeria R.; Smeal, Tod

    2015-01-01

    SUMMARY We report the preclinical evaluation of PF-06463922, a potent and brain penetrant ALK/ROS1 inhibitor. Compared to other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors due to secondary ALK kinase domain mutations and/or due to the failed control of brain metastases. PMID:26144315

  8. Evidence that the lung adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood

    PubMed Central

    Jen, Jin; Yi, Eunhee S.; Olivo-Marston, Susan; Yang, Ping; Harris, Curtis C.

    2014-01-01

    Background The EML4-ALK fusion gene is more frequently found in younger, never smoking, lung cancer patients. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking lung cancer patients that are not exposed. We therefore hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. Methods We compared the frequency of the EML4-ALK fusion gene among 197 never smoker lung cancer patients with and without a history of exposure to SHS during childhood at Mayo Clinic. Results The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, while 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. Conclusions The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. Impact These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer. PMID:24755712

  9. SEC31A-ALK Fusion Gene in Lung Adenocarcinoma.

    PubMed

    Kim, Ryong Nam; Choi, Yoon-La; Lee, Mi-Sook; Lira, Maruja E; Mao, Mao; Mann, Derrick; Stahl, Joshua; Licon, Abel; Choi, So Jung; Van Vrancken, Michael; Han, Joungho; Wlodarska, Iwona; Kim, Jhingook

    2016-01-01

    Anaplastic lymphoma kinase (ALK) fusion is a common mechanism underlying pathogenesis of non-small cell lung carcinoma (NSCLC) where these rearrangements represent important diagnostic and therapeutic targets. In this study, we found a new ALK fusion gene, SEC31A-ALK, in lung carcinoma from a 53-year-old Korean man. The conjoined region in the fusion transcript was generated by the fusion of SEC31A exon 21 and ALK exon 20 by genomic rearrangement, which contributed to generation of an intact, in-frame open reading frame. SEC31A-ALK encodes a predicted fusion protein of 1,438 amino acids comprising the WD40 domain of SEC31A at the N-terminus and ALK kinase domain at the C-terminus. Fluorescence in situ hybridization studies suggested that SEC31A-ALK was generated by an unbalanced genomic rearrangement associated with loss of the 3'-end of SEC31A. This is the first report of SEC31A-ALK fusion transcript in clinical NSCLC, which could be a novel diagnostic and therapeutic target for patients with NSCLC. PMID:25715771

  10. Combination of conventional immunohistochemistry and qRT-PCR to detect ALK rearrangement

    PubMed Central

    2014-01-01

    Background Compared with FISH and qRT-PCR analyses, immunohistochemistry (IHC) is the preferred screening test in most pathology practices for ALK-rearrangement detection. With 100% sensitivity and 98% specificity, the VENTANA ALK (D5F3) IHC assay has been approved in the EU and some Asian countries for ALK-rearrangement detection. However, an automated Ventana IHC platform is not available in most pathology labs. In this study, we evaluated the applicability of conventional IHC with D5F3 antibody in routine pathological practice and proposed detection methods and procedures that ensure that patients with ALK+ are not missed. Methods FISH and IHC analyses were performed on 297 lung adenocarcinoma cases. VENTANA IHC and qRT-PCR assay were applied to evaluate ALK-fusion status in the discordant cases of FISH and IHC. The association of ALK+ with clinicopathological characteristics was statistically analyzed. Results IHC had 100% sensitivity and 81.8% specificity for detecting ALK+. Eight ALK-expressed cases were ALK-, five of which had ALK fusion detected by qRT-PCR analysis. Three of these five cases showed ALK expression using VENTANA IHC assay. ALK+ was associated with younger age and lymph node metastasis in this Chinese lung adenocarcinoma patient cohort. Conclusions The advantages of low cost and 100% sensitivity allow conventional IHC to serve as a robust diagnostic tool for screening patients with ALK+, especially in pathology labs without a VENTANA IHC platform. For cases in which ALK is weakly expressed, qRT-PCR is necessary as a diagnostic test for ALK-fusion detection. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2269448351088278. PMID:24422905

  11. ALK-rearrangements and testing methods in non-small cell lung cancer: a review

    PubMed Central

    Shackelford, Rodney E.; Vora, Moiz; Mayhall, Kim; Cotelingam, James

    2014-01-01

    The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC. PMID:24955213

  12. A heterochronic genetic change from an EGFR mutation to an ALK rearrangement in a patient with lung adenocarcinoma: a case report.

    PubMed

    Shiroyama, Takayuki; Tamiya, Motohiro; Hayama, Manabu; Nishihara, Takashi; Nishida, Takuji; Tanaka, Ayako; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Kawahara, Kunimitsu; Hirashima, Tomonori

    2016-05-01

    An 87-year-old man with postoperative recurrent lung adenocarcinoma was treated with gefitinib. At the beginning of treatment, surgically resected archived tumor tissue revealed a deletion in exon 19 of the EGFR gene, but no ALK gene rearrangement. After gefitinib treatment for 9 months, the disease progressed. Bronchoscopic rebiopsy was used to evaluate resistance mechanisms, and revealed lung adenocarcinoma with wild-type EGFR genes and a newly emerged ALK gene rearrangement. Treatment was switched to alectinib and a partial response was achieved within 4 weeks. This is a rare case of heterochronic genetic change to an ALK gene rearrangement in EGFR mutant lung adenocarcinoma. PMID:27162697

  13. A heterochronic genetic change from an EGFR mutation to an ALK rearrangement in a patient with lung adenocarcinoma: a case report

    PubMed Central

    Tamiya, Motohiro; Hayama, Manabu; Nishihara, Takashi; Nishida, Takuji; Tanaka, Ayako; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Kawahara, Kunimitsu; Hirashima, Tomonori

    2016-01-01

    An 87-year-old man with postoperative recurrent lung adenocarcinoma was treated with gefitinib. At the beginning of treatment, surgically resected archived tumor tissue revealed a deletion in exon 19 of the EGFR gene, but no ALK gene rearrangement. After gefitinib treatment for 9 months, the disease progressed. Bronchoscopic rebiopsy was used to evaluate resistance mechanisms, and revealed lung adenocarcinoma with wild-type EGFR genes and a newly emerged ALK gene rearrangement. Treatment was switched to alectinib and a partial response was achieved within 4 weeks. This is a rare case of heterochronic genetic change to an ALK gene rearrangement in EGFR mutant lung adenocarcinoma. PMID:27162697

  14. Combined point mutation in KRAS or EGFR genes and EML4-ALK translocation in lung cancer patients.

    PubMed

    Jürgens, Jessica; Engel-Riedel, Walburga; Prickartz, Alexander; Ludwig, Corinna; Schildgen, Oliver; Tillmann, Ramona-Liza; Stoelben, Erich; Brockmann, Michael; Schildgen, Verena

    2014-03-01

    A total of three cases with novel constellations regarding mutation patterns in non-small-cell lung cancer (NSCLC) are reported. The mutation patterns that are observed are novel and unexpected. First, a combined simultaneous KRAS mutation and EML4-ALK translocation, both in the main tumor and a bone metastasis, were observed, these mutations are assumed to mutually exclude each other. A further two cases include a father and a daughter, both of whom are suffering from NSCLC with different EGFR mutation patterns. A common cause was assumed; however, could not be deduced to mutations in the KRAS, BRAF and EGFR genes. The aforementioned cases are important, as it must be taken into account that mutations previously assumed to be exclusive can occur in combination, may influence the clinical outcome and may require different therapy compared with single mutated tumors. It has to be discussed whether diagnostic algorithms need to be adapted. The cases of father and daughter show that further unknown factors can influence development of NSCLC. PMID:24754584

  15. Diagnostic Assays for Identification of Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

    PubMed Central

    Weickhardt, Andrew J.; Aisner, Dara L.; Franklin, Wilbur A.; Varella-Garcia, Marileila; Doebele, Robert C.; Camidge, D. Ross

    2014-01-01

    In series dominated by adenocarcinoma histology, approximately 5% of non–small cell lung cancers (NSCLCs) harbor an anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib, a tyrosine kinase inhibitor with significant activity against ALK, has demonstrated high response rates and prolonged progression-free survival in ALK-positive patients enrolled in phase 1/2 clinical trials. In 2011, crizotinib received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of proven ALK-positive NSCLC using an FDA-approved diagnostic test. Currently, only break-apart fluorescence in situ hybridization testing is FDA approved as a companion diagnostic for crizotinib; however, many other assays are available or in development. In the current review, the authors summarize the diagnostic tests available, or likely to become available, that could be used to identify patients with ALK-positive NSCLC, highlighting the pros and cons of each. PMID:23280244

  16. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma

    PubMed Central

    Infarinato, Nicole R.; Park, Jin H.; Krytska, Kateryna; Ryles, Hannah T.; Sano, Renata; Szigety, Katherine M.; Li, Yimei; Zou, Helen Y.; Lee, Nathan V.; Smeal, Tod; Lemmon, Mark A.; Mossé, Yael P.

    2015-01-01

    Neuroblastomas (NBs) harboring activating point mutations in Anaplastic Lymphoma Kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants, and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and sensitive xenograft mouse models of NB, as well as in PDXs harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance, and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in a R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated NB. PMID:26554404

  17. A Screening Method for the ALK Fusion Gene in NSCLC.

    PubMed

    Murakami, Yoshiko; Mitsudomi, Tetsuya; Yatabe, Yasushi

    2012-01-01

    Lung cancer research has recently made significant progress in understanding the molecular pathogenesis of lung cancer and in developing treatments for it. Such achievements are directly utilized in clinical practice. Indeed, the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (ALK) fusion gene was first described in non-small cell lung cancer in 2007, and a molecularly targeted drug against the fusion was approved in 2011. However, lung cancer with the ALK fusion constitutes only a small fraction of lung cancers; therefore, efficient patient selection is crucial for successful treatment using the ALK inhibitor. Currently, RT-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry are commonly used to detect the ALK fusion. Although FISH is currently the gold standard technique, there are no perfect methods for detecting these genetic alterations. In this article, we discuss the advantages and disadvantages of each method and the possible criteria for selecting patients who are more likely to have the ALK fusion. If we can successfully screen patients, then ALK inhibitor treatment will be the best example of personalized therapy in terms of selecting patients with an uncommon genotype from a larger group with the same tumor phenotype. In other words, the personalized therapy may offer a new challenge for current clinical oncology. PMID:22655265

  18. A Screening Method for the ALK Fusion Gene in NSCLC

    PubMed Central

    Murakami, Yoshiko; Mitsudomi, Tetsuya; Yatabe, Yasushi

    2012-01-01

    Lung cancer research has recently made significant progress in understanding the molecular pathogenesis of lung cancer and in developing treatments for it. Such achievements are directly utilized in clinical practice. Indeed, the echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (ALK) fusion gene was first described in non-small cell lung cancer in 2007, and a molecularly targeted drug against the fusion was approved in 2011. However, lung cancer with the ALK fusion constitutes only a small fraction of lung cancers; therefore, efficient patient selection is crucial for successful treatment using the ALK inhibitor. Currently, RT-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry are commonly used to detect the ALK fusion. Although FISH is currently the gold standard technique, there are no perfect methods for detecting these genetic alterations. In this article, we discuss the advantages and disadvantages of each method and the possible criteria for selecting patients who are more likely to have the ALK fusion. If we can successfully screen patients, then ALK inhibitor treatment will be the best example of personalized therapy in terms of selecting patients with an uncommon genotype from a larger group with the same tumor phenotype. In other words, the personalized therapy may offer a new challenge for current clinical oncology. PMID:22655265

  19. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach

    PubMed Central

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-01-01

    Abstract Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma. A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups. The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUVmax and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUVmax, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors. ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas. PMID:26469915

  20. Detection of rearrangement of anaplastic lymphoma kinase (ALK) and mutation of epidermal growth factor receptor (EGFR) in primary pulmonary lymphoepithelioma-like carcinoma

    PubMed Central

    Wang, Liang; Lin, Yongbin; Cai, Qingqing; Long, Hao; Zhang, Yu; Rong, Tiehua

    2015-01-01

    Background Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a distinct rare subtype of lung cancer. The prevalence of anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) mutation in primary pulmonary LELC had not been thoroughly investigated. Methods We investigated a cohort of 42 patients with primary pulmonary LELC and genotyped for ALK rearrangement and EGFR mutation. ALK rearrangement was detected by fluorescence in situ hybridization (FISH). EGFR mutational analysis of exons 18 through 21 was analyzed by TaqMan real-time polymerase chain reaction (PCR). Results Epstein-Barr virus-encoded RNAs (EBERs) showed positive signals in all 42 patients. By immunohistochemistry staining, all patients demonstrated positive expression of CK5/6 and P63, but almost all patients were negative for TTF-1 (34/34, 100%) or CK7 (34/35, 97.1%). None of the 42 patients had ALK rearrangement. Of 42 patients tested, only one patient (2.4%) harbored L858R mutation and gefitinib was applied to this case, however no objective response was observed and the progression free survival (PFS) time was only 1 month. Conclusions Primary pulmonary LELC is a unique histological subtype of lung cancer. ALK rearrangement and EGFR mutation are lack and they may not be the oncogenic driver gene in pulmonary LELC. Future efforts should be made to explore other oncogenic driver gene to guide targeted therapy in this rare disease to determine the optimal treatment. Keywords Pulmonary lymphoepithelioma-like carcinoma (LELC); anaplastic lymphoma kinase (ALK); epidermal growth factor receptor (EGFR); targeted therapy; Epstein-Barr virus (EBV) PMID:26543602

  1. New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK

    PubMed Central

    Di Paolo, Daniela; Yang, D.; Pastorino, Fabio; Emionite, Laura; Cilli, Michele; Daga, Antonio; Destefanis, Elisa; Di Fiore, Annarita; Piaggio, Francesca; Brignole, Chiara; Xu, Xiaobao; Liang, Chris; Gibbons, James

    2015-01-01

    Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors. PMID:26299615

  2. Alk1 controls arterial endothelial cell migration in lumenized vessels.

    PubMed

    Rochon, Elizabeth R; Menon, Prahlad G; Roman, Beth L

    2016-07-15

    Heterozygous loss of the arterial-specific TGFβ type I receptor, activin receptor-like kinase 1 (ALK1; ACVRL1), causes hereditary hemorrhagic telangiectasia (HHT). HHT is characterized by development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). However, how decreased ALK1 signaling leads to AVMs is unknown. To understand the cellular mis-steps that cause AVMs, we assessed endothelial cell behavior in alk1-deficient zebrafish embryos, which develop cranial AVMs. Our data demonstrate that alk1 loss has no effect on arterial endothelial cell proliferation but alters arterial endothelial cell migration within lumenized vessels. In wild-type embryos, alk1-positive cranial arterial endothelial cells generally migrate towards the heart, against the direction of blood flow, with some cells incorporating into endocardium. In alk1-deficient embryos, migration against flow is dampened and migration in the direction of flow is enhanced. Altered migration results in decreased endothelial cell number in arterial segments proximal to the heart and increased endothelial cell number in arterial segments distal to the heart. We speculate that the consequent increase in distal arterial caliber and hemodynamic load precipitates the flow-dependent development of downstream AVMs. PMID:27287800

  3. Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

    PubMed Central

    Aspalter, Irene Maria; Gordon, Emma; Dubrac, Alexandre; Ragab, Anan; Narloch, Jarek; Vizán, Pedro; Geudens, Ilse; Collins, Russell Thomas; Franco, Claudio Areias; Abrahams, Cristina Luna; Thurston, Gavin; Fruttiger, Marcus; Rosewell, Ian; Eichmann, Anne; Gerhardt, Holger

    2015-01-01

    Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling. PMID:26081042

  4. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer

    PubMed Central

    Hrustanovic, Gorjan; Olivas, Victor; Pazarentzos, Evangelos; Tulpule, Asmin; Asthana, Saurabh; Blakely, Collin M; Okimoto, Ross A; Lin, Luping; Neel, Dana S; Sabnis, Amit; Flanagan, Jennifer; Chan, Elton; Varella-Garcia, Marileila; Aisner, Dara L; Vaishnavi, Aria; Ou, Sai-Hong I; Collisson, Eric A; Ichihara, Eiki; Mack, Philip C; Lovly, Christine M; Karachaliou, Niki; Rosell, Rafael; Riess, Jonathan W; Doebele, Robert C; Bivona, Trever G

    2016-01-01

    One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS–mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRASWT) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK–positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes. PMID:26301689

  5. Successful oral desensitization against skin rash induced by alectinib in a patient with anaplastic lymphoma kinase-positive lung adenocarcinoma: A case report.

    PubMed

    Shirasawa, Masayuki; Kubotaa, Masaru; Harada, Shinya; Niwa, Hideyuki; Kusuhara, Seiichiro; Kasajima, Masashi; Hiyoshi, Yasuhiro; Ishihara, Mikiko; Igawa, Satoshi; Masuda, Noriyuki

    2016-09-01

    Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK-positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second-line therapy. However, she discontinued alectinib therapy after 11days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities. PMID:27565916

  6. Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non–Small Cell Lung Cancer

    PubMed Central

    Sargis, Robert M.; Salgia, Ravi

    2014-01-01

    Objectives Non–small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/ MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes. Materials and Methods Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions. Results Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range. Conclusions Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life. PMID:23934135

  7. EML4-ALK translocation is associated with early onset of disease and other clinicopathological features in Chinese female never-smokers with non-small-cell lung cancer

    PubMed Central

    REN, WEIHONG; ZHANG, BO; MA, JIE; LI, WENCAI; LAN, JIANYUN; MEN, HUI; ZHANG, QINXIAN

    2015-01-01

    Non-small-cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation is resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, but responds to the ALK-TKI crizotinib. Characterization of EML4-ALK translocation may provide invaluable information to facilitate disease diagnosis and improve the outcome of customized treatment. Although the occurrence of EML4-ALK translocation is likely to be affected by the smoking habits and gender of patients, the translocation has not been characterized extensively in female never-smokers with NSCLC. Therefore, 280 female never-smokers that were diagnosed with NSCLC were enrolled in the present study, and characteristics of EML4-ALK translocation, including the frequency, were determined in these NSCLC patients. EML4-ALK fusion variants were detected using Multiplex one-step reverse transcription-polymerase chain reaction and subsequently confirmed by DNA sequencing and Vysis ALK Break Apart fluorescence in situ hybridization analysis. The EML4-ALK fusion variants were detected in 21 carcinoma tissue specimens, accounting for 7.5% of the enrolled patients. Out of these patients with EML4-ALK fusion variants, EML4-ALK fusion variant 1 was identified in 12 patients, indicating that variant 1 is the most common type of EML4-ALK fusion gene in the present cohort of patients. ALK mRNA was aberrantly expressed in all the tissues with EML4-ALK translocation, but not in the carcinoma tissues without EML4-ALK translocation. In addition, the EML4-ALK translocation was more frequently found in younger patients. The median age of patients with EML4-ALK translocation was 50.95±2.29 years, which was significantly younger (P<0.01) than the median age of the patients without EML4-ALK translocation (57.15±0.56). The EML4-ALK translocation was detected exclusively in undifferentiated tumors that were graded as

  8. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer

    PubMed Central

    Kelly, Lindsey M.; Barila, Guillermo; Liu, Pengyuan; Evdokimova, Viktoria N.; Trivedi, Sumita; Panebianco, Federica; Gandhi, Manoj; Carty, Sally E.; Hodak, Steven P.; Luo, Jianhua; Dacic, Sanja; Yu, Yan P.; Nikiforova, Marina N.; Ferris, Robert L.; Altschuler, Daniel L.; Nikiforov, Yuri E.

    2014-01-01

    Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone–independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients. PMID:24613930

  9. Uterine ALK3 is essential during the window of implantation

    PubMed Central

    Monsivais, Diana; Clementi, Caterina; Peng, Jia; Titus, Mary M.; Barrish, James P.; Creighton, Chad J.; Lydon, John P.; DeMayo, Francesco J.; Matzuk, Martin M.

    2016-01-01

    The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3flox/flox-Pgr-cre–positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity. PMID:26721398

  10. Uterine ALK3 is essential during the window of implantation.

    PubMed

    Monsivais, Diana; Clementi, Caterina; Peng, Jia; Titus, Mary M; Barrish, James P; Creighton, Chad J; Lydon, John P; DeMayo, Francesco J; Matzuk, Martin M

    2016-01-19

    The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3(flox) (/flox)-Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity. PMID:26721398

  11. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

    PubMed

    Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

    2015-11-24

    The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC. PMID:26517679

  12. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells

    PubMed Central

    Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

    2015-01-01

    The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC. PMID:26517679

  13. ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance

    PubMed Central

    Li, Nan; Zhang, Yong; Jing, Pengyu; Chang, Ning; Wu, Jianxiong; Ren, Xinling; Zhang, Jian

    2016-01-01

    During the past decade, more than 10 targetable oncogenic driver genes have been validated in non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) and ROS1 kinase are two new driver genes implicated in ALK- and ROS1-rearranged NSCLC. Inhibition of ALK and ROS1 by crizotinib has been reported to be highly effective and well tolerated in these patients. However, resistance to crizotinib emerges years after treatment, and increasing efforts have been made to overcome this issue. Here, we review the biology of ALK and ROS1 and their roles in cancer progression. We also summarize the ongoing and completed clinical trials validating ALK and ROS1 as targets for cancer treatment. In the last section of the review, we will discuss the molecular mechanisms of crizotinib resistance and focus approaches to overcome it. This review describes an exciting new area of research and may provide new insights for targeted cancer therapies. PMID:26802023

  14. VCL-ALK Renal Cell Carcinoma in Children With Sickle-cell Trait

    PubMed Central

    Smith, Nathaniel E.; Deyrup, Andrea T.; Marinño-Enriquez, Adrian; Fletcher, Jonathan A.; Bridge, Julia A.; Illei, Peter B.; Netto, George J.; Argani, Pedram

    2015-01-01

    We report the third case of a renal cell carcinoma bearing a fusion of the vinculin (VCL) and anaplastic lymphoma kinase (ALK) genes. Like the 2 other reported cases, this neoplasm occurred in a young patient (6 y old) with sickle-cell trait and demonstrated distinctive morphologic features including medullary epicenter, discohesive polygonal or spindle-shaped cells with prominent cytoplasmic vacuoles, and prominent lymphocytic infiltrate. The neoplastic cells demonstrated focal membranous labeling for ALK protein by immunohistochemistry, ALK gene rearrangement by fluorescence in situ hybridization, and a specific VCL-ALK gene fusion by reverse transcriptase polymerase chain reaction. VCL-ALK renal cell carcinoma may represent the eighth sickle-cell nephropathy. PMID:24698962

  15. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer

    PubMed Central

    Wiesner, Thomas; Lee, William; Obenauf, Anna C.; Ran, Leili; Murali, Rajmohan; Zhang, Qi Fan; Wong, Elissa W. P.; Hu, Wenhuo; Scott, Sasinya N.; Shah, Ronak H.; Landa, Iñigo; Button, Julia; Lailler, Nathalie; Sboner, Andrea; Gao, Dong; Murphy, Devan A.; Cao, Zhen; Shukla, Shipra; Hollmann, Travis J.; Wang, Lu; Borsu, Laetitia; Merghoub, Taha; Schwartz, Gary K.; Postow, Michael A.; Ariyan, Charlotte E.; Fagin, James A.; Zheng, Deyou; Ladanyi, Marc; Busam, Klaus J.; Berger, Michael F.; Chen, Yu; Chi, Ping

    2016-01-01

    Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~ 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALKATI. In ALKATI-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites1. ALKATI is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALKATI transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALKATI stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALKATI, suggesting that patients with ALKATI-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. PMID:26444240

  16. Spitz Tumors: Comparison of Histological Features in Relationship to Immunohistochemical Staining for ALK and NTRK1.

    PubMed

    Kiuru, Maija; Jungbluth, Achim; Kutzner, Heinz; Wiesner, Thomas; Busam, Klaus J

    2016-05-01

    Spitz tumors are a group of melanocytic neoplasms with distinct morphological features that tend to affect young individuals. Distinguishing benign from malignant Spitz tumors can be challenging, but cytogenetic and molecular tests have contributed to improvements in diagnostic accuracy. Spitz tumors harbor diverse genetic alterations, including mutations in HRAS, loss of BAP1, or kinase fusions in ROS1, NTRK1, ALK, BRAF, and RET genes. Limited data exist on the correlation between histopathological features and kinase fusions. Here, we describe the histopathological features of 105 Spitz tumors (Spitz nevi and atypical Spitz tumors), comparing lesions according to their immunoreactivity for ALK or NTRK1. Intersecting fascicular growth of fusiform melanocytes was seen in all but one ALK-positive tumor (27 of 28 or 96.4%), whereas it was infrequent in NTRK1-positive tumors (5 of 20 or 25.0%) and tumors negative for both ALK and NTRK1 (96.4% vs 25.0% vs 8.7%, P < .0027). There was a trend toward ALK-positive tumors being amelanotic compared with NTRK1-positive tumors and combined ALK-/NTRK1-negative tumors (89.3% vs 45% vs 47.4%, respectively, P = .1023) and lacking epithelioid cell morphology (0% vs 45.0% vs 41%, respectively, P = .6985). In conclusion, this study confirms that although not specific, the growth pattern of intersecting fascicles of amelanotic fusiform melanocytes is strongly associated with ALK expression. PMID:26873340

  17. Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects.

    PubMed

    Lau, Yvonne Y; Gu, Wen; Lin, Tiffany; Song, Dongweon; Yu, Richard; Scott, Jeffrey W

    2016-05-01

    Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib because the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients. PMID:26272586

  18. EML4-ALK induces epithelial–mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells

    SciTech Connect

    Guo, Fuchun; Liu, Xiaoke Qing, Qin Sang, Yaxiong Feng, Chengjun Li, Xiaoyu Jiang, Li Su, Pei Wang, Yongsheng

    2015-04-10

    The echinoderm microtubule-associated protein-like 4(EML4) – anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation. - Highlights: • EML4-ALK induced epithelial–mesenchymal transition in H1299 cells. • Expression of EML4-ALK promotes invasion and migration in vitro. • EML4-ALK enhanced sphere formation and stem cell-like properties in H1299 cells. • Blockage of ERK1/2 reverse Epithelial–Mesenchymal transition induced by EML4-ALK.

  19. Automation of ALK gene rearrangement testing with fluorescence in situ hybridization (FISH): a feasibility study.

    PubMed

    Zwaenepoel, Karen; Merkle, Dennis; Cabillic, Florian; Berg, Erica; Belaud-Rotureau, Marc-Antoine; Grazioli, Vittorio; Herelle, Olga; Hummel, Michael; Le Calve, Michele; Lenze, Dido; Mende, Stefanie; Pauwels, Patrick; Quilichini, Benoit; Repetti, Elena

    2015-02-01

    In the past several years we have observed a significant increase in our understanding of molecular mechanisms that drive lung cancer. Specifically in the non-small cell lung cancer sub-types, ALK gene rearrangements represent a sub-group of tumors that are targetable by the tyrosine kinase inhibitor Crizotinib, resulting in significant reductions in tumor burden. Phase II and III clinical trials were performed using an ALK break-apart FISH probe kit, making FISH the gold standard for identifying ALK rearrangements in patients. FISH is often considered a labor and cost intensive molecular technique, and in this study we aimed to demonstrate feasibility for automation of ALK FISH testing, to improve laboratory workflow and ease of testing. This involved automation of the pre-treatment steps of the ALK assay using various protocols on the VP 2000 instrument, and facilitating automated scanning of the fluorescent FISH specimens for simplified enumeration on various backend scanning and analysis systems. The results indicated that ALK FISH can be automated. Significantly, both the Ikoniscope and BioView system of automated FISH scanning and analysis systems provided a robust analysis algorithm to define ALK rearrangements. In addition, the BioView system facilitated consultation of difficult cases via the internet. PMID:25576649

  20. Fiberoptic intubation with patients in sitting position.

    PubMed

    Lai, Yu-Yung; Chien, Jui-Teng; Huang, Shen-Jer

    2007-09-01

    Flexible fiberoptic endoscope is the most valuable tool for anesthesiologists to manage difficult airways. Correctly positioning of the patient during fiberoptic intubation aids the clinician to rapidly secure the airway, because it not only saves time, but also minimizes the risk of repeated attempts of intubation with possible serious consequences in the wake. In general, fiberoptic intubation is carried out with the patient in the supine position, but there are situations in which the intubation requires the subjects to be in the sitting position. The sitting position also changes the position of performing anesthesiologist relative to the patient, presenting an inverse view contrary to that of traditional laryngoscopy. We can often obtain a superior view from fiberoptic intubation. Fiberoptic intubation in the sitting position can be applied to all patients, as long as there is no contraindication of having a patient be sat. PMID:17972620

  1. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2016-01-01

    The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. PMID:26753004

  2. Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of Caucasian non-smokers.

    PubMed

    Just, Pierre-Alexandre; Cazes, Aurélie; Audebourg, Anne; Cessot, Anatole; Pallier, Karine; Danel, Claire; Vacher-Lavenu, Marie-Cécile; Laurent-Puig, Pierre; Terris, Benoît; Blons, Hélène

    2012-06-01

    EML4-ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFR(wt/wt) lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK-rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK-rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK-rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80-100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non-EML4-ALK ALK-rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step. PMID:22153831

  3. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer

    PubMed Central

    Lee, Christian C.; Gainor, Justin F.; Crystal, Adam S.; Michellys, Pierre-Yves; Awad, Mark M.; Yanagitani, Noriko; Kim, Sungjoon; Pferdekamper, AnneMarie C.; Li, Jie; Kasibhatla, Shailaja; Sun, Frank; Sun, Xiuying; Hua, Su; McNamara, Peter; Mahmood, Sidra; Lockerman, Elizabeth L.; Fujita, Naoya; Nishio, Makoto; Harris, Jennifer L.; Shaw, Alice T.; Engelman, Jeffrey A.

    2014-01-01

    Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that ceritinib potently overcomes crizotinib resistance mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to ceritinib. Altogether our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease. PMID:24675041

  4. The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53.

    PubMed

    Drakos, E; Atsaves, V; Schlette, E; Li, J; Papanastasi, I; Rassidakis, G Z; Medeiros, L J

    2009-12-01

    p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK+ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip(S/L), and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK+ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK+ ALCL patients. PMID:19741726

  5. ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma

    PubMed Central

    Tabbó, Fabrizio; Barreca, Antonella; Piva, Roberto; Inghirami, Giorgio

    2012-01-01

    The discovery by Morris et al. (1994) of the genes contributing to the t(2;5)(p23;q35) translocation has laid the foundation for a molecular based recognition of anaplastic large cell lymphoma and highlighted the need for a further stratification of T-cell neoplasia. Likewise the detection of anaplastic lymphoma kinase (ALK) genetic lesions among many human cancers has defined unique subsets of cancer patients, providing new opportunities for innovative therapeutic interventions. The objective of this review is to appraise the molecular mechanisms driving ALK-mediated transformation, and to maintain the neoplastic phenotype. The understanding of these events will allow the design and implementation of novel tailored strategies for a well-defined subset of cancer patients. PMID:22649787

  6. Clinical skills: bed making and patient positioning.

    PubMed

    Pellatt, Glynis Collis

    Providing a clean, comfortable bed and positioning a patient in the optimum posture for prevention of complications and to enable maximum independence are fundamental nursing skills. Bed-making is a daily routine that requires practical and technical skills. Selecting the correct posture for a patient in bed or in a chair is essential for physiological functioning and recovery. In this article bed-making is described, as are positioning and re-positioning in relation to patients in bed, armchairs and wheelchairs. Infection control and moving and handling issues are also considered. PMID:17505378

  7. ALK evaluation in the world of multiplex testing: Network Genomic Medicine (NGM): the Cologne model for implementing personalised oncology.

    PubMed

    Heydt, C; Kostenko, A; Merkelbach-Bruse, S; Wolf, J; Büttner, R

    2016-09-01

    Comprehensive molecular genotyping of lung cancers has become a key requirement for guiding therapeutic decisions. As a paradigm model of implementing next-generation comprehensive diagnostics, Network Genomic Medicine (NGM) has established central diagnostic and clinical trial platforms for centralised testing and decentralised personalised treatment in clinical practice. Here, we describe the structures of the NGM network and give a summary of technologies to identify patients with anaplastic lymphoma kinase (ALK) fusion-positive lung adenocarcinomas. As unifying test platforms will become increasingly important for delivering reliable, quick and affordable tests, the NGM diagnostic platform is currently implementing a comprehensive hybrid capture-based parallel sequencing pan-cancer assay. PMID:27573753

  8. Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function.

    PubMed

    de Vinuesa, Amaya García; Bocci, Matteo; Pietras, Kristian; Ten Dijke, Peter

    2016-08-15

    Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented. PMID:27528762

  9. Treatment for ALK-mutated non-small-cell lung cancer: a new miracle in the research race.

    PubMed

    de Castro-Carpeño, J; Perona, R; Belda-Iniesta, C

    2011-11-01

    The discovery of anaplastic lymphoma kinase (ALK) rearrangements in a subset of patients with nonsmall- cell lung cancer (NSCLC) and its potential blockage by specific inhibitors such as crizotinib has been one of the latest advances in the treatment of this disease. In this article, we will review the most important clinical aspects of ALK alterations in NSCLC patients and the pending questions to answer: the most effective means of diagnosing ALK-rearranged NSCLC, and efficacy, toxicity profile and potential mechanisms of resistance to crizotinib. PMID:22082640

  10. An unusual case of anaplastic lymphoma kinase-positive large B-cell lymphoma in an elderly patient: A case report and discussion

    PubMed Central

    XIONG, HANZHEN; LIU, SHAO-YAN; YANG, YUE-XIN; TAN, XUE-XIAN; LUO, QIU-PING; PENG, JUAN; XIONG, ZHONG-TANG; CHEN, HUI; CHEN, JUAN; LI, ZHI; JIANG, QING-PING

    2016-01-01

    We present an unusual case of anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma, with rapid clinical progression, which occurred in a 90-year-old male patient. The patient presented with numerous enlarged lymph nodes in the neck and mediastinum. Histopathological analysis of a single lymph node detected diffuse large immunoblastic- or plasmablastic-like tumor cells, which were strongly immunoreactive for ALK in a granular cytoplasmic distribution, but negative for the expression of CD20 and CD79a. In addition, polymerase chain reaction assays were unable to detect clonal rearrangements of the T cell receptor-γ and immunoglobulin heavy chain genes in the tumor lesion, and in situ hybridization tested negative for infection with Epstein-Barr virus. The patient underwent a single cycle of chemotherapy using the cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (E-CHOP) regimen; however, the patient developed pleural effusions with respiratory distress, associated with clinical deterioration. The patient succumbed to the disease within 4 months of initial presentation. To the best of our knowledge, this is the eldest patient with this type of lymphoma to be reported in the literature. PMID:27168806

  11. [Positioning of patients with acute respiratory failure].

    PubMed

    Bein, T

    2012-11-01

    The collapse of lung tissue, edema and intrapulmonary shunt are the main symptoms in patients with acute respiratory insufficiency. The techniques of ventilation in a prone position and continuous lateral rotational therapy (CLRT) are based on these pathophysiological changes. Ventilation in a prone position was found to improve ventilation and perfusion relationships and reduction in the pleural pressure gradient. In hypoxemic lung failure (PaO(2)/FIO(2) <100) a prone position was found to improve oxygenation as a rescue measure and to improve survival. In contrast CLRT is considered to be an early therapeutic or prophylactic measure aimed at prevention of ventilation-associated complications. In trauma patients these beneficial effects were demonstrated in several studies. Positioning therapy can be accompanied by potentially serious complications (e.g. face and skin ulceration, accidental loss of tubes and catheters and cardiac arrhythmias) and its use requires routine management and exact knowledge of indications and risks. PMID:23086293

  12. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer

    PubMed Central

    Nilsson, R. Jonas A.; Karachaliou, Niki; Berenguer, Jordi; Gimenez-Capitan, Ana; Schellen, Pepijn; Teixido, Cristina; Tannous, Jihane; Kuiper, Justine L.; Drees, Esther; Grabowska, Magda; van Keulen, Marte; Heideman, Danielle A.M.; Thunnissen, Erik; Dingemans, Anne-Marie C.; Viteri, Santiago; Tannous, Bakhos A.; Drozdowskyj, Ana; Rosell, Rafael; Smit, Egbert F.; Wurdinger, Thomas

    2016-01-01

    Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone. PMID:26544515

  13. Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non–Small Cell Lung Cancer Cells

    PubMed Central

    Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

    2016-01-01

    Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. PMID:26992917

  14. [Modalities of use of ceritinib (Zykadia™), a 2nd generation ALK inhibitor, in advanced stage non-small cell lung cancer].

    PubMed

    Giroux Leprieur, Etienne; Fallet, Vincent; Wislez, Marie

    2015-12-01

    Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib. PMID:26597476

  15. Downregulation of NPM-ALK by siRNA causes anaplastic large cell lymphoma cell growth inhibition and augments the anti cancer effects of chemotherapy in vitro.

    PubMed

    Hsu, Faye Yuan-yi; Zhao, Yi; Anderson, W French; Johnston, Patrick B

    2007-06-01

    The fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), results from the chromosome translocation t(2;5)(p23;q25) and is present in 50-70 percent of anaplastic large-cell lymphomas (ALCLs). NPM-ALK is a constitutively activated kinase that transforms cells through stimulating several mitogenic signaling pathways. To examine if the NPM-ALK is a potential therapeutic target in ALCL, we used siRNA to specifically downregulate the expression of the NPM-ALK in ALCL cell lines. In this report, we demonstrated viability loss in t(2;5)-positive ALCL cell lines, SUDHL-1 and Karpas 299 cells, but not in lymphoma cell lines without the chromosome translocation, Jurkat and Granta 519 cells. Further study demonstrated that the downregulation of NPM-ALK resulted in decreased cell proliferation and increased cell apoptosis. When used in combination with chemotherapeutic agents, such as doxorubicin, the inhibition of the NPM-ALK augments the chemosensitivity of the tumor cells. These results revealed the importance of continuous expression of NPM-ALK in maintaining the growth of ALCL cells. Our data also suggested that the repression of the fusion gene might be a potential novel therapeutic strategy for NPM-ALK positive ALCLs. PMID:17612934

  16. Patient position verification using small IMRT fields

    SciTech Connect

    Bol, G. H.; Heide, U. A. van der; Nederveen, A. J.; Kotte, A. N. T. J.; Lagendijk, J. J. W.

    2006-07-15

    A commonly used approach to quantify and minimize patient setup errors is by using electronic portal imaging devices (EPIDs). The position of the tumor can be verified indirectly by matching the bony anatomy to a reference image containing the same structures. In this paper we present two off-line methods for detecting the position of the bony anatomy automatically, even if every single portal image of each segment of an IMRT treatment beam contains insufficient matching information. Extra position verification fields will no longer be necessary, which reduces the total dose to the patient. The first method, the stack matching method (SMM), stacks the portal image of each segment of a beam to a three dimensional (3D) volume, and this volume is subsequently used during the matching phase. The second method [the averaged projection matching method (APMM)], is a simplification of the first one, since the initially created volume is reduced again to a 2D artificial image, which speeds up the matching procedure considerably, without a significant loss of accuracy. Matching is based on normalized mutual information. We demonstrate our methods by comparing them to existing matching routines, such as matching based on the largest segment. Both phantom and patient experiments show that our methods are comparable with the results obtained from standard position verification methods. The matches are verified by means of visual inspection. Furthermore, we show that when a distinct area of 40-60 cm{sup 2} of the EPID is exposed during one treatment beam, both SMM and APMM are able to deliver a good matching result.

  17. Structural and Mutational Analysis of Escherichia coli AlkB Provides Insight into Substrate Specificity and DNA Damage Searching

    SciTech Connect

    Holland, P.; Hollis, T

    2010-01-01

    In Escherichia coli, cytotoxic DNA methyl lesions on the N1 position of purines and N3 position of pyrimidines are primarily repaired by the 2-oxoglutarate (2-OG) iron(II) dependent dioxygenase, AlkB. AlkB repairs 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions, but it also repairs 1-methylguanine (1-meG) and 3-methylthymine (3-meT) at a much less efficient rate. How the AlkB enzyme is able to locate and identify methylated bases in ssDNA has remained an open question. We determined the crystal structures of the E. coli AlkB protein holoenzyme and the AlkB-ssDNA complex containing a 1-meG lesion. We coupled this to site-directed mutagenesis of amino acids in and around the active site, and tested the effects of these mutations on the ability of the protein to bind both damaged and undamaged DNA, as well as catalyze repair of a methylated substrate. A comparison of our substrate-bound AlkB-ssDNA complex with our unliganded holoenzyme reveals conformational changes of residues within the active site that are important for binding damaged bases. Site-directed mutagenesis of these residues reveals novel insight into their roles in DNA damage recognition and repair. Our data support a model that the AlkB protein utilizes at least two distinct conformations in searching and binding methylated bases within DNA: a 'searching' mode and 'repair' mode. Moreover, we are able to functionally separate these modes through mutagenesis of residues that affect one or the other binding state. Finally, our mutagenesis experiments show that amino acid D135 of AlkB participates in both substrate specificity and catalysis.

  18. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance

    PubMed Central

    Tupper, Tanya; Cheng, Katherine; Wang, Yuchuan; Tan, Xiaohong; Altabef, Abigail; Woo, Sue-Ann; Chen, Liang; Reibel, Jacob B.; Janne, Pasi A.; Sharpless, Norman E.; Engelman, Jeffrey A.; Shapiro, Geoffrey I.; Kung, Andrew L.; Wong, Kwok-Kin

    2014-01-01

    Purpose To extend the results of a phase III trial in non-small cell lung cancer patients with adenocarcinomas harboring EML4-ALK fusion. Experimental Design we performed a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared to chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared to chemotherapy-treated mice. Pemetrexed produced superior overall survival compared to docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. Additionally, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance. PMID:24327273

  19. Two Cases of Renal Cell Carcinoma Harboring a Novel STRN-ALK Fusion Gene.

    PubMed

    Kusano, Hironori; Togashi, Yuki; Akiba, Jun; Moriya, Fukuko; Baba, Katsuyoshi; Matsuzaki, Naomi; Yuba, Yoshiaki; Shiraishi, Yusuke; Kanamaru, Hiroshi; Kuroda, Naoto; Sakata, Seiji; Takeuchi, Kengo; Yano, Hirohisa

    2016-06-01

    Anaplastic lymphoma kinase (ALK) translocation renal cell carcinomas (RCCs) have been reported by several independent groups in recent times. The clinical behavior and histopathologic characteristics of these carcinomas are not fully understood because of the paucity of cases reported. Here, we describe 2 cases of RCC harboring a novel striatin (STRN)-ALK fusion. The first case was a 33-year-old woman with no sickle cell trait who underwent nephrectomy for right renal mass and had late recurrence in para-aortic lymph nodes twice 10 and 12 years after initial surgery. After the second recurrence, she was carefully observed without any treatment. Twenty-six years after the initial nephrectomy, the second para-aortic lymphadenectomy was performed, and gastrectomy was performed for newly developed primary gastric cancer. The resected para-aortic lymph nodes were largely replaced by metastatic carcinoma. The second case was a 38-year-old man with no sickle cell trait who underwent cytoreductive nephrectomy followed by sunitinib therapy for metastatic RCC. In both cases, the tumor showed solid, papillary, tubular, and mucinous cribriform structures. Psammoma bodies were occasionally seen in the stroma. Tumor cells had a large nucleus and prominent nucleoli with predominantly eosinophilic cytoplasm. Rhabdoid cells and signet-ring cells were also observed. Intracytoplasmic mucin deposition and background mucinous stroma were confirmed. In the second case, tumor necrosis was seen in some areas. Tumor cells exhibited diffuse positive staining for ALK in both cases. ALK translocation was confirmed by fluorescent in situ hybridization, and further gene analysis revealed a STRN-ALK fusion. These cases provide great insights into ALK translocation RCCs. PMID:26848800

  20. A new protein superfamily includes two novel 3-methyladenine DNA glycosylases from Bacillus cereus, AlkC and AlkD.

    PubMed

    Alseth, Ingrun; Rognes, Torbjørn; Lindbäck, Toril; Solberg, Inger; Robertsen, Kristin; Kristiansen, Knut Ivan; Mainieri, Davide; Lillehagen, Lucy; Kolstø, Anne-Brit; Bjørås, Magnar

    2006-03-01

    Soil bacteria are heavily exposed to environmental methylating agents such as methylchloride and may have special requirements for repair of alkylation damage on DNA. We have used functional complementation of an Escherichia coli tag alkA mutant to screen for 3-methyladenine DNA glycosylase genes in genomic libraries of the soil bacterium Bacillus cereus. Three genes were recovered: alkC, alkD and alkE. The amino acid sequence of AlkE is homologous to the E. coli AlkA sequence. AlkC and AlkD represent novel proteins without sequence similarity to any protein of known function. However, iterative and indirect sequence similarity searches revealed that AlkC and AlkD are distant homologues of each other within a new protein superfamily that is ubiquitous in the prokaryotic kingdom. Homologues of AlkC and AlkD were also identified in the amoebas Entamoeba histolytica and Dictyostelium discoideum, but no other eukaryotic counterparts of the superfamily were found. The alkC and alkD genes were expressed in E. coli and the proteins were purified to homogeneity. Both proteins were found to be specific for removal of N-alkylated bases, and showed no activity on oxidized or deaminated base lesions in DNA. B. cereus AlkC and AlkD thus define novel families of alkylbase DNA glycosylases within a new protein superfamily. PMID:16468998

  1. A new protein superfamily includes two novel 3-methyladenine DNA glycosylases from Bacillus cereus, AlkC and AlkD

    PubMed Central

    Alseth, Ingrun; Rognes, Torbjørn; Lindbäck, Toril; Solberg, Inger; Robertsen, Kristin; Kristiansen, Knut Ivan; Mainieri, Davide; Lillehagen, Lucy; Kolstø, Anne-Brit; Bjørås, Magnar

    2006-01-01

    Summary Soil bacteria are heavily exposed to environmental methylating agents such as methylchloride and may have special requirements for repair of alkylation damage on DNA. We have used functional complementation of an Escherichia coli tag alkA mutant to screen for 3-methyladenine DNA glycosylase genes in genomic libraries of the soil bacterium Bacillus cereus. Three genes were recovered: alkC, alkD and alkE. The amino acid sequence of AlkE is homologous to the E. coli AlkA sequence. AlkC and AlkD represent novel proteins without sequence similarity to any protein of known function. However, iterative and indirect sequence similarity searches revealed that AlkC and AlkD are distant homologues of each other within a new protein superfamily that is ubiquitous in the prokaryotic kingdom. Homologues of AlkC and AlkD were also identified in the amoebas Entamoeba histolytica and Dictyostelium discoideum, but no other eukaryotic counterparts of the superfamily were found. The alkC and alkD genes were expressed in E. coli and the proteins were purified to homogeneity. Both proteins were found to be specific for removal of N-alkylated bases, and showed no activity on oxidized or deaminated base lesions in DNA. B. cereus AlkC and AlkD thus define novel families of alkylbase DNA glycosylases within a new protein superfamily. PMID:16468998

  2. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer.

    PubMed

    Kohno, Takashi; Nakaoku, Takashi; Tsuta, Koji; Tsuchihara, Katsuya; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

    2015-04-01

    Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions. PMID:25870798

  3. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer

    PubMed Central

    Nakaoku, Takashi; Tsuta, Koji; Tsuchihara, Katsuya; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

    2015-01-01

    Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions. PMID:25870798

  4. Anaplastic large cell lymphoma in paediatric and young adult patients.

    PubMed

    Turner, Suzanne D; Lamant, Laurence; Kenner, Lukas; Brugières, Laurence

    2016-05-01

    Anaplastic large cell lymphoma (ALCL) is a heterogeneous disease of debateable origin that, in children, is largely anaplastic lymphoma kinase (ALK) positive with aberrant ALK activity induced following the formation of chromosomal translocations. Whilst the survival rates for this disease are relatively high, a significant proportion (20-40%) of patients suffer disease relapse, in some cases on multiple occasions and therefore suffer the toxic side-effects of combination chemotherapy. Traditionally, patients are treated with a combination of agents although recent data from relapse patients have suggested that low risk patients might benefit from single agent vinblastine and, going forward, the addition of ALK inhibitors to the therapeutic regimen may have beneficial consequences. There are also a plethora of other drugs that might be advantageous to patients with ALCL and many of these have been identified through laboratory research although the decision as to which drugs to implement in trials will not be trivial. PMID:26913827

  5. Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC.

    PubMed

    Kim, Bu-Yeo; Jeong, SangKyun; Lee, Seo-Young; Lee, So Min; Gweon, Eun Jeong; Ahn, Hyunjun; Kim, Janghwan; Chung, Sun-Ku

    2016-01-01

    Fibrodysplasia ossificans progressiva (FOP) syndrome is caused by mutation of the gene ACVR1, encoding a constitutive active bone morphogenetic protein type I receptor (also called ALK2) to induce heterotopic ossification in the patient. To genetically correct it, we attempted to generate the mutant ALK2-iPSCs (mALK2-iPSCs) from FOP-human dermal fibroblasts. However, the mALK2 leads to inhibitory pluripotency maintenance, or impaired clonogenic potential after single-cell dissociation as an inevitable step, which applies gene-correction tools to induced pluripotent stem cells (iPSCs). Thus, current iPSC-based gene therapy approach reveals a limitation that is not readily applicable to iPSCs with ALK2 mutation. Here we developed a simplified one-step procedure by simultaneously introducing reprogramming and gene-editing components into human fibroblasts derived from patient with FOP syndrome, and genetically treated it. The mixtures of reprogramming and gene-editing components are composed of reprogramming episomal vectors, CRISPR/Cas9-expressing vectors and single-stranded oligodeoxynucleotide harboring normal base to correct ALK2 c.617G>A. The one-step-mediated ALK2 gene-corrected iPSCs restored global gene expression pattern, as well as mineralization to the extent of normal iPSCs. This procedure not only helps save time, labor and costs but also opens up a new paradigm that is beyond the current application of gene-editing methodologies, which is hampered by inhibitory pluripotency-maintenance requirements, or vulnerability of single-cell-dissociated iPSCs. PMID:27256111

  6. Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC

    PubMed Central

    Kim, Bu-Yeo; Jeong, SangKyun; Lee, Seo-Young; Lee, So Min; Gweon, Eun Jeong; Ahn, Hyunjun; Kim, Janghwan; Chung, Sun-Ku

    2016-01-01

    Fibrodysplasia ossificans progressiva (FOP) syndrome is caused by mutation of the gene ACVR1, encoding a constitutive active bone morphogenetic protein type I receptor (also called ALK2) to induce heterotopic ossification in the patient. To genetically correct it, we attempted to generate the mutant ALK2-iPSCs (mALK2-iPSCs) from FOP-human dermal fibroblasts. However, the mALK2 leads to inhibitory pluripotency maintenance, or impaired clonogenic potential after single-cell dissociation as an inevitable step, which applies gene-correction tools to induced pluripotent stem cells (iPSCs). Thus, current iPSC-based gene therapy approach reveals a limitation that is not readily applicable to iPSCs with ALK2 mutation. Here we developed a simplified one-step procedure by simultaneously introducing reprogramming and gene-editing components into human fibroblasts derived from patient with FOP syndrome, and genetically treated it. The mixtures of reprogramming and gene-editing components are composed of reprogramming episomal vectors, CRISPR/Cas9-expressing vectors and single-stranded oligodeoxynucleotide harboring normal base to correct ALK2 c.617G>A. The one-step-mediated ALK2 gene-corrected iPSCs restored global gene expression pattern, as well as mineralization to the extent of normal iPSCs. This procedure not only helps save time, labor and costs but also opens up a new paradigm that is beyond the current application of gene-editing methodologies, which is hampered by inhibitory pluripotency-maintenance requirements, or vulnerability of single-cell-dissociated iPSCs. PMID:27256111

  7. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Light beam patient position indicator. 892.5780... (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5780 Light beam patient position indicator. (a) Identification. A light beam patient position indicator is a device that projects a beam...

  8. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Light beam patient position indicator. 892.5780... (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5780 Light beam patient position indicator. (a) Identification. A light beam patient position indicator is a device that projects a beam...

  9. Economic Analysis of Alternative Strategies for Detection of ALK Rearrangements in Non Small Cell Lung Cancer.

    PubMed

    Doshi, Shivang; Ray, David; Stein, Karen; Zhang, Jie; Koduru, Prasad; Fogt, Franz; Wellman, Axel; Wat, Ricky; Mathews, Charles

    2016-01-01

    Identification of alterations in ALK gene and development of ALK-directed therapies have increased the need for accurate and efficient detection methodologies. To date, research has focused on the concordance between the two most commonly used technologies, fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). However, inter-test concordance reflects only one, albeit important, aspect of the diagnostic process; laboratories, hospitals, and payors must understand the cost and workflow of ALK rearrangement detection strategies. Through literature review combined with interviews of pathologists and laboratory directors in the U.S. and Europe, a cost-impact model was developed that compared four alternative testing strategies-IHC only, FISH only, IHC pre-screen followed by FISH confirmation, and parallel testing by both IHC and FISH. Interviews were focused on costs of reagents, consumables, equipment, and personnel. The resulting model showed that testing by IHC alone cost less ($90.07 in the U.S., $68.69 in Europe) than either independent or parallel testing by both FISH and IHC ($441.85 in the U.S. and $279.46 in Europe). The strategies differed in cost of execution, turnaround time, reimbursement, and number of positive results detected, suggesting that laboratories must weigh the costs and the clinical benefit of available ALK testing strategies. PMID:26838801

  10. Economic Analysis of Alternative Strategies for Detection of ALK Rearrangements in Non Small Cell Lung Cancer

    PubMed Central

    Doshi, Shivang; Ray, David; Stein, Karen; Zhang, Jie; Koduru, Prasad; Fogt, Franz; Wellman, Axel; Wat, Ricky; Mathews, Charles

    2016-01-01

    Identification of alterations in ALK gene and development of ALK-directed therapies have increased the need for accurate and efficient detection methodologies. To date, research has focused on the concordance between the two most commonly used technologies, fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). However, inter-test concordance reflects only one, albeit important, aspect of the diagnostic process; laboratories, hospitals, and payors must understand the cost and workflow of ALK rearrangement detection strategies. Through literature review combined with interviews of pathologists and laboratory directors in the U.S. and Europe, a cost-impact model was developed that compared four alternative testing strategies—IHC only, FISH only, IHC pre-screen followed by FISH confirmation, and parallel testing by both IHC and FISH. Interviews were focused on costs of reagents, consumables, equipment, and personnel. The resulting model showed that testing by IHC alone cost less ($90.07 in the U.S., $68.69 in Europe) than either independent or parallel testing by both FISH and IHC ($441.85 in the U.S. and $279.46 in Europe). The strategies differed in cost of execution, turnaround time, reimbursement, and number of positive results detected, suggesting that laboratories must weigh the costs and the clinical benefit of available ALK testing strategies. PMID:26838801

  11. Effects of different compost amendments on the abundance and composition of alkB harboring bacterial communities in a soil under industrial use contaminated with hydrocarbons

    PubMed Central

    Wallisch, Stefanie; Gril, Tjasa; Dong, Xia; Welzl, Gerd; Bruns, Christian; Heath, Ester; Engel, Marion; Suhadolc, Marjetka; Schloter, Michael

    2014-01-01

    Alkane degrading microorganisms play an important role for the bioremediation of petrogenic contaminated environments. In this study, we investigated the effects of compost addition on the abundance and diversity of bacteria harboring the alkane monooxygenase gene (alkB) in an oil-contaminated soil originated from an industrial zone in Celje, Slovenia (Technosol). Soil without any amendments (control soil) and soil amended with two composts differing in their maturation stage and nutrient availability, were incubated under controlled conditions in a microcosm experiment and sampled after 0, 6, 12, and 36 weeks of incubation. As expected the addition of compost stimulated the degradation of alkanes in the investigated soil shortly after the addition. By using quantitative real-time PCR higher number of alkB genes were detected in soil samples amended with compost compared to the control soils. To get an insight into the composition of alkB harboring microbial communities, we performed next generation sequencing of amplicons of alkB gene fragment. Richness and diversity of alkB gene harboring prokaryotes was higher in soil mixed with compost compared to control soils with stronger effects of the less maturated, nutrient poor compost. The phylogenetic analysis of communities suggested that the addition of compost stimulated the abundance of alkB harboring Actinobacteria during the experiment independent from the maturation stage of the compost. AlkB harboring γ-proteobacteria like Shewanella or Hydrocarboniphaga as well as α-proteobacteria of the genus Agrobacterium responded also positively to the addition of compost to soil. The amendment of the less maturated, nutrient poor compost resulted in addition in a large increase of alkB harboring bacteria of the Cytophaga group (Microscilla) mainly at the early sampling time points. Our data indicates that compost amendments significantly change abundance and diversity pattern of alkB harboring microbes in Technosol and

  12. NPM-ALK mediates phosphorylation of MSH2 at tyrosine 238, creating a functional deficiency in MSH2 and the loss of mismatch repair

    PubMed Central

    Bone, K M; Wang, P; Wu, F; Wu, C; Li, L; Bacani, J T; Andrew, S E; Lai, R

    2015-01-01

    The vast majority of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ALCL) tumors express the characteristic oncogenic fusion protein NPM-ALK, which mediates tumorigenesis by exerting its constitutive tyrosine kinase activity on various substrates. We recently identified MSH2, a protein central to DNA mismatch repair (MMR), as a novel binding partner and phosphorylation substrate of NPM-ALK. Here, using liquid chromatography–mass spectrometry, we report for the first time that MSH2 is phosphorylated by NPM-ALK at a specific residue, tyrosine 238. Using GP293 cells transfected with NPM-ALK, we confirmed that the MSH2Y238F mutant is not tyrosine phosphorylated. Furthermore, transfection of MSH2Y238F into these cells substantially decreased the tyrosine phosphorylation of endogenous MSH2. Importantly, gene transfection of MSH2Y238F abrogated the binding of NPM-ALK with endogenous MSH2, re-established the dimerization of MSH2:MSH6 and restored the sensitivity to DNA mismatch-inducing drugs, indicative of MMR return. Parallel findings were observed in two ALK+ALCL cell lines, Karpas 299 and SUP-M2. In addition, we found that enforced expression of MSH2Y238F into ALK+ALCL cells alone was sufficient to induce spontaneous apoptosis. In conclusion, our findings have identified NPM-ALK-induced phosphorylation of MSH2 at Y238 as a crucial event in suppressing MMR. Our studies have provided novel insights into the mechanism by which oncogenic tyrosine kinases disrupt MMR. PMID:25978431

  13. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    Background We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAFV600E) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. Methods The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription–polymerase chain reaction and 5′ rapid amplification of cDNA ends (5′ RACE). Results We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK

  14. Promoting positive outcomes in obese patients.

    PubMed

    Troia, Cecilia

    2002-01-01

    Obese patients are seen in every practice setting. Obesity is a chronic disease that may lead to physical and emotional problems, which may have an impact on the social and psychological functioning of the patient. With appropriate preoperative, intraoperative, and postoperative precautions; monitoring; and restructuring the environment to promote care and safety, the incidence of poor surgical outcomes can be minimized. This paper will address the significance of obesity, related diseases, and proper care of the obese patient. PMID:12035338

  15. Insertion element analysis and mapping of the Pseudomonas plasmid alk regulon.

    PubMed Central

    Fennewald, M; Benson, S; Oppici, M; Shapiro, J

    1979-01-01

    We characterized and mapped new mutations of the alk (alkane utilization) genes found on Pseudomonas plasmids of the Inc P-2 group. These mutations were isolated after (i) nitrosoguanidine mutagenesis, (ii) transposition of the Tn7 trimethoprim and streptomycin resistance determinant, and (iii) reversion of polarity effects of alk::Tn7 insertion mutations. Our results indicate the existence of two alk loci not previously described--alkD, whose product is required for synthesis of membrane alkane-oxidizing activities, and alkE, whose product is required for synthesis of inducible membrane alcohol dehydrogenase activity. Polarity of alk::Tn7 insertion mutations indicates the existence of an alkBAE operon. Mapping of alk loci by transduction in P. aeruginosa shows that there are at least three alk clusters in the CAM-OCT plasmid--alkRD, containing regulatory genes; alkBAE, containing genes for specific biochemical activities; and alkC, containing one or more genes needed for normal synthesis of membrane alcohol dehydrogenase. The alkRD and alkBAE clusters are linked but separated by about 42 kilobases. The alkC cluster is not linked to either of the other two alk regions. Altogether, these results indicate a complex genetic control of the alkane utilization phenotype in P. putida and P. aeruginosa involving at least six separate genes. Images PMID:479111

  16. CD30-Positive Anaplastic Lymphoma Kinase-Negative Systemic Anaplastic Large-Cell Lymphoma in a 9-Year-Old Boy

    PubMed Central

    Kim, Jeong Eun; Oh, Eui Hyun; Ro, Young Suck

    2016-01-01

    Anaplastic large-cell lymphoma (ALCL) is a CD30-positive T-cell/null-cell lymphoma that is clinically classified into either primary cutaneous ALCL or systemic ALCL (S-ALCL) sub-types. Because 90% of childhood S-ALCL cases are anaplastic lymphoma kinase (ALK)-positive, there is a lack of data on ALK-negative S-ALCL cases among pediatric patients. Herein, we report a rare case of ALK-negative S-ALCL in a 9-year-old Korean boy who initially presented with itchy erythematous maculopapules and an erosive nodule on the trunk area. We emphasize the need of high index of suspicion of an underlying malignant disease in the presence of refractory eczematous lesions. PMID:27274637

  17. CD30-Positive Anaplastic Lymphoma Kinase-Negative Systemic Anaplastic Large-Cell Lymphoma in a 9-Year-Old Boy.

    PubMed

    Kim, Jeong Eun; Oh, Eui Hyun; Ro, Young Suck; Ko, Joo Yeon

    2016-06-01

    Anaplastic large-cell lymphoma (ALCL) is a CD30-positive T-cell/null-cell lymphoma that is clinically classified into either primary cutaneous ALCL or systemic ALCL (S-ALCL) sub-types. Because 90% of childhood S-ALCL cases are anaplastic lymphoma kinase (ALK)-positive, there is a lack of data on ALK-negative S-ALCL cases among pediatric patients. Herein, we report a rare case of ALK-negative S-ALCL in a 9-year-old Korean boy who initially presented with itchy erythematous maculopapules and an erosive nodule on the trunk area. We emphasize the need of high index of suspicion of an underlying malignant disease in the presence of refractory eczematous lesions. PMID:27274637

  18. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5780 Light beam patient position... light (incoherent light or laser) to determine the alignment of the patient with a radiation beam....

  19. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5780 Light beam patient position... light (incoherent light or laser) to determine the alignment of the patient with a radiation beam....

  20. Fatal Haemoptysis Associated with Dramatic Response to Crizotinib in an ALK-Rearranged Lung Adenocarcinoma.

    PubMed

    Mussat, Elodie; Giraud, Violaine; Julie, Catherine; Chinet, Thierry; Leprieur, Etienne Giroux

    2016-03-01

    The presence of an ALK (Anaplastic Lymphoma Kinase) rearrangement is a rare molecular feature in Non-Small Cell Lung Carcinoma (NSCLC), and concerns mainly non- or light smokers, young patients, with adenocarcinoma histological type. These tumours are particularly sensitive to Alk-targeted therapies, as crizotinib. Crizotinib is usually well-tolerated. We report a case of fatal haemoptysis associated with dramatic response to crizotinib in a patient with an ALK-rearranged lung adenocarcinoma. The patient presented a mediastinal invasion with tracheal involvement and compression of the right pulmonary artery. The initial evolution under crizotinib was good with tumour response. At 6 weeks of crizotinib the patient presented a massive haemoptysis with a tracheobronchial fistula and pneumomediastinum. She died of acute respiratory failure. Our case is the first to report a fatal effect of crizotinib associated with tumour necrosis and good tumour response on a massive mediastinal infiltration. Precautions are recommended with the use of crizotinib in proximal lung tumours with vascular invasion. PMID:27134984

  1. Fatal Haemoptysis Associated with Dramatic Response to Crizotinib in an ALK-Rearranged Lung Adenocarcinoma

    PubMed Central

    Mussat, Elodie; Giraud, Violaine; Julie, Catherine; Chinet, Thierry

    2016-01-01

    The presence of an ALK (Anaplastic Lymphoma Kinase) rearrangement is a rare molecular feature in Non-Small Cell Lung Carcinoma (NSCLC), and concerns mainly non- or light smokers, young patients, with adenocarcinoma histological type. These tumours are particularly sensitive to Alk-targeted therapies, as crizotinib. Crizotinib is usually well-tolerated. We report a case of fatal haemoptysis associated with dramatic response to crizotinib in a patient with an ALK-rearranged lung adenocarcinoma. The patient presented a mediastinal invasion with tracheal involvement and compression of the right pulmonary artery. The initial evolution under crizotinib was good with tumour response. At 6 weeks of crizotinib the patient presented a massive haemoptysis with a tracheobronchial fistula and pneumomediastinum. She died of acute respiratory failure. Our case is the first to report a fatal effect of crizotinib associated with tumour necrosis and good tumour response on a massive mediastinal infiltration. Precautions are recommended with the use of crizotinib in proximal lung tumours with vascular invasion. PMID:27134984

  2. Development of an automatic evaluation method for patient positioning error.

    PubMed

    Kubota, Yoshiki; Tashiro, Mutsumi; Shinohara, Ayaka; Abe, Satoshi; Souda, Saki; Okada, Ryosuke; Ishii, Takayoshi; Kanai, Tatsuaki; Ohno, Tatsuya; Nakano, Takashi

    2015-01-01

    Highly accurate radiotherapy needs highly accurate patient positioning. At our facility, patient positioning is manually performed by radiology technicians. After the positioning, positioning error is measured by manually comparing some positions on a digital radiography image (DR) to the corresponding positions on a digitally reconstructed radiography image (DRR). This method is prone to error and can be time-consuming because of its manual nature. Therefore, we propose an automated measuring method for positioning error to improve patient throughput and achieve higher reliability. The error between a position on the DR and a position on the DRR was calculated to determine the best matched position using the block-matching method. The zero-mean normalized cross correlation was used as our evaluation function, and the Gaussian weight function was used to increase importance as the pixel position approached the isocenter. The accuracy of the calculation method was evaluated using pelvic phantom images, and the method's effectiveness was evaluated on images of prostate cancer patients before the positioning, comparing them with the results of radiology technicians' measurements. The root mean square error (RMSE) of the calculation method for the pelvic phantom was 0.23 ± 0.05 mm. The coefficients between the calculation method and the measurement results of the technicians were 0.989 for the phantom images and 0.980 for the patient images. The RMSE of the total evaluation results of positioning for prostate cancer patients using the calculation method was 0.32 ± 0.18 mm. Using the proposed method, we successfully measured residual positioning errors. The accuracy and effectiveness of the method was evaluated for pelvic phantom images and images of prostate cancer patients. In the future, positioning for cancer patients at other sites will be evaluated using the calculation method. Consequently, we expect an improvement in treatment throughput for these other sites

  3. Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases

    PubMed Central

    Lee, Taebum; Lee, Boram; Choi, Yoon-La; Han, Joungho; Ahn, Myung-Ju; Um, Sang-Won

    2016-01-01

    Background: Although epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) were thought to be mutually exclusive, some tumors harbor concomitant mutations. Discovering a driver mutation on the basis of morphologic features and therapeutic responses with mutation analysis can be used to understand pathogenesis and predict resistance in targeted therapy. Methods: In 6,637 patients with NSCLC, 12 patients who had concomitant mutations were selected and clinicopathologic features were reviewed. Clinical characteristics included sex, age, smoking history, previous treatment, and targeted therapy with response and disease-free survival. Histologic features included dominant patterns, nuclear and cytoplasmic features. Results: All patients were diagnosed with adenocarcinoma and had an EGFR mutation. Six patients had concomitant KRAS mutations and the other six had KRAS mutations. Five of six EGFR-KRAS mutation patients showed papillary and acinar histologic patterns with hobnail cells. Three of six received EGFR tyrosine kinase inhibitor (TKI) and showed partial response for 7–29 months. All six EGFR-ALK mutation patients showed solid or cribriform patterns and three had signet ring cells. Five of six EGFR-ALK mutation patients received EGFR TKI and/or ALK inhibitor and four showed partial response or stable disease, except for one patient who had acquired an EGFR mutation. Conclusions: EGFR and ALK mutations play an important role as driver mutations in double mutated NSCLC, and morphologic analysis can be used to predict treatment response. PMID:27086595

  4. Patients report positive impacts of collaborative care.

    PubMed

    Wasson, John H; Johnson, Deborah J; Benjamin, Regina; Phillips, Jill; MacKenzie, Todd A

    2006-01-01

    Collaborative Care refers to a partnership between healthcare professionals and patients who feel confident to manage their health conditions. Using an Internet-based assessment of health needs and healthcare quality, we surveyed 24,609 adult Americans aged 19 to 69 who had common chronic diseases or significant dysfunction. In these patients, we examined the association of Collaborative Care with specific measures for treatment effect, disease control, prevention, and economic impacts. These measures were adjusted for respondents' demographic characteristics, burden of illness, health behaviors, and overall quality of healthcare. Only 21% of respondents participated in good Collaborative Care, 36% attained fair Collaborative Care, and 43% experienced poor Collaborative Care. Regardless of overall care quality or the respondents' personal characteristics, burden of illness, or health behaviors, good Collaborative Care was associated with better control of blood pressure, blood glucose level, serum cholesterol level, and treatment effectiveness for pain and emotional problems. Some preventive actions were better, and some adverse economic impacts of illness were mitigated. PMID:16788352

  5. Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells

    PubMed Central

    Montavon, Gisèle; Jauquier, Nicolas; Coulon, Aurélie; Peuchmaur, Michel; Flahaut, Marjorie; Bourloud, Katia Balmas; Yan, Pu; Delattre, Olivier; Sommer, Lukas; Joseph, Jean-Marc; Janoueix-Lerosey, Isabelle; Gross, Nicole; Mühlethaler-Mottet, Annick

    2014-01-01

    The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC-1 parental cells in nude mice generated various tumor types, such as NB, osteo/chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro. PMID:24947326

  6. Regioselective alkane hydroxylation with a mutant AlkB enzyme

    DOEpatents

    Koch, Daniel J.; Arnold, Frances H.

    2012-11-13

    AlkB from Pseudomonas putida was engineered using in-vivo directed evolution to hydroxylate small chain alkanes. Mutant AlkB-BMO1 hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. Mutant AlkB-BMO2 similarly hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. These biocatalysts are highly active for small chain alkane substrates and their regioselectivity is retained in whole-cell biotransformations.

  7. Overcoming acquired resistance to kinase inhibition: the cases of EGFR, ALK and BRAF.

    PubMed

    Giroux, Simon

    2013-01-15

    In the past decade, several kinase inhibitors have been approved based on their clinical benefit for cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. This review will focus on the cases of acquired resistance to EGFR and ALK inhibitors for non-small cell lung cancer patients and BRAF inhibitors for melanoma patients. I will overview the main causes of acquired resistance, and explore the chemical scaffolds as well as combination of drugs, used to tackle these major causes of resistance. PMID:23245516

  8. Metachronous primary uterine cancer surgically resected during Crizotinib treatment in a ALK-rearranged advanced lung adenocarcinoma

    PubMed Central

    Misino, Andrea; Scattone, Anna; Caldarola, Lucia; Petroni, Stella; Logroscino, Antonio; Montagna, Elisabetta Sara; Serio, Gabriella; Simone, Giovanni; Galetta, Domenico

    2016-01-01

    Rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in 3% to 7% of non-small-cell lung cancers (NSCLCs). Patients harboring ALK rearrangements show very favourable outcomes if treated with targeted agents, among which crizotinib is the first and best studied. Crizotinib, an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases, is a very active and well tolerated drug. Nevertheless, the optimal therapy management with this new drug is still partially unknown, especially with regard to the safety of combined treatments. Recently, the integration of locoregional treatments has been proposed as a feasible multimodality strategy in selected patients with good clinical conditions and slow-growing or oligoprogressive disease. In this report, a case of advanced lung adenocarcinoma, progressed after first line chemotherapy and re-biopsied detecting ALK rearrangement, is described. During crizotinib treatment the primary lung tumor showed an excellent regression; meanwhile a major surgery for a metachronous uterine cancer was safely and successfully carried out. PMID:26958511

  9. ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma.

    PubMed

    Hasan, Md Kamrul; Nafady, Asmaa; Takatori, Atsushi; Kishida, Satoshi; Ohira, Miki; Suenaga, Yusuke; Hossain, Shamim; Akter, Jesmin; Ogura, Atsushi; Nakamura, Yohko; Kadomatsu, Kenji; Nakagawara, Akira

    2013-01-01

    Human anaplastic lymphoma kinase (ALK) has been identified as an oncogene that is mutated or amplified in NBLs. To obtain a better understanding of the molecular events associated with ALK in the pathogenesis of NBL, it is necessary to clarify how ALK gene contributes to NBL progression. In the present study, we found that ALK expression was significantly high in NBL clinical samples with amplified MYCN (n = 126, P < 0.01) and in developing tumors of MYCN-transgenic mice. Indeed, promoter analysis revealed that ALK is a direct transcriptional target of MYCN. Overexpression and knockdown of ALK demonstrated its function in cell proliferation, migration and invasion. Moreover, treatment with an ALK inhibitor, TAE-684, efficiently suppressed such biological effects in MYCN amplified cells and tumor growth of the xenograft in mice. Our present findings explore the fundamental understanding of ALK in order to develop novel therapeutic tools by targeting ALK for aggressive NBL treatment. PMID:24356251

  10. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES RADIOLOGY DEVICES Therapeutic Devices § 892.5780 Light beam patient...

  11. Basic Hip Arthroscopy: Supine Patient Positioning and Dynamic Fluoroscopic Evaluation

    PubMed Central

    Mannava, Sandeep; Howse, Elizabeth A.; Stone, Austin V.; Stubbs, Allston J.

    2015-01-01

    Hip arthroscopy serves as both a diagnostic and therapeutic tool for the management of various conditions that afflict the hip. This article reviews the basics of hip arthroscopy by demonstrating supine patient positioning, fluoroscopic evaluation of the hip under anesthesia, and sterile preparation and draping. Careful attention to detail during the operating theater setup ensures adequate access to the various compartments of the hip to facilitate the diagnosis of disease and treatment with minimally invasive arthroscopy. Furthermore, having a routine method for patient positioning and operative setup improves patient safety, as well as operative efficiency, as the operative team becomes familiar with the surgeon's standard approach to hip arthroscopy cases. PMID:26759783

  12. Benefit-Risk Summary of Crizotinib for the Treatment of Patients With ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer

    PubMed Central

    Blumenthal, Gideon M.; Luo, Lola; He, Kun; Fran, Ingrid; Lemery, Steven; Pazdur, Richard

    2016-01-01

    On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25–77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%–79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%–84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication. Implications for Practice: Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non-small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status. PMID:27328934

  13. Clinical effect of pemetrexed as the first‐line treatment in Chinese patients with advanced anaplastic lymphoma kinase‐positive non‐small cell lung cancer

    PubMed Central

    Ma, Di; Hao, Xuezhi; Wang, Yan; Xing, Puyuan

    2016-01-01

    Background The efficacy of pemetrexed‐based first‐line chemotherapy in anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC) has been demonstrated in several studies; however, there is a lack of data from Chinese populations. Methods The clinicopathological characteristics and treatment outcomes of 52 patients with ALK‐positive advanced NSCLC who received pemetrexed as first‐line chemotherapy at the Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively reviewed. The primary end points were response rate and progression‐free survival (PFS). Results The gender proportion was balanced and the median age was 51 years (range 26–76). Of the 52 patients, 46 (88.5%) had stage IV disease, predominantly adenocarcinoma (98.1%). Sixteen patients were current/former smokers and 36 were never/light smokers. The most common sites of metastasis were the pleura (36.5%), bone (30.8%), lung (26.9%), and brain (17.3%). The median PFS was 9.5 months (95% confidence interval 7.454–11.536). At the time of analysis, partial remission was achieved in 18 (34.6%) patients, stable disease in 26 (50.0%), and progressive disease in eight (15.4%); none of the patients achieved complete remission. The objective response rate was 34.6% and the disease control rate was 84.6%. Common adverse events with pemetrexed were neutropenia (53.8%), nausea and vomiting (51.9%), leukopenia (32.7%), and fatigue (25.0%), mainly at grades 1 or 2. Conclusions Pemetrexed is efficient and tolerated as first‐line treatment for ALK‐positive NSCLC in a cohort of Chinese patients and may prove to be an alternative option for the treatment of ALK‐positive NSCLC. PMID:27385988

  14. Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells

    PubMed Central

    Aveic, Sanja; Pantile, Marcella; Seydel, Anke; Esposito, Maria Rosaria; Zanon, Carlo; Li, Gary; Tonini, Gian Paolo

    2016-01-01

    Neuroblastoma (NB) is a threatening childhood malignancy. Its prognosis is affected by several morphological, and biological characteristics, including the constitutive expression of ALK tyrosine kinase. In this study we examined the therapeutic potential of a novel ALK inhibitor, entrectinib, in obliterating NB tumor cells. Entrectinib showed the growth-inhibitory effects on NB cells with a 50% inhibitory concentration range of 0.03–5 μM. In the ALK-dependent cells, entrectinib mediated G1-arrest, which was associated with modified expression of multiple cell-cycle regulators. Down-regulation of Ki-67, and attenuated phosphorylation of ERK1/2, and STAT3, correlated with observed antiproliferative capacity of entrectinib. Initial cytostatic activity of entrectinib was followed by concentration-dependent apoptotic cell death, and Caspase-3 activation. However, we delineated a reduced sensitivity of ALK mutated NB cells to entrectinib, and demonstrated strong activation of autophagy in SH-SY5YF1174L NB cell line. Abrogation of autophagy by chloroquine increased significantly the toxicity of entrectinib, as confirmed by enhanced death rate, and PARP protein cleavage in SH-SY5YF1174L cells. In aggregate, our data show that entrectinib inhibits proliferation, and induces G1-arrest, and apoptosis in NB cells. We propose entrectinib for further consideration in treatment of NB, and recommend pharmacological inhibition of autophagy to be explored for a combined therapeutic approach in NB patients that might develop resistance to entrectinib. PMID:26735175

  15. Reducing patient posture variability using the predicted couch position

    SciTech Connect

    Kruijf, Wilhelmus J.M. de Martens, Rob J.W.

    2015-10-01

    A method is presented in which the couch position is predicted before the treatment instead of obtaining a reference position at the first treatment fraction. This prevents systematic differences in patient posture between preparation and treatment. In literature, only limited data are available on couch positioning. We position our patients at the planned couch position, allowing a small difference between skin marks and lasers, followed by online imaging. For a 3-month period, our standard deviations (mm) in couch position in the vertical, longitudinal, and lateral directions were head and neck—1.6, 2.8, and 2.5; thorax—2.9, 5.5, and 4.5; breast—3.0, 4.1, and 4.0; and pelvis—3.5, 4.0, and 4.7, respectively. We have improved the reproducibility of patient posture in our institute by using the predicted couch position. Our data may serve as a reference for other institutes because the couch position variation is less than that published in literature.

  16. [Positive exercise test in hypertensive patients correlated with coronary angiography].

    PubMed

    Rosado, J; de los Santos, C; Iturralde, P; Pérez, G; Romero, L; Colín, L; González Hermosillo, A; Casanova, J M

    1991-01-01

    With the purpose of evaluate the state of the coronary arteries in hypertensive patients with positive exercise test, 82 patients were selected, 50 male and 32 female with mean age of 56.9 +/- 13.2 years. Angiography was normal in 25 patients thirteen patients had a single coronary arteries narrow of less than 50% and 44 cases with significant coronary arteries lesions of more than 50%. The parameters obtained in the exercise test are not significant for statistic purposes. Systolic hypertension or flat response was more frequent in the group with advanced coronary lesions with a predicted positive value in coronary obstructions of 66 and 75%. We conclude that 70% of hypertensive patients have obstructive coronary lesions of some degree. PMID:1929669

  17. Identification of ALK as the Major Familial Neuroblastoma Predisposition Gene

    PubMed Central

    Mossë, Yalë P; Laudenslager, Marci; Longo, Luca; Cole, Kristina A; Wood, Andrew; Attiyeh, Edward F; Laquaglia, Michael J; Sennett, Rachel; Lynch, Jill E; Perri, Patrizia; Laureys, Geneviève; Speleman, Frank; Hakonarson, Hakon; Torkamani, Ali; Schork, Nicholas J; Brodeur, Garrett M; Tonini, Gian Paolo; Rappaport, Eric; Devoto, Marcella; Maris, John M

    2009-01-01

    SUMMARY Survival rates for the childhood cancer neuroblastoma have not substantively improved despite dramatic escalation in chemotherapy intensity. Like most human cancers, this embryonal malignancy can be inherited, but the genetic etiology of familial and sporadically occurring neuroblastoma was largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase gene (ALK) explain the majority of hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at the short arm of chromosome 2 (maximum nonparametric LOD=4.23 at rs1344063) using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate missense mutations in the tyrosine kinase domain of ALK (G1128A, R1192P and R1275Q) that segregated with the disease in eight separate families. Examination of 491 sporadically occurring human neuroblastoma samples showed that the ALK locus was gained in 22.8%, and highly amplified in an additional 3.3%, and that these aberrations were highly associated with death from disease (P=0.0003). Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations within the tyrosine kinase domain in 12.4%. Nine of the ten mutations map to critical regions of the kinase domain and were predicted to be oncogenic drivers with high probability. Mutations resulted in constitutive phosphorylation consistent with activation, and targeted knockdown of ALK mRNA resulted in profound growth inhibition of 4 of 4 cell lines harboring mutant or amplified ALK, as well as 2 of 6 wild type for ALK. Our results demonstrate that heritable mutations of ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this cell surface kinase is a tractable therapeutic target for this lethal pediatric malignancy. PMID:18724359

  18. Remission of ALK-negative primary pulmonary inflammatory myofibroblastic tumor on treatment with clarithromycin: A case report and review of the literature

    PubMed Central

    WATANABE, HIDEHIRO; URUMA, TOMONORI; TAZAKI, GEN; TAJIRI, TAKUMA; KIKUCHI, RYOTA; ITOH, MASAYUKI; AOSHIBA, KAZUTETSU; NAKAMURA, HIROYUKI

    2016-01-01

    Inflammatory myofibroblastic tumors (IMTs) belong to an intermediate group of soft-tissue tumors, they are relatively rare but exhibit a wide range of pathologies, from benign to malignant. At present, no standard treatment has been established, however, it is known to be important to determine the grade of malignancy of the tumor, prior to treatment. The present study reports a 73-year-old female patient with no clinical manifestations, who, when examined radiographically at a health check exhibited bilateral thoracic infiltrative shadows and nodular shadows by chest CT. A metastatic tumor or an organizing pneumonia were suspected. Blood examination showed no abnormal findings, and a pathological diagnosis of IMT was given from the histological findings of the tissue extracted by video-assisted thoracic surgery. Histological analysis established the lack of expression of anaplastic lymphoma kinase (ALK1) and immunoglobulin subtype G4 (IgG4). Alteration of the radiological shadows was observed over several weeks, and after concluding that chronic inflammation was worsening the patient's condition, clarithromycin was administered as a long-term macrolide therapy. The IMT decreased in size, and eight months later it had almost resolved. The patient was last reported to be maintaining a stable condition with no relapse. Some IMT cases have malignant pathology, and should be carefully followed-up. However, in the present case, where the IMT is both ALK1-negative and IgG4-negative, its biological immune responsiveness appears to differ from positive cases, and an inflammatory response was predominant. Clarithromycin, has immunomodulatory and anti-inflammatory effects and appeared to be effective in treating the IMT of the patient in the present study. PMID:26998073

  19. Treatment of snoring with positional therapy in patients with positional obstructive sleep apnea syndrome.

    PubMed

    Chen, Wen-Chyuan; Lee, Li-Ang; Chen, Ning-Hung; Fang, Tuan-Jen; Huang, Chung-Guei; Cheng, Wen-Nuan; Li, Hsueh-Yu

    2015-01-01

    Position therapy plays a role in treating snoring and obstructive sleep apnea syndrome (OSAS). The purpose of this study was to investigate whether position therapy using a head-positioning pillow (HPP) could reduce snoring sounds in patients with mild-to-moderate positional OSAS, taking into account the potential confounding effects of body weight. A total of 25 adults with positional OSAS (apnea-hypopnea index [AHI]supine:AHInon-supine ≥ 2) were prospectively enrolled. Patients were asked to use their own pillows at home during the first night (N0), and the HPP during the second (N1) and third (N2) nights. The primary outcome measures included the subjective snoring severity (SS, measured on a visual analogue scale ranging from 0 to 10) and the objective snoring index (SI, expressed as the number of snoring events per hour measured on an acoustic analytical program). Both endpoints were recorded over three consecutive nights. From N0 to N2, the median SS and SI values in the entire study cohort decreased significantly from 5.0 to 4.0 and from 218.0 events/h to 115.0 events/h, respectively. In the subgroup of overweight patients, SS showed a significant improvement, whereas SI did not. Both SS and SI were found to be significantly improved in normal-weight patients. PMID:26657174

  20. Treatment of snoring with positional therapy in patients with positional obstructive sleep apnea syndrome

    PubMed Central

    Chen, Wen-Chyuan; Lee, Li-Ang; Chen, Ning-Hung; Fang, Tuan-Jen; Huang, Chung-Guei; Cheng, Wen-Nuan; Li, Hsueh-Yu

    2015-01-01

    Position therapy plays a role in treating snoring and obstructive sleep apnea syndrome (OSAS). The purpose of this study was to investigate whether position therapy using a head-positioning pillow (HPP) could reduce snoring sounds in patients with mild-to-moderate positional OSAS, taking into account the potential confounding effects of body weight. A total of 25 adults with positional OSAS (apnea-hypopnea index [AHI]supine:AHInon-supine ≥ 2) were prospectively enrolled. Patients were asked to use their own pillows at home during the first night (N0), and the HPP during the second (N1) and third (N2) nights. The primary outcome measures included the subjective snoring severity (SS, measured on a visual analogue scale ranging from 0 to 10) and the objective snoring index (SI, expressed as the number of snoring events per hour measured on an acoustic analytical program). Both endpoints were recorded over three consecutive nights. From N0 to N2, the median SS and SI values in the entire study cohort decreased significantly from 5.0 to 4.0 and from 218.0 events/h to 115.0 events/h, respectively. In the subgroup of overweight patients, SS showed a significant improvement, whereas SI did not. Both SS and SI were found to be significantly improved in normal-weight patients. PMID:26657174

  1. The significance of a positive DAT in thalassemia patients.

    PubMed

    Arinsburg, S A; Skerrett, D L; Kleinert, D; Giardina, P J; Cushing, M M

    2010-01-01

    The DAT is performed for the detection of antibody or complement on the surface of RBCs. Our institution previously performed DATs on all chronically transfused thalassemia patients before each transfusion episode to detect early alloimmunization. The medical records of all thalassemia patients treated at our institution from 2004 to 2007 were reviewed to determine the significance of the high rate of positive DATs (52.5% of 80 patients). The majority of IgG-reactive DATs were associated with a nonreactive eluate (65.4% of 286 eluates performed). A positive DAT was significantly associated with splenectomy (χ² = 15.4; p < 0.001), elevated IgG levels (χ² = 26.8; p < 0.001), HCV (χ² = 20.7; p < 0.001), and warm autoantibody (χ² = 5.87; p = 0.03). Multivariate analysis revealed that only HCV (OR, 5.0; p = 0.037) and elevated IgG levels (OR, 9.0; p = 0.001) were independently associated with a positive DAT. Alloimmunized thalassemic patients were more likely to have a positive DAT than nonalloimmunized patients, but this association was not significant (OR, 2.2; p = 0.11). A positive DAT did not correlate with decreased response to transfusion, RBC survival, hemolysis, or increased transfusion requirements. Only two cases of early alloimmunization were detected by DAT among 288 DAT-positive samples studied during 4 years. This study demonstrated that the routine performance of DATs on pretransfusion specimens in thalassemic patients has limited clinical utility, and the elimination of this test will improve turnaround time and decrease costs. PMID:21214294

  2. TGF-ß induces Lysyl hydroxylase 2b in human synovial osteoarthritic fibroblasts through ALK5 signaling.

    PubMed

    Remst, Dennis F G; Blaney Davidson, Esmeralda N; Vitters, Elly L; Bank, Ruud A; van den Berg, Wim B; van der Kraan, Peter M

    2014-01-01

    Lysyl hydroxylase 2b (LH2b) is known to increase pyridinoline cross-links, making collagen less susceptible to enzymatic degradation. Previously, we observed a relationship between LH2b and osteoarthritis-related fibrosis in murine knee joint. For this study, we investigate if transforming growth factor-beta (TGF-ß) and connective tissue growth factor (CTGF) regulate procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) (gene encoding LH2b) and LH2b expression differently in osteoarthritic human synovial fibroblasts (hSF). Furthermore, we investigate via which TGF-ß route (Smad2/3P or Smad1/5/8P) LH2b is regulated, to explore options to inhibit LH2b during fibrosis. To answer these questions, fibroblasts were isolated from knee joints of osteoarthritis patients. The hSF were stimulated with TGF-ß with or without a kinase inhibitor of ALK4/5/7 (SB-505124) or ALK1/2/3/6 (dorsomorphin). TGF-ß, CTGF, constitutively active (ca)ALK1 and caALK5 were adenovirally overexpressed in hSF. The gene expression levels of PLOD1/2/3, CTGF and COL1A1 were analyzed with Q-PCR. LH2 protein levels were determined with western blot. As expected, TGF-ß induced PLOD2/LH2 expression in hSF, whereas CTGF did not. PLOD1 and PLOD3 were not affected by either TGF-ß or CTGF. SB-505124 prevented the induction of TGF-ß-induced PLOD2, CTGF and COL1A1. Surprisingly, dorsomorphin completely blocked the induction of CTGF and COL1A1, whereas TGF-ß-induced PLOD2 was only slightly reduced. Overexpression of caALK5 in osteoarthritic hSF significantly induced PLOD2/LH2 expression, whereas caALK1 had no effect. We showed, in osteoarthritic hSF, that TGF-ß induced PLOD2/LH2 via ALK5 Smad2/3P. This elevation of LH2b in osteoarthritic hSF makes LH2b an interesting target to interfere with osteoarthritis-related persistent fibrosis. PMID:24192939

  3. Pregnancy in HIV-Positive Patients: Effects on Vaginal Flora

    PubMed Central

    Vallone, Cristina; Rigon, Giuliano; Lucantoni, Valeria; Putignani, Lorenza; Signore, Fabrizio

    2012-01-01

    A high proportion of HIV-infected pregnant women present pathogenic organisms in their lower genital tract. This has been associated with the development of postpartum morbility, HIV transmission to the partner and offspring, and other gynaecological conditions, such as cervical dysplasia or cancer. Vaginal flora alterations can range from 47% in Western countries to 89% in Africa in pregnant HIV-positive patients, much higher than about 20% of the general population. Pathogen organism retrieval is high. As peripartum complications due to vaginal infections seem higher in HIV-positive patients, accurate investigation and treatment of such infections are strongly mandatory. PMID:22675241

  4. A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement.

    PubMed

    Shiroyama, Takayuki; Tanaka, Ayako; Tamiya, Motohiro; Hamaguchi, Masanari; Osa, Akio; Takeoka, Sawa; Tani, Eriko; Azuma, Yuichiro; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Kimura, Kenji; Kadota, Yoshihisa; Kawahara, Kunimitsu; Hirashima, Tomonori; Kawase, Ichiro

    2015-01-01

    Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma. PMID:26521903

  5. 40 CFR 721.435 - Alkylphenylpolyether-alk-a-nol-a-mines (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkylphenylpolyether-alk-a-nol-a-mines... Specific Chemical Substances § 721.435 Alkylphenylpolyether-alk-a-nol-a-mines (generic). (a) Chemical... as alkylphenylpolyether-alk-a-nol-a-mines (PMNs P-97-880/881/882) are subject to reporting under...

  6. 40 CFR 721.435 - Alkylphenylpolyether-alk-a-nol-a-mines (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkylphenylpolyether-alk-a-nol-a-mines... Specific Chemical Substances § 721.435 Alkylphenylpolyether-alk-a-nol-a-mines (generic). (a) Chemical... as alkylphenylpolyether-alk-a-nol-a-mines (PMNs P-97-880/881/882) are subject to reporting under...

  7. 40 CFR 721.435 - Alkylphenylpolyether-alk-a-nol-a-mines (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkylphenylpolyether-alk-a-nol-a-mines... Specific Chemical Substances § 721.435 Alkylphenylpolyether-alk-a-nol-a-mines (generic). (a) Chemical... as alkylphenylpolyether-alk-a-nol-a-mines (PMNs P-97-880/881/882) are subject to reporting under...

  8. 40 CFR 721.435 - Alkylphenylpolyether-alk-a-nol-a-mines (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkylphenylpolyether-alk-a-nol-a-mines... Specific Chemical Substances § 721.435 Alkylphenylpolyether-alk-a-nol-a-mines (generic). (a) Chemical... as alkylphenylpolyether-alk-a-nol-a-mines (PMNs P-97-880/881/882) are subject to reporting under...

  9. Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis

    PubMed Central

    Zhu, Shizhen; Lee, Jeong-Soo; Guo, Feng; Shin, Jimann; Perez-Atayde, Antonio R.; Kutok, Jeffery L.; Rodig, Scott J.; Neuberg, Donna S.; Helman, Daniel; Feng, Hui; Stewart, Rodney A.; Wang, Wenchao; George, Rani E.; Kanki, John P.; Look, A. Thomas

    2012-01-01

    SUMMARY Amplification of the MYCN oncogene in childhood neuroblastoma is often accompanied by mutational activation of ALK (anaplastic lymphoma kinase), suggesting their pathogenic cooperation. We generated a transgenic zebrafish model of neuroblastoma in which MYCN-induced tumors arise from a subpopulation of neuroblasts that migrate into the adrenal medulla analogue following organogenesis. Coexpression of activated ALK with MYCN in this model triples the disease penetrance and markedly accelerates tumor onset. MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. Coexpression of activated ALK with MYCN provides prosurvival signals that block this apoptotic response and allow continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. PMID:22439933

  10. A Suicide Prevention Program for HIV-Positive Patients.

    ERIC Educational Resources Information Center

    Shaw, Seana; Rothberg, Joseph M.

    Research has shown that suicide risk is elevated in the patient who has tested positive for Human Immunodeficiency Virus (HIV). Studies within the Army have found that the three most turbulent periods for the soldier with HIV infection are: (1) at the time of notification of diagnosis; (2) when the family and peer group learn of the diagnosis; and…

  11. Error compensation algorithm for patient positioning robotics system

    NASA Astrophysics Data System (ADS)

    Murty, Pilaka V.; Talpasanu, Ilie; Roz, Mugur A.

    2009-03-01

    Surgeons in various medical areas (orthopedic surgery, neurosurgery, dentistry etc.) are using motor-driven drilling tools to make perforations in hard tissues (bone, enamel, dentine, cementum etc.) When the penetration requires very precise angles and accurate alignment with respect to different targets, precision cannot be obtained by using visual estimation and hand-held tools. Robots have been designed to allow for very accurate relative positioning of the patient and the surgical tools, and in certain classes of applications the location of bone target and inclination of the surgical tool can be accurately specified with respect to an inertial frame of reference. However, patient positioning errors as well as position changes during surgery can jeopardize the precision of the operation, and drilling parameters have to be dynamically adjusted. In this paper the authors present a quantitative method to evaluate the corrected position and inclination of the drilling tool, to account for translational and rotational errors in displaced target position. The compensation algorithm applies principles of inverse kinematics wherein a faulty axis in space caused by the translational and rotational errors of the target position is identified with an imaginary true axis in space by enforcing identity through a modified trajectory. In the absence of any specific application, this algorithm is verified on Solid Works, a commercial CAD tool and found to be correct. An example problem given at the end vindicates this statement.

  12. An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.

    PubMed

    Peddi, Saikiran Reddy; Sivan, Sree Kanth; Manga, Vijjulatha

    2016-10-01

    Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed. PMID:26758803

  13. Sublingual allergen immunotherapy in HIV-positive patients.

    PubMed

    Iemoli, E; Borgonovo, L; Fusi, A; Magni, C; Ricci, E D; Rizzardini, G; Piconi, S

    2016-03-01

    HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV-infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen-allergic HAART-treated HIV-positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes©) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom-medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT-treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro-immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated. PMID:26228482

  14. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer.

    PubMed

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-05-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10-12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  15. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

    PubMed Central

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-01-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10–12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  16. Positional changes of the third molar in orthodontically treated patients

    PubMed Central

    Mihai, AM; Lulache, IR; Grigore, R; Sanabil, AS; Boiangiu, S; Ionescu, E

    2013-01-01

    Objective and Rationale. Over the years, the effects of the third molars eruption on the dental arches have been studied extensively. Still, literature provides less data regarding the effects of the orthodontic treatment on the third molars position. The aim of our study was to assess the positional changes of the third molars relative to the occlusal plane and to the second molar long axis, changes occurred during orthodontic treatment performed with or without premolar extractions. Method. This study included 20 orthodontic treated patients: 10 of them with premolar extractions and 10 without premolar extractions. The pretreatment and post treatment panoramic radiographs were analyzed, and the angles between the third molar long axis and the occlusal plane and between the long axis of the third molar and the long axis of the second molar were measured. Results. Changes in third molar position, from pretreatment to post treatment, for the two groups of patients were evaluated by using the Student’s t-test. The results of the statistical analysis revealed an improvement in third molars position, the best results were seen in the lower third molars, in the group of patients treated with premolar extractions. PMID:23904878

  17. Ocular disease in patients with ANCA-positive vasculitis

    PubMed Central

    Watkins, Angela S.; Kempen, John H.; Choi, Dongseok; Liesegang, Teresa L.; Pujari, S. S.; Newcomb, Craig; Nussenblatt, Robert B.; Rosenbaum, James T.; Thorne, Jennifer E.; Foster, C. Stephen; Jabs, Douglas A.; Levy-Clarke, Grace A.; Suhler, Eric B.

    2009-01-01

    Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis—the term recently applied to Wegener's granulomatosis—is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease. PMID:20835396

  18. Positive and negative religious coping in German breast cancer patients.

    PubMed

    Zwingmann, Christian; Wirtz, Markus; Müller, Claudia; Körber, Jürgen; Murken, Sebastian

    2006-12-01

    A growing interest has been focusing on the relationship between religious coping and psychosocial adjustment among cancer patients. However, previous research mostly has not differentiated between positive and negative components of religious coping. The current cross-sectional study investigated the role of both positive religious coping, i.e., a confident and constructive turning to religion, and negative religious coping, i.e., religious struggle and doubt, in a sample of 156 German breast cancer patients. Participants were assessed upon admission to an inpatient rehabilitation program. In addition to religious coping, two basic nonreligious coping styles (depressive coping and active problem-focused coping) and psychosocial adjustment (anxiety and depression) were measured. Major research questions concerning the mediating role of nonreligious coping and the relative predictive power of positive and negative religious coping were primarily addressed using structural equation modeling. Results indicated that the relationship between religious coping and psychosocial outcomes was completely mediated by nonreligious coping, whereby only depressive coping and not active problem-focused coping proved to be a mediating variable. Positive and negative religious coping were somewhat positively related to each other; their (indirect) predictive power on psychosocial adjustment was identical though in an opposite direction. All in all, the results correspond to previous Anglo-American research. There are, however, some discrepancies which may be due to the specific religious-cultural background in Germany. PMID:16951991

  19. Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells

    PubMed Central

    Sattu, Kamaraj; Hochgräfe, Falko; Wu, Jianmin; Umapathy, Ganesh; Schönherr, Christina; Ruuth, Kristina; Chand, Damini; Witek, Barbara; Fuchs, James; Li, Pui-Kai; Hugosson, Fredrik; Daly, Roger J; Palmer, Ruth H; Hallberg, Bengt

    2013-01-01

    Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin–ALK and echinoderm microtubule-associated protein-like 4–ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma. PMID:23889739

  20. Adenovirus infection of the large bowel in HIV positive patients.

    PubMed Central

    Maddox, A.; Francis, N.; Moss, J.; Blanshard, C.; Gazzard, B.

    1992-01-01

    AIMS: To describe the microscopic appearance of adenovirus infection in the large bowel of human immunodeficiency virus (HIV) positive patients with diarrhoea. METHODS: Large bowel biopsy specimens from 10 HIV positive patients, eight of whom were also infected with other gastrointestinal pathogens, with diarrhoea were examined, together with six small bowel biopsy specimens from the same group of patients. Eight of the patients had AIDS. The biopsy specimens were examined by light microscopy performed on haematoxylin and eosin stained and immunoperoxidase preparations, the latter using a commercially available antibody (Serotec MCA 489). Confirmation was obtained with electron microscopy. RESULTS: The morphological appearance of cells infected with adenovirus showed characteristic nuclear and cellular changes, although the inflammatory reaction was non-specific. Immunoperoxidase staining for adenovirus was sensitive and specific, and the presence of viral inclusions consistent with adenovirus was confirmed by electron microscopy. CONCLUSIONS: The light microscopic features of adenovirus infection are distinctive and immunocytochemistry with a commercially available antibody is a sensitive and specific means of confirming the diagnosis. Further studies of the role of adenovirus in causing diarrhoea in these patients are indicated. Images PMID:1401177

  1. When Patients Divorce: The Family Physician's Legal Position

    PubMed Central

    Mesbur, Ruth E.

    1983-01-01

    When divorce and family disintegration loom, the family physician is often the first outsider on the scene. The family physician may, indeed, have a critical role to play in handling the crisis; he may advise, refer to other professionals like therapists or lawyers, or appear in court as an expert witness. The physician must consider his legal position. Is reconciliation counselling confidential, privileged information? Can he recommend a lawyer for a patient? What is the physician's vulnerability as an expert witness in divorce and custody proceedings? Knowledge, understanding and skillful handling of the legal and human processes involved can limit family destruction and help maintain the physician/patient relationship. PMID:21283420

  2. Spectral classifications of Gaia16alk (AT2016brw) as type II SN and AT2016brv as type Ia SN

    NASA Astrophysics Data System (ADS)

    Piascik, A. S.; Steele, I. A.

    2016-04-01

    We conducted a spectroscopic observation of transient Gaia16alk (AT2016brw) at 2016-04-24T01:58:41 UT. This transient was observed by the Gaia Photometric Science survey on 2016-04-18T09:16:07 UT at position RA = 17:08:26.60, DEC = 25:30:51.00.

  3. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis

    PubMed Central

    Wang, Yongfeng; Wang, Long; Guan, Shan; Cao, Wenming; Wang, Hao; Chen, Zhenghu; Zhao, Yanling; Yu, Yang; Zhang, Huiyuan; Pang, Jonathan C.; Huang, Sophia L.; Akiyama, Yo; Yang, Yifan; Sun, Wenjing; Xu, Xin; Shi, Yan; Zhang, Hong; Kim, Eugene S.; Muscal, Jodi A.; Lu, Fengmin; Yang, Jianhua

    2016-01-01

    ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB. PMID:26786851

  4. Intraoral Burkitt's lymphoma in an HIV positive patient

    PubMed Central

    Ajila, Vidya; Gopakumar, R.; Hegde, Shruthi; Babu, Subhas G.

    2012-01-01

    Burkitt's lymphoma is an aggressive form of Non-Hodgkin's lymphoma composed of malignant cells of B lymphocyte origin. Burkitt's lymphoma is a rarity in the Indian subcontinent. Though intraoral Burkitt's lymphoma in HIV positive individuals is very uncommon, its importance lies in the fact that it is often the first sign of the underlying immunosuppression. We present a case of Burkitt's lymphoma in right maxillary region which was the first manifestation of HIV in the patient. PMID:23188938

  5. Comparison of CRP and ALK-P serum levels in prediction of preterm delivery

    PubMed Central

    Shahshahan, Zahra; Iravani, Hoda

    2016-01-01

    Background: Preterm birth, defined as birth occurring before 37 weeks of gestation, is a common complication of pregnancy and may lead to death or long-term disability in newborns. Accurate diagnosis is, therefore, crucial for identifying those women undergoing preterm labor who are at greatest risk of preterm delivery. This may allow transport to a regional obstetrical center and permit time for corticosteroid therapy. Recent study recommends several markers such as CRP (C-reactive protein) and ALK-P (alkaline phosphatase) to predict preterm delivery. Materials and Methods: We select a total of 300 pregnant women that had symptoms of premature birth. All of them were under treatment with tocolytic and serum sample were taken to assess the level of CRP-ALKp. Cervix length and the time of response to tocolytic were measured. 110 pregnant of them had preterm labor. 110 patient that had a term labor selected as a control group. Results: Qualitative evaluation of efficacy CRP level on preterm delivery showed a significant relationship with 27 as a cut of point of CRP (P < 0.00001 –OR = 7.5). Investigate of effect of ALK-P level on preterm delivery refers to a significant relationship with 399 as a cut of point of ALKP (P < 0.00001 –OR = 5). Inquire of efficacy of CRP level and ALK-P level on preterm delivery demonstrate a significant relationship (P < 0.0001 1OR = 9). Conclusions: Maternal concentrations of CRP and ALKP and cervix length can be used as appropriate biomarker for predicting preterm labor and response to tocolytic therapy in pregnant women. PMID:26962519

  6. Identification of Five Driver Gene Mutations in Patients with Treatment-Naïve Lung Adenocarcinoma in Taiwan

    PubMed Central

    Su, Kang-Yi; Wu, Ming-Fang; Chiu, Kuo-Liang; Yang, Tsung-Ying; Chen, Kun-Chieh; Ooi, Hean; Wu, Tzu-Chin; Chen, Hung-Jen; Chen, Hsuan-Yu; Chang, Chi-Sheng; Hsu, Chung-Ping; Hsia, Jiun-Yi; Chuang, Cheng-Yen; Lin, Chin-Hung; Chen, Jeremy J. W.; Chen, Kuan-Yu; Liao, Wei-Yu; Shih, Jin-Yuan; Yu, Sung-Liang; Yu, Chong-Jen; Yang, Pan-Chyr; Chang, Gee-Chen

    2015-01-01

    Background It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. Methods This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). Results From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. Conclusion This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials. PMID:25789627

  7. Role of liver transplantation in human immunodeficiency virus positive patients

    PubMed Central

    Joshi, Deepak; Agarwal, Kosh

    2015-01-01

    End-stage liver disease (ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus (HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus (HCV) infection, drug-induced hepatotoxicity related to combined anti-retro-viral therapy, alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore, anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However, HIV-HCV co-infection transplant outcomes remain suboptimal due to recurrence. In this article, we review the key challenges faced by this patient cohort in the pre- and post-transplant period. PMID:26604639

  8. Bar code technology improves positive patient identification and transfusion safety.

    PubMed

    Sandler, S G; Langeberg, A; Dohnalek, L

    2005-01-01

    As a result of human error, an estimated 1 in 12,000 blood transfusions is given to the wrong patient. The cause of nearly all of these errors is failure of hospital personnel to identify positively intended transfusion recipients, their blood samples for cross-matching, or their correct blood components. We describe our experience using a point-of-care bar code transfusion safety system that links patients' bar-coded wristbands, with bar-coded labels on blood sample tubes, blood component bags, and nurses' identification badges. The result was 100 % accuracy of matching patients, their blood samples, and components for transfusions. For verifying information before starting blood transfusions, nurses preferred bar code "double checks" to conventional visual "double checks" by a second nurse. Methods are needed to reinforce nurses' proficiency with technological approaches to transfusion safety, such as software-driven bar code scanning, in situations where transfusions are administered infrequently. PMID:16050151

  9. Extensive Giant Molluscum Contagiosum in a HIV Positive Patient.

    PubMed

    Vora, Rita V; Pilani, Abhishek P; Kota, Rahul Krishna

    2015-11-01

    Molluscum contagiosum (MC) is a very common benign self-limiting cutaneous viral infection caused by molluscum contagiosum virus. Disease is self-limiting in immunocompetent individuals, while it is severe and prolonged when associated with Human Immunodeficiency Virus (HIV) infection. The widespread and refractory mollusca of HIV disease occur especially on the face. In advanced stages of immunosuppression, giant or verrucous forms of MC may occur. Molluscum contagiosum tends to take a chronic course and is usually not responsive to various treatments in immunocompromised patients. Here, we present a HIV positive male patient with extensive papulonodular lesions over face, neck, bilateral upper limbs since 2 months, diagnosed as giant molluscum contagiosum, treated with cryotherapy with little improvement for few weeks after which patient did not turn up. PMID:26672647

  10. Extensive Giant Molluscum Contagiosum in a HIV Positive Patient

    PubMed Central

    Pilani, Abhishek P.; Kota, Rahul Krishna

    2015-01-01

    Molluscum contagiosum (MC) is a very common benign self-limiting cutaneous viral infection caused by molluscum contagiosum virus. Disease is self-limiting in immunocompetent individuals, while it is severe and prolonged when associated with Human Immunodeficiency Virus (HIV) infection. The widespread and refractory mollusca of HIV disease occur especially on the face. In advanced stages of immunosuppression, giant or verrucous forms of MC may occur. Molluscum contagiosum tends to take a chronic course and is usually not responsive to various treatments in immunocompromised patients. Here, we present a HIV positive male patient with extensive papulonodular lesions over face, neck, bilateral upper limbs since 2 months, diagnosed as giant molluscum contagiosum, treated with cryotherapy with little improvement for few weeks after which patient did not turn up. PMID:26672647

  11. Necrotizing stomatitis: report of 3 Pseudomonas aeruginosa-positive patients.

    PubMed

    Barasch, Andrei; Gordon, Sara; Geist, Rose Y; Geist, James R

    2003-08-01

    Necrotizing oral lesions have been described in immunosuppressed patients, usually in association with gingival and periodontal pathoses. The etiology of these lesions has not been completely elucidated. We present 3 patients with a type of necrotizing stomatitis in which clinical patterns appear distinct from the periodontal forms of the disease. The lesions yielded bacterial cultures positive for Pseudomonas aeruginosa and reverted to no growth in 2 patients after proper antibiotic therapy. We propose that P aeruginosa may be responsible for selected necrotizing oral lesions with a clinical presentation lacking typical necrotizing periodontal disease and that this condition may represent the intraoral counterpart of ecthyma gangrenosum. In such cases, bacterial culture of the lesion becomes imperative because the disease does not respond to typical periodontal and antimicrobial therapy. PMID:12931084

  12. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS

    PubMed Central

    Vincent, M.D.; Kuruvilla, M.S.; Leighl, N.B.; Kamel–Reid, S.

    2012-01-01

    New drugs such as pemetrexed, the epidermal growth factor receptor (egfr) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-small-cell lung cancer (nsclc). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of nsclc, and optimizing their utility requires some degree of subgrouping of nsclc by the presence or absence of certain biomarkers. The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-egfr monoclonal antibodies, EGFR immunohistochemistry is also of potential interest. Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents. These biomarkers have all enabled the co-development of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in nsclc, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies. PMID:22787409

  13. Progress of EGFR-TKI and ALK/ROS1 inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Ge, Liangqing; Shi, Ruizheng

    2015-01-01

    To discuss the mechanism and clinical application of EGFR-TKI and ALK/ROS1 inhibitors in non-small cell lung cancer (NSCLC), we reviewed recent available data mainly from PubMed. We found that chemotherapy, progression-free survival (PFS), objective response rate (ORR), and quality of life of patients with advanced NSCLC can be greatly improved in these drugs medication compared with conventional chemotherapy. Though many questions like resistance to EGFR-TKI and ALK/ROS1 inhibitors exist, molecular targeted therapy is an important therapeutic method for the management of NSCLC. The role of molecule targeted therapy in the initiation and development of NSCLC deserves further study. PMID:26379824

  14. Viral AlkB proteins repair RNA damage by oxidative demethylation

    PubMed Central

    van den Born, Erwin; Omelchenko, Marina V.; Bekkelund, Anders; Leihne, Vibeke; Koonin, Eugene V.; Dolja, Valerian V.; Falnes, Pål Ø.

    2008-01-01

    Bacterial and mammalian AlkB proteins are iron(II)- and 2-oxoglutarate-dependent dioxygenases that reverse methylation damage, such as 1-methyladenine and 3-methylcytosine, in RNA and DNA. An AlkB-domain is encoded by the genome of numerous single-stranded, plant-infecting RNA viruses, the majority of which belong to the Flexiviridae family. Our phylogenetic analysis of AlkB sequences suggests that a single plant virus might have acquired AlkB relatively recently, followed by horizontal dissemination among other viruses via recombination. Here, we describe the first functional characterization of AlkB proteins from three plant viruses. The viral AlkB proteins efficiently reactivated methylated bacteriophage genomes when expressed in Escherichia coli, and also displayed robust, iron(II)- and 2-oxoglutarate-dependent demethylase activity in vitro. Viral AlkB proteins preferred RNA over DNA substrates, and thus represent the first AlkBs with such substrate specificity. Our results suggest a role for viral AlkBs in maintaining the integrity of the viral RNA genome through repair of deleterious methylation damage, and support the notion that AlkB-mediated RNA repair is biologically relevant. PMID:18718927

  15. Pill impaction mimicking appendicitis in an HIV-positive patient.

    PubMed

    Torno, Mauro; Shallman, Michael

    2009-01-01

    Abdominal pain is a frequent presenting symptom among HIV-positive patients seeking care at emergency departments. We report a case of a 45-year-old HIV-infected Hispanic man who presented with right lower quadrant pain accompanied by fever, decreased appetite, nausea, and vomiting. The results of a CT scan of his abdomen were normal with no evidence of appendicitis. A colonoscopy was performed and revealed an impacted pill in the appendiceal orifice. The pill was removed endoscopically, and pill impaction has not recurred. PMID:19209455

  16. Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice.

    PubMed

    Schweitzer, Paul; Cates-Gatto, Chelsea; Varodayan, Florence P; Nadav, Tali; Roberto, Marisa; Lasek, Amy W; Roberts, Amanda J

    2016-08-01

    Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk -/-) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk -/- mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk -/- mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk -/- mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk -/- mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA. PMID:26946429

  17. Activin Receptor-Like Kinase Receptors ALK5 and ALK1 Are Both Required for TGFβ-Induced Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

    PubMed Central

    de Kroon, Laurie M. G.; Narcisi, Roberto; Blaney Davidson, Esmeralda N.; Cleary, Mairéad A.; van Beuningen, Henk M.; Koevoet, Wendy J. L. M.; van Osch, Gerjo J. V. M.; van der Kraan, Peter M.

    2015-01-01

    Introduction Bone marrow-derived mesenchymal stem cells (BMSCs) are promising for cartilage regeneration because BMSCs can differentiate into cartilage tissue-producing chondrocytes. Transforming Growth Factor β (TGFβ) is crucial for inducing chondrogenic differentiation of BMSCs and is known to signal via Activin receptor-Like Kinase (ALK) receptors ALK5 and ALK1. Since the specific role of these two TGFβ receptors in chondrogenesis is unknown, we investigated whether ALK5 and ALK1 are expressed in BMSCs and whether both receptors are required for chondrogenic differentiation of BMSCs. Materials & Methods ALK5 and ALK1 gene expression in human BMSCs was determined with RT-qPCR. To induce chondrogenesis, human BMSCs were pellet-cultured in serum-free chondrogenic medium containing TGFβ1. Chondrogenesis was evaluated by aggrecan and collagen type IIα1 RT-qPCR analysis, and histological stainings of proteoglycans and collagen type II. To overexpress constitutively active (ca) receptors, BMSCs were transduced either with caALK5 or caALK1. Expression of ALK5 and ALK1 was downregulated by transducing BMSCs with shRNA against ALK5 or ALK1. Results ALK5 and ALK1 were expressed in in vitro-expanded as well as in pellet-cultured BMSCs from five donors, but mRNA levels of both TGFβ receptors did not clearly associate with chondrogenic induction. TGFβ increased ALK5 and decreased ALK1 gene expression in chondrogenically differentiating BMSC pellets. Neither caALK5 nor caALK1 overexpression induced cartilage matrix formation as efficient as that induced by TGFβ. Moreover, short hairpin-mediated downregulation of either ALK5 or ALK1 resulted in a strong inhibition of TGFβ-induced chondrogenesis. Conclusion ALK5 as well as ALK1 are required for TGFβ-induced chondrogenic differentiation of BMSCs, and TGFβ not only directly induces chondrogenesis, but also modulates ALK5 and ALK1 receptor signaling in BMSCs. These results imply that optimizing cartilage formation by

  18. A patient positioning system for the ESRF medical imaging facility

    NASA Astrophysics Data System (ADS)

    Dabin, Y.; Draperi, A.; Elleaume, H.; Charvet, A.-M.; Brochard, T.; Perez, M.; Nemoz, C.; Blattmann, G.; Renier, M.; Fournier, F.; Dupuy, J.-L.; Lemoine, B.; Bouhaniche, P.; Thomlinson, W.; Suortti, P.

    2001-07-01

    The medical imaging facility of the ESRF is devoted to human coronary angiography, computed tomography, diffraction enhanced imaging (DEI), bronchography, and also radiation therapy programs. Most of the imaging is performed in a satellite building located at 150 m from the wiggler source (H. Elleaume et al., Nucl. Instr. and Meth. A 428 (1999) 513). A multi-purpose device known as the Patient Positioning System (PPS or medical chair) has been designed to perform in different modes of research on patients. This device operates in the angiography mode, with alternating up and down movements in 1.6 s cycles over a period of about 30 s. The tomography mode is used mainly for the imaging of the brain. It consists of turning the patient around an axis perfectly perpendicular to the beam plane. A dual-energy scan involves two rotations with one image recorded each turn at a different energy (Phys. Med. Biol. 45 (2000) L39). The first angiography imaging on patients was undertaken in January 2000 after successful pre-clinical tests on animals.

  19. Enzymological and Structural Studies of the Mechanism of Promiscuous Substrate Recognition by the Oxidative DNA Repair Enzyme AlkB

    SciTech Connect

    Yu, B.; Hunt, J

    2009-01-01

    Promiscuous substrate recognition, the ability to catalyze transformations of chemically diverse compounds, is an evolutionarily advantageous, but poorly understood phenomenon. The promiscuity of DNA repair enzymes is particularly important, because it enables diverse kinds of damage to different nucleotide bases to be repaired in a metabolically parsimonious manner. We present enzymological and crystallographic studies of the mechanisms underlying promiscuous substrate recognition by Escherichia coli AlkB, a DNA repair enzyme that removes methyl adducts and some larger alkylation lesions from endocyclic positions on purine and pyrimidine bases. In vitro Michaelis-Menten analyses on a series of alkylated bases show high activity in repairing N1-methyladenine (m1A) and N3-methylcytosine (m3C), comparatively low activity in repairing 1,N6-ethenoadenine, and no detectable activity in repairing N1-methylguanine or N3-methylthymine. AlkB has a substantially higher kcat and Km for m3C compared with m1A. Therefore, the enzyme maintains similar net activity on the chemically distinct substrates by increasing the turnover rate of the substrate with nominally lower affinity. Cocrystal structures provide insight into the structural basis of this 'kcat/Km compensation,' which makes a significant contribution to promiscuous substrate recognition by AlkB. In analyzing a large ensemble of crystal structures solved in the course of these studies, we observed 2 discrete global conformations of AlkB differing in the accessibility of a tunnel hypothesized to control diffusion of the O2 substrate into the active site. Steric interactions between a series of protein loops control this conformational transition and present a plausible mechanism for preventing O2 binding before nucleotide substrate binding.

  20. Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva*S⃞

    PubMed Central

    Fukuda, Toru; Kohda, Masakazu; Kanomata, Kazuhiro; Nojima, Junya; Nakamura, Atsushi; Kamizono, Jyunji; Noguchi, Yasuo; Iwakiri, Kiyofumi; Kondo, Takeo; Kurose, Junichi; Endo, Ken-ichi; Awakura, Takeshi; Fukushi, Junichi; Nakashima, Yasuharu; Chiyonobu, Tomohiro; Kawara, Akira; Nishida, Yoshihiro; Wada, Ikuo; Akita, Masumi; Komori, Tetsuo; Nakayama, Konosuke; Nanba, Akira; Maruki, Yuichi; Yoda, Tetsuya; Tomoda, Hiroshi; Yu, Paul B.; Shore, Eileen M.; Kaplan, Frederick S.; Miyazono, Kohei; Matsuoka, Masaru; Ikebuchi, Kenji; Ohtake, Akira; Oda, Hiromi; Jimi, Eijiro; Owan, Ichiro; Okazaki, Yasushi; Katagiri, Takenobu

    2009-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP. PMID:18684712

  1. Positive patient experiences in an Australian integrative oncology centre

    PubMed Central

    2014-01-01

    Background The purpose of this study was to explore the experiences of cancer patients’ utilising complementary and integrative therapies (CIT) within integrative oncology centres across Western Australia. Methods Across four locations 135 patients accessed CIT services whilst undergoing outpatient medical treatment for cancer. Of the 135 patients, 66 (61 ± 12 y; female n = 45; male n = 21) agreed to complete a personal accounts questionnaire consisting of open-ended questions designed to explore patients’ perceptions of CIT. All results were transcribed into nVivo (v9) and using thematic analysis, key themes were identified. Results Of the 66 participants, 100% indicated they would “recommend complementary therapies to other patients” and 92% stated “CIT would play a significant role in their future lifestyle”. A mean score of 8 ± 1 indicated an improvement in participants’ perception of wellbeing following a CIT session. Three central themes were identified: empowerment, support and relaxation. Fourteen sub-themes were identified, with all themes clustered into a framework of multifaceted views held by cancer patients in relation to wellbeing, role of significant others and control. Conclusions Exploration of patients’ experiences reveals uniformly positive results. One of the key merits of the environment created within the centres is patients are able to work through their cancer journey with an increased sense of empowerment, without placing them in opposition to conventional medical treatment. In order to effectively target integrative support services it is crucial to explore the experiences of patients in their own words and use those forms of expression to drive service delivery. PMID:24886476

  2. Analysis of Pseudomonas putida alkane-degradation gene clusters and flanking insertion sequences: evolution and regulation of the alk genes.

    PubMed

    van Beilen, J B; Panke, S; Lucchini, S; Franchini, A G; Röthlisberger, M; Witholt, B

    2001-06-01

    The Pseudomonas putida GPo1 (commonly known as Pseudomonas oleovorans GPo1) alkBFGHJKL and alkST gene clusters, which encode proteins involved in the conversion of n-alkanes to fatty acids, are located end to end on the OCT plasmid, separated by 9.7 kb of DNA. This DNA segment encodes, amongst others, a methyl-accepting transducer protein (AlkN) that may be involved in chemotaxis to alkanes. In P. putida P1, the alkBFGHJKL and alkST gene clusters are flanked by almost identical copies of the insertion sequence ISPpu4, constituting a class 1 transposon. Other insertion sequences flank and interrupt the alk genes in both strains. Apart from the coding regions of the GPo1 and P1 alk genes (80-92% sequence identity), only the alkB and alkS promoter regions are conserved. Competition experiments suggest that highly conserved inverted repeats in the alkB and alkS promoter regions bind ALKS: PMID:11390693

  3. Regulation of alkane degradation pathway by a TetR family repressor via an autoregulation positive feedback mechanism in a Gram-positive Dietzia bacterium.

    PubMed

    Liang, Jie-Liang; Nie, Yong; Wang, Miaoxiao; Xiong, Guangming; Wang, Yi-Ping; Maser, Edmund; Wu, Xiao-Lei

    2016-01-01

    n-Alkanes are ubiquitous in nature and serve as important carbon sources for both Gram-positive and Gram-negative bacteria. Hydroxylation of n-alkanes by alkane monooxygenases is the first and most critical step in n-alkane metabolism. However, regulation of alkane degradation genes in Gram-positive bacteria remains poorly characterized. We therefore explored the transcriptional regulation of an alkB-type alkane hydroxylase-rubredoxin fusion gene, alkW1, from Dietzia sp. DQ12-45-1b. The alkW1 promoter was characterized and so was the putative TetR family regulator, AlkX, located downstream of alkW1 gene. We further identified an unusually long 48 bp inverted repeat upstream of alkW1 and demonstrated the binding of AlkX to this operator. Analytical ultracentrifugation and microcalorimetric results indicated that AlkX formed stable dimers in solution and two dimers bound to one operator in a positive cooperative fashion characterized by a Hill coefficient of 1.64 (± 0.03) [k(D)  = 1.06 (± 0.16) μM, k(D) ' = 0.05 (± 0.01) μM]. However, the DNA-binding affinity was disrupted in the presence of long-chain fatty acids (C10-C24), suggesting that AlkX can sense the concentrations of n-alkane degradation metabolites. A model was therefore proposed where AlkX controls alkW1 expression in a metabolite-dependent manner. Bioinformatic analysis revealed that the alkane hydroxylase gene regulation mechanism may be common among Actinobacteria. PMID:26418273

  4. Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

    PubMed Central

    Ying, Shaozhen; Cao, Hong; Hu, He; Wang, Xin; Tang, Yanhong; Huang, Congxin

    2016-01-01

    We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7-/- mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7-/- hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K+ currents Ito and IK1 were profoundly reduced in Alk7-/- ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of Ito carrying channel) and KCHIP2 (a key accessory subunit of Ito carrying channel), was markedly decreased in Alk7-/- hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K+ currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia. PMID:26882027

  5. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency.

    PubMed

    Ceccon, M; Merlo, M E Boggio; Mologni, L; Poggio, T; Varesio, L M; Menotti, M; Bombelli, S; Rigolio, R; Manazza, A D; Di Giacomo, F; Ambrogio, C; Giudici, G; Casati, C; Mastini, C; Compagno, M; Turner, S D; Gambacorti-Passerini, C; Chiarle, R; Voena, C

    2016-07-21

    Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A 'drug holiday' where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification. PMID:26657151

  6. Patient Positioning and Port Placement for Robot-Assisted Surgery

    PubMed Central

    Chang, Charles; Steinberg, Zoe; Shah, Anup

    2014-01-01

    Abstract The introduction of robotic surgical systems and their integration into minimally invasive procedures have changed the landscape of laparoscopic surgery dramatically. Intuitive Surgical's da Vinci Surgical System was first approved by the Food and Drug Administration for cardiothoracic procedures in the late 1990s. This trend quickly spread through other surgical specialties, with urologists as one of the frontrunners in adoption. Subsequently, pediatric urologists have adopted robot-assisted procedures in selected centers, performing procedures such as pyeloplasty for ureteropelvic junction obstruction, partial and complete nephrectomy, and both intravesical and extravesical ureteral reimplantation. In this article, we will discuss technical considerations related to patient positioning and port placement in pediatric robot-assisted surgery. PMID:24548088

  7. ALK-rearranged adenocarcinoma with extensive mucin production can mimic mucinous adenocarcinoma: clinicopathological analysis and comprehensive histological comparison with KRAS-mutated mucinous adenocarcinoma.

    PubMed

    Cha, Yoon Jin; Han, Joungho; Hwang, Soo Hyun; Lee, Tae Bum; Kim, Hojoong; Zo, Jea Ill

    2016-06-01

    We aimed to investigate clinicopathological features and histology of ALK-rearranged adenocarcinomas with extensive mucin production (AEM) that mimic mucinous adenocarcinoma (MA). Retrospectively, 12 cases of AEM and 25 cases of MA harbouring KRAS mutation were retrieved. The clinicopathological profile and detailed histological features were analysed and compared based on the ALK and KRAS status. AEMs occurred in younger patients (p = 0.044) and were characterised by floating tubulopapillary pattern (p < 0.001), prominent nucleolus (p < 0.001), and apical cytoplasmic snouts (p < 0.001). In contrast, KRAS-mutated MAs lacked ALK-specific histological patterns (p < 0.05). Instead, tumour-infiltrating leukocytes (p = 0.018) and smooth cytoplasmic borders (p < 0.001) with vesicular nuclei (p = 0.004) were prominent in KRAS-mutated MAs. AEMs demonstrated characteristic tubulopapillary pattern and apical snouts, which were distinguishing features from MAs with KRAS mutation. Apical snouts can be a useful histological surrogate for ALK rearrangement in the pulmonary adenocarcinomas showing extensive mucin that mimic MA. PMID:27114375

  8. Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy.

    PubMed

    Gu, Fei-Fei; Zhang, Yong; Liu, Yang-Yang; Hong, Xiao-Hua; Liang, Jin-Yan; Tong, Fan; Yang, Jing-Song; Liu, Li

    2016-01-01

    Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK). However, the concomitant oncogenic drivers may affect the sensitivity of crizotinib. Herein, we present a 69-year-old never-smoker Chinese male with advanced lung adenocarcinoma harboring concomitant spectrin beta non-erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. Although the patient received timely and comprehensive treatment, the overall survival was only 8 months. Therefore, c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis. In addition, the novel SPTBN1-ALK fusion gene may become a potential target for anti-tumor therapy. PMID:27496196

  9. The Effects of Positive Patient Testimonials on PTSD Treatment Choice

    PubMed Central

    Pruitt, Larry D.; Zoellner, Lori A.; Feeny, Norah C.; Caldwell, Daniel; Hanson, Robert

    2012-01-01

    Despite the existence of effective treatment options for PTSD, these treatments are failing to reach those that stand to benefit from PTSD treatment. Understanding the processes underlying an individual’s treatment seeking behavior holds the potential for reducing treatment-seeking barriers. The current study investigates the effects that positive treatment testimonials have on decisions regarding PTSD treatment. An undergraduate (N = 439) and a trauma-exposed community (N = 203) sample were provided with videotaped treatment rationales for prolonged exposure (PE) and sertraline treatments of PTSD. Half of each sample also viewed testimonials, detailing a fictional patient’s treatment experience. All participants then chose among treatment options and rated the credibility of- and personal reactions toward- those options. Among treatment naïve undergraduates, testimonials increased the proportion choosing PE alone; and among treatment naïve members of the trauma-exposed community sample, testimonials increased the proportion choosing a combined PE plus sertraline treatment. These effects were not observed for those with prior history of either psychotherapeutic or pharmacological treatment. Major barriers exist that prevent individuals with PTSD from seeking treatment. For a critical unreached treatment sample, those who are treatment naïve, positive patient testimonials offer a mechanism in which to make effective treatments more appealing and accessible. PMID:23103234

  10. The Use of a Combination of alkB Primers to Better Characterize the Distribution of Alkane-Degrading Bacteria

    PubMed Central

    Jurelevicius, Diogo; Alvarez, Vanessa Marques; Peixoto, Raquel; Rosado, Alexandre S.; Seldin, Lucy

    2013-01-01

    The alkane monooxygenase AlkB, which is encoded by the alkB gene, is a key enzyme involved in bacterial alkane degradation. To study the alkB gene within bacterial communities, researchers need to be aware of the variations in alkB nucleotide sequences; a failure to consider the sequence variations results in the low representation of the diversity and richness of alkane-degrading bacteria. To minimize this shortcoming, the use of a combination of three alkB-targeting primers to enhance the detection of the alkB gene in previously isolated alkane-degrading bacteria was proposed. Using this approach, alkB-related PCR products were detected in 79% of the strains tested. Furthermore, the chosen set of primers was used to study alkB richness and diversity in different soils sampled in Carmópolis, Brazil and King George Island, Antarctica. The DNA extracted from the different soils was PCR amplified with each set of alkB-targeting primers, and clone libraries were constructed, sequenced and analyzed. A total of 255 alkB phylotypes were detected. Venn diagram analyses revealed that only low numbers of alkB phylotypes were shared among the different libraries derived from each primer pair. Therefore, the combination of three alkB-targeting primers enhanced the richness of alkB phylotypes detected in the different soils by 45% to 139%, when compared to the use of a single alkB-targeting primer. In addition, a dendrogram analysis and beta diversity comparison of the alkB composition showed that each of the sampling sites studied had a particular set of alkane-degrading bacteria. The use of a combination of alkB primers was an efficient strategy for enhancing the detection of the alkB gene in cultivable bacteria and for better characterizing the distribution of alkane-degrading bacteria in different soil environments. PMID:23825163

  11. Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma.

    PubMed

    Gonzales, Cara B; De La Chapa, Jorge J; Saikumar, Pothana; Singha, Prajjal K; Dybdal-Hargreaves, Nicholas F; Chavez, Jeffery; Horning, Aaron M; Parra, Jamie; Kirma, Nameer B

    2016-08-01

    Squamous cell carcinoma (SCC) comprises 90% of all head and neck cancers and has a poor survival rate due to late-stage disease that is refractive to traditional therapies. Epidermal growth factor receptor (EGFR) is over-expressed in greater than 80% of head and neck SCC (HNSCC). However, EGFR targeted therapies yielded little to no efficacy in clinical trials. This study investigated the efficacy of co-targeting EGFR and the anaplastic lymphoma kinase (ALK) whose promoter is hypomethylated in late-stage oral SCC (OSCC). We observed increased ALK activity in late-stage human OSCC tumors and invasive OSCC cell lines. We also found that while ALK inhibition alone had little effect on proliferation, co-targeting ALK and EGFR significantly reduced OSCC cell proliferation in vitro. Further analysis showed significant efficacy of combined treatment in HSC3-derived xenografts resulting in a 30% decrease in tumor volumes by 14days (p<0.001). Western blot analysis showed that co-targeting ALK and EGFR significantly reduced EGFR phosphorylation (Y1148) in HSC3 cells but not Cal27 cells. ALK and EGFR downstream signaling interactions are also demonstrated by Western blot analysis in which lone EGFR and ALK inhibitors attenuated AKT activity whereas co-targeting ALK and EGFR completely abolished AKT activation. No effects were observed on ERK1/2 activation. STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells. Together, these data illustrate that ALK inhibitors enhance anti-tumor activity of EGFR inhibitors in susceptible tumors that display increased ALK expression, most likely through abolition of AKT activation. PMID:27424178

  12. Defective processing of methylated single-stranded DNA by E. coli alkB mutants

    PubMed Central

    Dinglay, Suneet; Trewick, Sarah C.; Lindahl, Tomas; Sedgwick, Barbara

    2000-01-01

    Escherichia coli alkB mutants are very sensitive to DNA methylating agents. Despite these mutants being the subject of many studies, no DNA repair or other function has been assigned to the AlkB protein or to its human homolog. Here, we report that reactivation of methylmethanesulfonate (MMS)-treated single-stranded DNA phages, M13, f1, and G4, was decreased dramatically in alkB mutants. No such decrease occurred when using methylated λ phage or M13 duplex DNA. These data show that alkB mutants have a marked defect in processing methylation damage in single-stranded DNA. Recombinant AlkB protein bound more efficiently to single- than double-stranded DNA. The single-strand damage processed by AlkB was primarily cytotoxic and not mutagenic and was induced by SN2 methylating agents, MMS, DMS, and MeI but not by SN1 agent N-methyl-N-nitrosourea or by γ irradiation. Strains lacking other DNA repair activities, alkA tag, xth nfo, uvrA, mutS, and umuC, were not defective in reactivation of methylated M13 phage and did not enhance the defect of an alkB mutant. A recA mutation caused a small but additive defect. Thus, AlkB functions in a novel pathway independent of these activities. We propose that AlkB acts on alkylated single-stranded DNA in replication forks or at transcribed regions. Consistent with this theory, stationary phase alkB cells were less MMS sensitive than rapidly growing cells. PMID:10950872

  13. Anaplastic lymphoma kinase-positive squamous cell carcinoma of the lung: A case report

    PubMed Central

    YAMAMOTO, YOKO; KODAMA, KEN; MANIWA, TOMOHIRO; TAKEDA, MASASHI; KISHIMA, HIROKI

    2016-01-01

    It is widely known that echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement mostly occurs in the adenocarcinoma subtype of non-small-cell lung cancer (NSCLC). Patients with squamous cell carcinoma harboring the ALK rearrangement are extremely rare. This is a case report of a squamous cell carcinoma patient with EML4-ALK rearrangement. An elderly man with a heavy smoking history presented with a mass lesion in the right main bronchus. Bronchoscopic biopsy of the tumor confirmed a diagnosis of squamous cell carcinoma, and it was proven to harbor ALK rearrangement, based on fluorescence in situ hybridization, but not epidermal growth factor receptor mutations. The patient underwent radiation therapy, with a markedly favorable response. ALK-targeted treatment may be a viable option if disease progression occurs in such a case in the future. PMID:27330767

  14. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

    The key to positioning is the creation of a clear benefit image in the consumer's mind. One positioning strategy is creating in the prospect's mind a position that takes into consideration the company's or agency's strengths and weaknesses as well as those of its competitors. Another strategy is to gain entry into a position ladder owned by…

  15. Shear induced collateral artery growth modulated by endoglin but not by ALK1

    PubMed Central

    Seghers, Leonard; de Vries, Margreet R; Pardali, Evangelia; Hoefer, Imo E; Hierck, Beerend P; ten Dijke, Peter ten; Goumans, Marie Jose; Quax, Paul HA

    2012-01-01

    Transforming growth factor-beta (TGF-β) stimulates both ischaemia induced angiogenesis and shear stress induced arteriogenesis by signalling through different receptors. How these receptors are involved in both these processes of blood flow recovery is not entirely clear. In this study the role of TGF-β receptors 1 and endoglin is assessed in neovascularization in mice. Unilateral femoral artery ligation was performed in mice heterozygous for either endoglin or ALK1 and in littermate controls. Compared with littermate controls, blood flow recovery, monitored by laser Doppler perfusion imaging, was significantly hampered by maximal 40% in endoglin heterozygous mice and by maximal 49% in ALK1 heterozygous mice. Collateral artery size was significantly reduced in endoglin heterozygous mice compared with controls but not in ALK1 heterozygous mice. Capillary density in ischaemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared with controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or ischaemia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced increased levels of endoglin mRNA but not ALK1. In this study it is demonstrated that both endoglin and ALK1 facilitate blood flow recovery. Importantly, endoglin contributes to both shear induced collateral artery growth and to ischaemia induced angiogenesis, whereas ALK1 is only involved in ischaemia induced angiogenesis. PMID:22436015

  16. Characteristics of interstitial lung disease in SS-A positive/Jo-1 positive inflammatory myopathy patients.

    PubMed

    Váncsa, Andrea; Csípo, I; Németh, J; Dévényi, K; Gergely, L; Dankó, K

    2009-07-01

    The strongest predictive factor for the development of interstitial lung disease (ILD) in myositis (IIM) patients is the presence of different antisynthetase antibodies. The aim of this study was to compare the clinical characteristics, radiological findings and therapeutic response between the anti-SS-A positive and negative antisynthetase syndrome (ASS) patients. A prospective study of 315 IIM patients was conducted including 27 anti-Jo-1 positive ASS patients. Mean disease duration was 46.6 (range 4-198) months. All patients fulfilled the classification criteria for IIM. All patients underwent chest radiography, pulmonary function tests and HRCT at he time of diagnosis and 6 months after the immunosuppressive therapy. Routine laboratory tests, RF, ANA, anti-ENA, anti-SS-A, anti-histidyl-transfer RNA antibody (Jo-1) measurements were performed in all patients. ILD was found to be present in 70.4% of ASS patients. The anti-SS-A negative ASS group had a more frequent association with alveolitis and responded well to immunosuppressive therapy (p < 0.05). HRCT scan showed more fibrosis in the SS-A positive group. 15.8% of patients died due to pulmonary or cardiac complications. In conclusion, coexistence of anti-SS-A and anti-Jo-1 antibody may be a good predictor for a more coarse and severe ILD in IIM patients who require a more aggressive approach in therapy. PMID:19266202

  17. A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

    PubMed Central

    Wilson, Frederick H.; Johannessen, Cory M.; Piccioni, Federica; Tamayo, Pablo; Kim, Jong Wook; Van Allen, Eliezer M.; Corsello, Steven M.; Capelletti, Marzia; Calles, Antonio; Butaney, Mohit; Sharifnia, Tanaz; Gabriel, Stacey B.; Mesirov, Jill P.; Hahn, William C.; Engelman, Jeffrey A.; Meyerson, Matthew; Root, David E.; Jänne, Pasi A.; Garraway, Levi A.

    2015-01-01

    Summary We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein kinase C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naïve controls, supporting a role for identified resistance mechanisms in clinical resistance. PMID:25759024

  18. USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

    PubMed Central

    Herhaus, Lina; Al-Salihi, Mazin A.; Dingwell, Kevin S.; Cummins, Timothy D.; Wasmus, Lize; Vogt, Janis; Ewan, Richard; Bruce, David; Macartney, Thomas; Weidlich, Simone; Smith, James C.; Sapkota, Gopal P.

    2014-01-01

    Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis. PMID:24850914

  19. Precision medicine in NSCLC and pathology: how does ALK fit in the pathway?

    PubMed

    Kerr, K M; López-Ríos, F

    2016-09-01

    The evolution of personalised medicine in lung cancer has dramatically impacted diagnostic pathology. Current challenges centre on the growing demands placed on small tissue samples by molecular diagnostic techniques. In this review, expert recommendations are provided regarding successful identification of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Steps to correctly process and conserve tumour tissue during diagnostic testing are essential to ensure tissue availability. For example, storing extra tissue sections ready for molecular diagnostic steps allows faster testing and preserves tissue. Fluorescence in situ hybridisation (FISH) is commonly used to detect ALK rearrangements, with most laboratories favouring screening by immunohistochemistry followed by a confirmatory FISH assay. Reverse transcription-polymerase chain reaction can also identify ALK fusion gene mRNA transcripts but can be limited by the quality of RNA and the risk that rare fusion variants may not be captured. Next-generation sequencing (NGS) technology has recently provided an alternative method for detecting ALK rearrangements. While current experience is limited, NGS is set to become the most efficient approach as an increasing number of genetic abnormalities is required to be tested. Upfront, reflex testing for ALK gene rearrangement should become routine as ALK tyrosine kinase inhibitor therapy moves into the first-line setting. Guidelines recommend that EGFR and ALK tests are carried out in parallel on all confirmed and potential adenocarcinomas, and this is more efficient in terms of tissue usage and testing turnaround time for both of these actionable gene alterations. The practice of sequential testing is not recommended. Identification of ALK rearrangements is now essential for the diagnosis of NSCLC, underpinned by the benefits of ALK inhibitors. As scientific understanding and diagnostic technology develops, ALK testing will continue to be an

  20. Oncogenic TPM3-ALK activation requires dimerization through the coiled-coil structure of TPM3

    SciTech Connect

    Amano, Yosuke; Ishikawa, Rie; Sakatani, Toshio; Ichinose, Junji; Sunohara, Mitsuhiro; Watanabe, Kousuke; Kage, Hidenori; Nakajima, Jun; Nagase, Takahide; Ohishi, Nobuya; Takai, Daiya

    2015-02-13

    Inflammatory myofibroblastic tumor (IMT) is a mesenchymal tumor that can arise from anywhere in the body. Anaplastic lymphoma kinase (ALK) gene rearrangements, most often resulting in the tropomyosin 3 (TPM3)-ALK fusion gene, are the main causes of IMT. However, the mechanism of malignant transformation in IMT has yet to be elucidated. The purpose of this study was to clarify the role of the TPM3 region in the transformation of IMT via TPM3-ALK. Lentivirus vectors containing a TPM3-ALK fusion gene lacking various lengths of TPM3 were constructed and expressed in HEK293T and NIH3T3 cell lines. Focus formation assay revealed loss of contact inhibition in NIH3T3 cells transfected with full-length TPM3-ALK, but not with ALK alone. Blue-native polyacrylamide gel electrophoresis (BN-PAGE) revealed that TPM3-ALK dimerization increased in proportion to the length of TPM3. Western blot showed phosphorylation of ALK, ERK1/2, and STAT3 in HEK293T cells transfected with TPM3-ALK. Thus, the coiled-coil structure of TPM3 contributes to the transforming ability of the TPM3-ALK fusion protein, and longer TPM3 region leads to higher dimer formation. - Highlights: • TPM3-ALK fusion protein dimerizes through the coiled-coil structure of TPM3. • Longer coiled-coil structure of TPM3 leads to higher TPM3-ALK dimer formation. • Presence of TPM3-ALK dimer leads to ALK, STAT3, and ERK1/2 phosphorylation. • Presence of TPM3-ALK leads to loss of contact inhibition. • BN-PAGE is a simple technique for visualizing oncogenic dimerization.

  1. Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Yeh, Chun-Nan; Hsieh, Feng-Jen; Chiang, Kun-Chun; Chen, Jen-Shi; Yeh, Ta-Sen; Jan, Yi-Yin; Chen, Miin-Fu

    2015-01-01

    Background Several unfavorable prognostic factors have been proposed for peripheral cholangiocarcinoma (PCC) in patients undergoing hepatectomy, including gross type of tumor, vascular invasion, lymph node metastasis, a high carbohydrate antigen 19-9 level, and a positive resection margin. However, the clinical effect of a positive surgical margin on the survival of patients with PCC after hepatectomy still needs to be clarified due to conflicting results. Methods A total of 224 PCC patients who underwent hepatic resection with curative intent between 1977 and 2007 were retrospectively reviewed. Eighty-nine patients had a positive resection margin, with 62 having a microscopically positive margin and 27 a grossly positive margin (R2). The clinicopathological features, outcomes, and recurrence pattern were compared with patients with curative hepatectomy. Results PCC patients with hepatolithiasis, periductal infiltrative or periductal infiltrative mixed with mass-forming growth, higher T stage, and more advanced stage tended to have higher positive resection margin rates after hepatectomy. PCC patients who underwent curative hepatectomy had a significantly higher survival rate than did those with a positive surgical margin. When PCC patients underwent hepatectomy with a positive resection margin, the histological grade of the tumor, nodal positivity, and chemotherapy significantly affected overall survival. Locoregional recurrence was the most common pattern of recurrence. Conclusion A positive resection margin had an unfavorable effect on overall survival in PCC patients undergoing hepatectomy. In these patients, the prognosis was determined by the biology of the tumor, including differentiation and nodal positivity, and chemotherapy increased overall survival. PMID:25552905

  2. Clinicopathologic Features of Colorectal Carcinoma in HIV-Positive Patients

    PubMed Central

    Sigel, Carlie; Cavalcanti, Marcela S.; Daniel, Tanisha; Vakiani, Efsevia; Shia, Jinru; Sigel, Keith

    2016-01-01

    Background Emerging evidence suggests differences in colo-rectal cancer in HIV-infected patients (HIV+) compared with HIV− patients. Microsatellite instability (MSI), occurring in a subset of colorectal cancer, is present at a higher rate in certain cancers in HIV+ patients. Colorectal cancer with MSI share some characteristics with those reported for HIV+ colorectal cancer. On this premise, we studied clinical and pathologic features of HIV+ colorectal cancer and evaluated for MSI using matched HIV− colorectal cancer controls. Methods Two nested, matched cohorts were identified from a hospital-based cohort of colorectal cancer patients. HIV+ colo-rectal cancers were identified and random control patients were matched for selected characteristics. Mismatch repair protein (MMR) IHC was performed as the detection method for MSI. Variables were compared between cases and controls using fixed-effects logit modeling to account for matching. Results We included 184 colorectal cancer samples (38 HIV+, 146 HIV− control). Median patient age at colorectal cancer onset was 55. When compared with HIV− colorectal cancer, HIV+patients were more likely to have smoked (P = 0.001), have right-sided colorectal cancer (37% vs. 14%; P = 0.003), and tumor-infiltrating lymphocytes (TIL) above 50/10 high-power fields (21% vs. 7%). There was no difference in MMR protein expression (P = 0.6). HIV+ colorectal cancer patients had reduced overall survival (P = 0.02) but no difference in progression-free survival. Conclusions HIV+ patients developed colorectal cancer at a lower median age than population estimates, had a higher frequency of right-sided disease, and increased TILs, suggesting potential biologic differences compared with uninfected patients. Impact Clinicopathologic differences in colorectal cancer of HIV+ persons may have implications for tumor pathogenesis. PMID:27197294

  3. Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage.

    PubMed

    Li, Qi; Huang, Yue; Liu, Xichun; Gan, Jianhua; Chen, Hao; Yang, Cai-Guang

    2016-05-20

    The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N(1)-methyladenine and N(3)-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N(1)-methyladenine and N(3)-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment. PMID:27015802

  4. Alk Is a Transcriptional Target of LMO4 and ERα that Promotes Cocaine Sensitization and Reward

    PubMed Central

    Lasek, Amy W.; Gesch, Julie; Giorgetti, Francesco; Kharazia, Viktor; Heberlein, Ulrike

    2011-01-01

    Previously, we showed that the mouse LIM-domain only 4 (Lmo4) gene, which encodes a protein containing two zinc-finger LIM domains that interact with various DNA-binding transcription factors, attenuates behavioral sensitivity to repeated cocaine administration. Here we show that transcription of anaplastic lymphoma kinase (Alk) is repressed by LMO4 in the striatum and that Alk promotes the development of cocaine sensitization and conditioned place preference, a measure of cocaine reward. Since LMO4 is known to interact with estrogen receptor α (ERα) at the promoters of target genes, we investigated whether Alk expression might be controlled by a similar mechanism. We found that LMO4 and ERα are associated with the Alk promoter by chromatin immunoprecipitation and that Alk is an estrogen-responsive gene in the striatum. Moreover, we show that ERα knockout mice exhibit enhanced cocaine sensitization and conditioned place preference and an increase in Alk expression in the nucleus accumbens. These data define a novel regulatory network involved in behavioral responses to cocaine. Interestingly, sex differences in several behavioral responses to cocaine in humans and rodents have been described and estrogen is thought to mediate some of these differences. Our data suggest that estrogen regulation of Alk may be one mechanism responsible for sexually dimorphic responses to cocaine. PMID:21976498

  5. Percutaneous nephrolithotomy in prone position in patients with spinal deformities

    PubMed Central

    Izol, Volkan; Aridogan, Ibrahim Atilla; Borekoglu, Ali; Gokalp, Fatih; Hatipoglu, Zehra; Bayazit, Yildirim; Zeren, Sinan

    2015-01-01

    Introduction: The feasibility, safety and efficacy of percutaneous nephrolithotomy (PCNL) in patients with spinal deformities were evaluated and the results of a single centre experience were reported. Patients and methods: Between July 1999 and December 2014, 16 patients with spinal deformities underwent PCNL. The anomalies included 5 cases with kyphoscoliosis, 4 with post-polio syndrome, 3 with osteogenesis imperfecta, 3 with myotonic dystrophy, and 1 with ankylosing spondylitis. All patients were preoperatively evaluated by an intravenous urogram and computerized tomography to assess the anatomy and appropriate access. The operative details, stone clearance rates, and complications were retrospectivelyanalyzed. Results: A total of 16 standard PCNL procedures were performed on 16 renal-units. The mean age of the patients was 30.7 ± 17.2 (5-62) years, and the mean stone burden was 609.6 ± 526.9 (100-1800) mm2. The mean operative and fluoroscopy times were 76.6 ± 35.1 (35-150) minutes and 12.5 ± 8.5 (3-34) minutes, respectively. At the end of the surgery, 13 (81.2%) of the patients were stone free. The overall success rate was 93.7% with the inclusion of 2 patients with clinically insignificant residual fragments (<3 mm). Complications (31.2%) included haemorrhage requiring a transfusion in 2 patients, prolonged urine leakage requiring double J catheter insertion in 1, infection in 1, and nephrectomy due to bleeding in 1. Mean hospitalization time was 4.6 ± 2.4 (3-13) days. Conclusion: PCNL is an effective, safe and minimally invasive procedure for the treatment of kidney stones in patients with spinal deformities, and it can be performed with low morbidity and high success rates. To achieve better results and minimizing the risk factors, systematic and anatomic evaluations for anaesthesia and operative planning are crucial before surgery. PMID:26885036

  6. ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.

    PubMed

    Debruyne, D N; Bhatnagar, N; Sharma, B; Luther, W; Moore, N F; Cheung, N-K; Gray, N S; George, R E

    2016-07-14

    The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance. PMID:26616860

  7. Case report: immediate dentures in an HIV positive patient.

    PubMed

    Singh, Puneeta H; Jones, John D

    2014-07-01

    A 35-year-old patient with a previous history of recreational drug use, mainly cocaine, presented to the UTHSCSA Dental School with grossly carious remaining dentition. The pattern of the wear and caries on the teeth also indicated other recreational drug such as methamphetamine over a long period of time. He was planned for extractions of the remaining teeth and placement of immediate dentures considering the patient's wish for not being edentulous for the healing period. PMID:25265685

  8. Positive Predictive Value of True Bacteremia according to the Number of Positive Culture Sets in Adult Patients

    PubMed Central

    Kitaura, Tsuyoshi; Chikumi, Hiroki; Fujiwara, Hiromitsu; Okada, Kensaku; Hayabuchi, Tatsuya; Nakamoto, Masaki; Takata, Miyako; Yamasaki, Akira; Igishi, Tadashi; Burioka, Naoto; Shimizu, Eiji

    2014-01-01

    Background Performing multiple blood culture sets simultaneously is a standard blood culture methodology, although it is often difficult to distinguish true bacteremia from contamination when only one of several blood culture sets is positive. This study clarified the relationship between the number of positive blood culture sets and clinical significance in patients with positive blood culture. Methods Patients aged 18 years and over with at least 1 positive blood culture were enrolled. Positive blood culture episodes were categorized from clinical records as true bacteremia, contamination, or unknown clinical significance. The associations among episodes of true bacteremia, isolated bacteria, the number of positive blood culture sets from among the performed sets, and the clinical background of patients were analyzed. Results Among a total of 407 episodes, 262, 67 and 78 were true bacteremia, contamination and unknown clinical significance, respectively. The positive predictive values (PPVs) of 1 out of 1, 1 out of 2 and 2 out of 2 positive sets in cases of Staphylococcus aureus, were 81.3%, 50% and 100% respectively; those in cases of coagulase-negative Staphylococci were 20.5%, 10.8% and 63.5%, respectively. Almost all cases of Escherichia coli, Pseudomonas aeruginosa, Klebsiella species and Candida species were true bacteremia. The probability of true bacteremia was strongly associated with recent surgery in multivariate analysis (P < 0.05). Conclusion The probability of true bacteremia based on the number of positive culture sets from among the performed sets varies by microorganism. Therefore, PPVs calculated using this method may help physicians distinguish true bacteremia from contamination. PMID:25901103

  9. Disseminated Kaposi's Sarcoma in an HIV-Positive Patient: A Rare Entity in an Indian Patient

    PubMed Central

    Behera, Biswanath; Chandrashekar, Laxmisha; Thappa, Devinder Mohan; Toi, Pampa Ch; Vinod, Kolar Vishwanath

    2016-01-01

    AIDS-associated disseminated Kaposi sarcoma (KS) is a rare entity, especially in India due to the low prevalence of human herpes virus-8 infections in Indian population. Due to its rapid and progressive nature, early diagnosis and institution of highly active antiretroviral therapy is crucial in AIDS-associated KS, with a view to achieving favorable prognosis. We report a case of disseminated KS in an HIV-1 positive patient, who presented with two months history of multiple violaceous patches and plaques over the trunk, bilateral upper limbs, lower limbs, and hard palate. The patient died of recurrent massive pleural effusion before starting antiretroviral therapy. This case is being reported due to the paucity of KS in the Indian literature, especially the disseminated type and to highlight its rapidly progressive course which can be fatal. PMID:27293276

  10. Upright position mechanical ventilation: an alternative strategy for ALI/ARDS patients?

    PubMed

    Zhu, Min; Zhang, Wei; Wang, Jia-Ning; Yan, Hua; Li, Yang-Kai; Ai, Bo; Fu, Sheng-Lin; Fu, Xiang-Ning

    2009-11-01

    Use of body positioning to improve oxygenation in mechanically ventilated patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has been well documented. However, neither prone position ventilation nor side lying ventilation has been reported to improve the survival. Whether there is a body position superior to routine supine position or other positions as therapeutic adjunct for ventilated patients with ALI and ARDS? We propose the hypothesis that upright position ventilation may be helpful to improve oxygenation and benefit patients with ALI/ARDS. According to the existing physiologic and pathophysiologic data of upright position investigation, we suppose that improvement of V/Q matching, increased functional residual capacity, alveolar recruitment, accelerated diaphragm recovery, early gastric emptying and enteric feeding may be a potential protect mechanism of upright position ventilation. Whether this can be translated into improvement in patient outcome should be further tested in clinical trial. PMID:19683402

  11. Regulation of Endothelial Barrier Function by TGF-β type I Receptor ALK5: Potential Role of Contractile Mechanisms and Heat Shock Protein 90

    PubMed Central

    Antonov, Alexander S.; Antonova, Galina N.; Fujii, Makiko; Dijke, Peter ten; Handa, Vaishali; Catravas, John D.; Verin, Alexander D.

    2013-01-01

    Multifunctional cytokine transforming growth factor-beta (TGF-β1) plays a critical role in the pathogenesis of acute lung inflammation by controlling endothelial monolayer permeability. TGF-β1 regulates endothelial cell (EC) functions via two distinct receptors, activin receptor-like kinase 1 (ALK1) and activin receptor-like kinase 5 (ALK5). The precise roles of ALK1 and ALK5 in the regulation of TGF-β1-induced lung endothelium dysfunction remain mostly unknown. We now report that adenoviral infection with constitutively active ALK5 (caALK5), but not caALK1, induces EC retraction and that this receptor predominantly controls EC permeability. We demonstrate that ubiquitinated ALK5 and phosphorylated heat shock protein 27 (phospho-Hsp27) specifically accumulate in the cytoskeleton fraction, which parallels with microtubule collapse, cortical actin disassembly and increased EC permeability. We have found that ALK1 and ALK5 interact with heat shock protein 90 (Hsp90). Moreover, the Hsp90 inhibitor radicicol (RA) prevents accumulation of ubiquitinated caALK5 and phospho-Hsp27 in the cytoskeletal fraction and restore the decreased EC permeability induced by caALK5. We hypothesize that specific translocation of ubiquitinated ALK5 receptor into the cytoskeleton compartment due to its lack of degradation is the mechanism that causes the divergence of caALK1 and caALK5 signaling. PMID:21465483

  12. HPV 6-positive giant keratoacanthoma in an immunocompetent patient.

    PubMed

    Saftic, Marina; Batinac, Tanja; Zamolo, Gordana; Coklo, Miran; Simat, Marina; Mustac, Elvira; Bosnar, Alan; Grahovac, Blazenka

    2006-01-01

    Keratoacanthoma (KA) is a clinically distinct, rapidly growing lesion that generally presents as a solitary crateriform nodule in sun-exposed areas in elderly, fair-skinned individuals. A KA larger than 20-30 mm is referred to as giant keratoacanthoma, a relatively rare lesion especially in young patients. Such lesions grow rapidly with possible destruction of underlying tissues. In addition to ultraviolet exposure, KAs have also been associated with chemical carcinogens, chemical peels, genetic factors, chronic skin conditions that produce scarring, trauma and thermal burns. Immunosuppressed patients, especially after transplantation, also develop KAs. A viral etiology has been suggested but not confirmed. We encountered a case of giant keratoacanthoma (greater than 50 mm in diameter) with induration of underlying structures on the upper lip of a 39-year-old male sailor. The patient reported sudden appearance and rapid enlargement of the lesion in only three weeks. Biopsy of the cutaneous lesion and the characteristic clinical history suggested the diagnosis of keratoacanthoma. Total excision with primary closure of the defect by a nasolabial advancement flap was performed. Histological examination of the tumor mass confirmed the diagnosis of KA with infiltrative growth and perineural invasion. Immunosuppression was excluded by blood analyses, as were HIV, syphilis and hepatitis infections. Only low-risk genital HPV type 6 was detected in the lesion, suggesting a possible cocarcinogenic effect of HPV and UV light in a chronically sun-exposed patient. PMID:16683389

  13. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma

    PubMed Central

    Das, Arabinda; Cheng, Ron Ron; Hilbert, Megan L.T.; Dixon-Moh, Yaenette N.; Decandio, Michele; Vandergrift, William Alex; Banik, Naren L.; Lindhorst, Scott M.; Cachia, David; Varma, Abhay K.; Patel, Sunil J.; Giglio, Pierre

    2015-01-01

    Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the

  14. Patient position alters attenuation effects in multipinhole cardiac SPECT

    SciTech Connect

    Timmins, Rachel; Ruddy, Terrence D.; Wells, R. Glenn

    2015-03-15

    Purpose: Dedicated cardiac cameras offer improved sensitivity over conventional SPECT cameras. Sensitivity gains are obtained by large numbers of detectors and novel collimator arrangements such as an array of multiple pinholes that focus on the heart. Pinholes lead to variable amounts of attenuation as a source is moved within the camera field of view. This study evaluated the effects of this variable attenuation on myocardial SPECT images. Methods: Computer simulations were performed for a set of nine point sources distributed in the left ventricular wall (LV). Sources were placed at the location of the heart in both an anthropomorphic and a water-cylinder computer phantom. Sources were translated in x, y, and z by up to 5 cm from the center. Projections were simulated with and without attenuation and the changes in attenuation were compared. A LV with an inferior wall defect was also simulated in both phantoms over the same range of positions. Real camera data were acquired on a Discovery NM530c camera (GE Healthcare, Haifa, Israel) for five min in list-mode using an anthropomorphic phantom (DataSpectrum, Durham, NC) with 100 MBq of Tc-99m in the LV. Images were taken over the same range of positions as the simulations and were compared based on the summed perfusion score (SPS), defect width, and apparent defect uptake for each position. Results: Point sources in the water phantom showed absolute changes in attenuation of ≤8% over the range of positions and relative changes of ≤5% compared to the apex. In the anthropomorphic computer simulations, absolute change increased to 20%. The changes in relative attenuation caused a change in SPS of <1.5 for the water phantom but up to 4.2 in the anthropomorphic phantom. Changes were larger for axial than for transverse translations. These results were supported by SPS changes of up to six seen in the physical anthropomorphic phantom for axial translations. Defect width was also seen to significantly increase. The

  15. Hepatitis E virus infection in the HIV-positive patient.

    PubMed

    Debes, Jose D; Pisano, Maria Belen; Lotto, Martin; Re, Viviana

    2016-07-01

    Hepatitis E virus (HEV) is a RNA virus that can cause hepatitis. In immunocompetent individuals, infection with HEV usually leads to asymptomatic seroconversion. However, in immunosuppressed patients, such as transplant recipients, HEV can develop into a chronic infection. Studies regarding the seroprevalence and clinical implications of HEV in patients infected with the human immunodeficiency virus (HIV) are conflicting. Levels of CD4 count in blood seem to be the most widely associated risk factor, while other factors such as meat consumption or proximity to animals are less clearly associated with HEV infection. Progression to chronicity, as well as extrahepatic manifestations of HEV seem rare in HIV, and the implications of HEV in liver disease progression are poorly understood in the HIV-infected. In this review we describe the epidemiology, risk factors, and clinical implications of HEV infection in individuals infected with HIV. PMID:27243210

  16. Optimizing care for African-American HIV-positive patients.

    PubMed

    Smith, Kimberly Y; Brutus, Andre; Cathcart, Ronald; Gathe, Joseph; Johnson, William; Jordan, Wilbert; Kwakwa, Helena A; Nkwanyou, Joseph; Page, Carlos; Scott, Robert; Vaughn, Anita C; Virgil, Luther A; Williamson, Diana

    2003-10-01

    The African-American community has been disproportionately affected HIV/AIDS, as noted by higher reported rates of HIV infection, higher proportion of AIDS cases, and more deaths caused by complications of AIDS than whites and other ethnic groups. In addition, epidemiologic trends suggest that African Americans with HIV infection are more often diagnosed later in the course of HIV disease than whites. Numerous reasons account for this disparity, including the lack of perception of risk and knowledge about HIV transmission as well as a delays in HIV testing and diagnosis in the African-American community. Understanding the important considerations in the management of HIV infection in the African-American patient may create awareness among health care professionals and broaden the knowledge of HIV-infected patients within the African-American community. PMID:14588093

  17. Perioperative care of the morbidly obese patient in the lithotomy position.

    PubMed

    Bennicoff, Geraldine

    2010-09-01

    The lithotomy position is used daily in the OR to position patients for vaginal, rectal, and urologic procedures. Use of this position requires a careful nursing assessment to ensure that the patient can tolerate having his or her legs placed in the stirrups and to ensure that no pressure points exist for the duration of the surgery. Caring for a patient who is morbidly obese and who requires surgery in the lithotomy position can be especially challenging, and the possibility of injury to the patient or staff members should be considered. A case study involving the care of a patient who weighed almost 600 lb undergoing surgery in the lithotomy position demonstrates ways to provide safe care for this type of challenging patient. PMID:20816103

  18. Automated Verification of IGRT-based Patient Positioning

    PubMed Central

    Jiang, Xiaojun; Fox, Tim; Cordova, Scott S; Schreibmann, Eduard

    2016-01-01

    A system for automated quality assurance in radiotherapy of a therapist’s registration was designed and tested in clinical practice. The approach compliments the clinical software’s automated registration in terms of algorithm configuration and performance, and constitutes a practical approach for ensuring safe patient setups. Per our convergence analysis, evolutionary algorithms perform better in finding the global optima of the cost function with discrepancies from a deterministic optimizer seen sporadically. PMID:26699548

  19. The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut

    SciTech Connect

    Varshney, Gaurav K.; Palmer, Ruth H. . E-mail: Ruth.Palmer@ucmp.umu.se

    2006-12-29

    During embryonic development the midgut visceral muscle is formed by fusion of cells within the visceral mesoderm, a process initiated by the specification of a specialised cell type, the founder cell, within this tissue. Activation of the receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) in the developing visceral muscle of Drosophila melanogaster initiates a signal transduction pathway required for muscle fusion. In this paper, we have investigated downstream components which are regulated by this novel signalling pathway. Here we show that Alk-mediated signal transduction drives the expression of the bHLH transcription factor Hand in vivo. Loss of Alk function results in a complete lack of Hand expression in this tissue, whereas Alk gain of function results in an expansion of Hand expression. Finally, we have investigated the process of muscle fusion in the gut of Hand mutant animals and can find no obvious defects in this process, suggesting that Hand is not critical for visceral muscle fusion per se.

  20. [COMPLICATIONS RELATED TO PATIENT POSITIONING: KEY POINTS IN PREVENTION AND MANAGEMENT].

    PubMed

    Gal Rinott, Mizrahi; Bat-Chen, Friedman; Boris, Friedman

    2015-11-01

    Patient positioning during surgery can have profound short and long term implications for the patient. Each position carries some degree of risk to the patient, which is magnified in prolonged operations, surgeries performed under general anesthesia and when position manipulations are required in order to gain best surgical access. Prevention is the mainstay of the management of positioning. Therefore, it is crucial that all operating room personnel will be familiar with the different surgical positions and their general and specific position-related injury potential. It is also important that these complications are diagnosed promptly and managed appropriately in the post-operative period. The purpose of the following review is to summarize the positioning-related complications, in particular peripheral nerve injuries, and emphasize correct positioning recommendations and preventive measures. PMID:26821504

  1. Porphyria cutanea tarda in a HIV- positive patient*

    PubMed Central

    Franzon, Valéria Aparecida Zanela; Mikilita, Emanuella Stella; Camelo, Fernanda Henriques; Camargo, Rosana

    2016-01-01

    This is a case report about Porphyria cutanea tarda (PCT) and its relationship with the infection caused by the human immunodeficiency virus (HIV). Cutaneous porphyria is an illness caused by enzymatic modification that results in partial deficiency of uroporphyrinogen decarboxylase (Urod), which may be hereditary or acquired. Several studies suggest that HIV infection associated with cofactors might trigger the development of porphyria cutanea tarda. In this case report, we present a patient infected with HIV, who after the introduction of antiretroviral therapy (ART) enjoyed clinical improvement of porphyria cutanea tarda symptoms. PMID:27579753

  2. Porphyria cutanea tarda in a HIV- positive patient.

    PubMed

    Franzon, Valéria Aparecida Zanela; Mikilita, Emanuella Stella; Camelo, Fernanda Henriques; Camargo, Rosana

    2016-01-01

    This is a case report about Porphyria cutanea tarda (PCT) and its relationship with the infection caused by the human immunodeficiency virus (HIV). Cutaneous porphyria is an illness caused by enzymatic modification that results in partial deficiency of uroporphyrinogen decarboxylase (Urod), which may be hereditary or acquired. Several studies suggest that HIV infection associated with cofactors might trigger the development of porphyria cutanea tarda. In this case report, we present a patient infected with HIV, who after the introduction of antiretroviral therapy (ART) enjoyed clinical improvement of porphyria cutanea tarda symptoms. PMID:27579753

  3. Enhanced Effectivity of an ALK5-Inhibitor after Cell-Specific Delivery to Hepatic Stellate Cells in Mice with Liver Injury

    PubMed Central

    van Beuge, Marike Marjolijn; Prakash, Jai; Lacombe, Marie; Post, Eduard; Reker-Smit, Catharina; Beljaars, Leonie; Poelstra, Klaas

    2013-01-01

    Transforming growth factor-β (TGF-β) is a major pro-fibrotic cytokine, causing the overproduction of extracellular matrix molecules in many fibrotic diseases. Inhibition of its type-I receptor (ALK5) has been shown to effectively inhibit fibrosis in animal models. However, apart from its pro-fibrotic effects, TGF-β also has a regulatory role in the immune system and influences tumorigenesis, which limits the use of inhibitors. We therefore explored the cell-specific delivery of an ALK5-inhibitor to hepatic stellate cells, a key cell in the development of liver fibrosis. We synthesized a conjugate of the ALK5-inhibitor LY-364947 coupled to mannose-6-phosphate human serum albumin (M6PHSA), which binds to the insulin-like growth factor II receptor on activated HSC. The effectivity of the conjugate was evaluated in primary HSC and in an acute liver injury model in mice. In vitro, the free drug and the conjugate significantly inhibited fibrotic markers in HSC. In hepatocytes, TGF-β-dependent signaling was inhibited by free drug, but not by the conjugate, thus showing its cell-specificity. In vivo, the conjugate localized in desmin-positive cells in the liver and not in hepatocytes or immune cells. In the acute liver injury model in mice, the conjugate reduced fibrogenic markers and collagen deposition more effectively than free drug. We conclude that we can specifically deliver an ALK5-inhibitor to HSC using the M6PHSA carrier and that this targeted drug reduces fibrogenic parameters in vivo, without affecting other cell-types. PMID:23441194

  4. Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors

    SciTech Connect

    Gellibert, F.; Fouchet, M.-H.; Nguyen, V.-L.; Wang, R.; Krysa, G.; de Gouville, A.-C.; Huet, S.; Dodic, N.

    2009-07-23

    Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5 mg/kg (bid).

  5. Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation

    PubMed Central

    Mercado-Pimentel, Melania E.; Hubbard, Antony D.; Runyan, Raymond B.

    2007-01-01

    Endoglin is an accessory receptor for TGFß and can associate with Alk5 or Alk2. Although prior studies indicated that endoglin and Alk5 were not directly involved in epithelial-mesenchymal transformation (EMT) in the heart, the expression pattern of endoglin prompted a re-examination. We here show that loss of endoglin expression mediated by either antisense DNA or siRNA results in a direct perturbation of EMT and reduced expression of EMT markers including slug, runx2, RhoA, and latrophilin-2. An examination of BrdU incorporation shows that, while endoglin regulates proliferation at an early stage, reduced endothelial cell proliferation does not account for the loss of mesenchyme. As Alk5 interacts with endoglin, we utilized siRNA and a specific inhibitor, HTS466284 (HTS), to perturb this receptor as well. Alk5 inhibition produced similar effects to inhibition of endoglin. There was a reduction in mesenchymal cell formation and loss of EMT marker expression similar to that seen with endoglin. Alk5 kinase inhibition produced a similar loss of EMT marker expression but showed a contrasting upregulation of the proliferation and remodeling markers, Cyclin B2 and ß-catenin. Alk5 and endoglin both mediate endothelial cell proliferation in younger explants but, by stage 16, loss of endoglin no longer alters proliferation rates. These data show that both Alk5 and endoglin are directly involved in the process of EMT, that they interact with both TGFß-regulated activation and invasion pathways and that the roles of these receptors change during cardiac development. PMID:17250821

  6. Investigations of Activated ACVR1/ALK2, a Bone Morphogenetic Protein Type I Receptor, That Causes Fibrodysplasia Ossificans Progressiva

    PubMed Central

    Kaplan, Frederick S.; Seemann, Petra; Haupt, Julia; Xu, Meiqi; Lounev, Vitali Y.; Mullins, Mary; Shore, Eileen M.

    2016-01-01

    Bone morphogenetic protein (BMP) type I receptors are serine-threonine kinase transmembrane signal transduction proteins that regulate a vast array of ligand-dependent cell-fate decisions with temporal and spatial fidelity during development and postnatal life. A recent discovery identified a recurrent activating heterozygous missense mutation in a BMP type I receptor [Activin receptor IA/activin-like kinase 2 (ACVR1; also known as ALK2)] in patients with the disabling genetic disorder fibrodysplasia ossificans progressiva (FOP). Individuals with FOP experience episodes of tissue metamorphosis that convert soft connective tissue such as skeletal muscle into a highly ramified and disabling second skeleton of heterotopic bone. The single nucleotide ACVR1/ALK2 mutation that causes FOP is one of the most specific disease-causing mutations in the human genome and to date the only known inherited activating mutation of a BMP receptor that causes a human disease. Thus, the study of FOP provides the basis for understanding the clinically relevant effects of activating mutations in the BMP signaling pathway. Here we briefly review methodologies that we have applied to studying activated BMP signaling in FOP. PMID:21036241

  7. Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients

    PubMed Central

    Heng, Lei; Wang, Ming-Yu; Sun, Hou-Liang; Zhu, Shan-Shan

    2016-01-01

    Abstract Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia. Sixty-two patients (ASA physical status I–II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance. Fifty-eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self-positioning, which were tolerable. These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID:27512858

  8. Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity

    PubMed Central

    Guo, Tingqing; Marmol, Patricia; Moliner, Annalena; Björnholm, Marie; Zhang, Chao; Shokat, Kevan M; Ibanez, Carlos F

    2014-01-01

    Obesity is associated with blunted β-adrenoreceptor (β-AR)-mediated lipolysis and lipid oxidation in adipose tissue, but the mechanisms linking nutrient overload to catecholamine resistance are poorly understood. We report that targeted disruption of TGF-β superfamily receptor ALK7 alleviates diet-induced catecholamine resistance in adipose tissue, thereby reducing obesity in mice. Global and fat-specific Alk7 knock-out enhanced adipose β-AR expression, β-adrenergic signaling, mitochondrial biogenesis, lipid oxidation, and lipolysis under a high fat diet, leading to elevated energy expenditure, decreased fat mass, and resistance to diet-induced obesity. Conversely, activation of ALK7 reduced β-AR-mediated signaling and lipolysis cell-autonomously in both mouse and human adipocytes. Acute inhibition of ALK7 in adult mice by a chemical-genetic approach reduced diet-induced weight gain, fat accumulation, and adipocyte size, and enhanced adipocyte lipolysis and β-adrenergic signaling. We propose that ALK7 signaling contributes to diet-induced catecholamine resistance in adipose tissue, and suggest that ALK7 inhibitors may have therapeutic value in human obesity. DOI: http://dx.doi.org/10.7554/eLife.03245.001 PMID:25161195

  9. [Prone position: effect on gas exchange and functional capacity for exercise in patients with pulmonary hypertension].

    PubMed

    Bastidas-L, Andrea Carolina; Colina-Chourio, José A; Guevara, Jesnel M; Nunez, Alexis

    2015-03-01

    The objective of this investigation was to evaluate gas exchange and cardiopulmonary functional behavior in patients with pulmonary hypertension (PH) before, during and after the change to a prone position. Thirty patients with PH and alterations in gas exchange were included in the study. Gas exchange measurements were performed in four stages: at the baseline supine position and after 30, 120 and 240 minutes in prone position. Also, the patients were evaluated by the six minutes walking test (6MWT) after 30 days in prone position during night's sleep. After four hours in prone position, all patients showed an increase of PaO2 and arterial saturation of oxygen (SaO2), with a decrease of intrapulmonary shunts, improving the gas exchange and therefore the physiological demand imposed by exercise in patients with PH. PMID:25920183

  10. Skin reactivity to metallic cobalt in patients with a positive patch test to cobalt chloride.

    PubMed

    de Fine Olivarius, F; Menné, T

    1992-10-01

    458 consecutive patients were patch tested with a metallic cobalt disc as a supplement to the standard series. 23 patients had a positive reaction to CoCl2 1% pet. Of these, 19 were tested with the cobalt disc. 11 had a positive reaction and 5 a questionable reaction. There were no positive reactions to the cobalt disc in patients with a negative patch test to CoCl2 1% pet. Patch testing with CoCl2 1% pet. diagnoses all patients with allergy to metallic cobalt, but the test method is limited by a high number of irritant and questionable reactions. PMID:1451489

  11. Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission

    PubMed Central

    Haq, R.; Gulasingam, P.

    2016-01-01

    Background Outcomes in metastatic breast cancer (mbc) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2-positive mbc. Some her2-positive mbc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2-positive mbc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission. Methods We conducted a literature review of the duration of trastuzumab in her2-positive mbc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2-positive mbc patients. Results The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2-positive mbc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2-positive mbc patients revealed that 82.93% of respondents (n = 34) follow the currently available guidelines. Conclusions With the emergence of patients in prolonged remission, duration of trastuzumab in her2-positive mbc has become an important and relevant clinical question worldwide. Collaborative efforts are needed for the further study of this topic. PMID:27122973

  12. Adaptive Response Enzyme AlkB Preferentially Repairs 1-Methylguanine and 3-Methylthymine Adducts in Double-Stranded DNA.

    PubMed

    Chen, Fangyi; Tang, Qi; Bian, Ke; Humulock, Zachary T; Yang, Xuedong; Jost, Marco; Drennan, Catherine L; Essigmann, John M; Li, Deyu

    2016-04-18

    The AlkB protein is a repair enzyme that uses an α-ketoglutarate/Fe(II)-dependent mechanism to repair alkyl DNA adducts. AlkB has been reported to repair highly susceptible substrates, such as 1-methyladenine and 3-methylcytosine, more efficiently in ss-DNA than in ds-DNA. Here, we tested the repair of weaker AlkB substrates 1-methylguanine and 3-methylthymine and found that AlkB prefers to repair them in ds-DNA. We also discovered that AlkB and its human homologues, ABH2 and ABH3, are able to repair the aforementioned adducts when the adduct is present in a mismatched base pair. These observations demonstrate the strong adaptability of AlkB toward repairing various adducts in different environments. PMID:26919079

  13. Optimal management of cervical cancer in HIV-positive patients: a systematic review.

    PubMed

    Ntekim, Atara; Campbell, Oladapo; Rothenbacher, Dietrich

    2015-09-01

    The clinical management of cervical cancer in HIV-positive patients has challenges mainly due to the concerns on immune status. At present, their mode of management is similar to HIV-seronegative patients involving the use of chemotherapy and radiotherapy concurrently as indicated. HIV infection, cancer, radiotherapy, and chemotherapy lower immunity through reduction in CD4 cell counts. At present there are no treatment guidelines for HIV-positive patients. This study was done to systematically review the literature on cervical cancer management in HIV-positive patients and treatment outcomes. A systematic literature search was done in the major databases to identify studies on the management of HIV-positive patients with cervical cancer. Identified studies were assessed for eligibility and inclusion in the review following the guidelines of The Cochrane Handbook for Systematic Reviews and CRD's (Centre for Reviews and Dissemination) guidance for undertaking reviews in health care. Eight eligible studies were identified from the literature. Three of them were prospective while five were retrospective studies. Notably, the average age at diagnosis of cervical cancer in HIV-positive patients was a decade lower than in seronegative patients. There was no difference in distribution of stages of disease at presentation between HIV-positive and negative patients. Mild acute toxicity (Grades 1 and 2) was higher in HIV-positive patients than in HIV-negative patients in hematopoietic system. In the grades 3 and 4 reactions, anemia was reported in 4% versus 2% while gastrointestinal reactions were reported in 5% versus 2% respectively. In general, patients who were started early on HAART had higher rates of treatment completion. The study supports the suggestion that HAART should be commenced early at cervical cancer diagnosis in HIV-positive patients diagnosed with cervical cancer to ensure less toxicity and better treatment compliance. PMID:26136407

  14. The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

    SciTech Connect

    Liebl, Jakob; Paganetti, Harald; Zhu, Mingyao; Winey, Brian A.

    2014-09-15

    Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patient positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R{sup 2} < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions

  15. Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap

    PubMed Central

    Rohrbough, Jeffrey; Broadie, Kendal

    2010-01-01

    Bidirectional trans-synaptic signals induce synaptogenesis and regulate subsequent synaptic maturation. Presynaptically secreted Mind the gap (Mtg) molds the synaptic cleft extracellular matrix, leading us to hypothesize that Mtg functions to generate the intercellular environment required for efficient signaling. We show in Drosophila that secreted Jelly belly (Jeb) and its receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) are localized to developing synapses. Jeb localizes to punctate aggregates in central synaptic neuropil and neuromuscular junction (NMJ) presynaptic terminals. Secreted Jeb and Mtg accumulate and colocalize extracellularly in surrounding synaptic boutons. Alk concentrates in postsynaptic domains, consistent with an anterograde, trans-synaptic Jeb-Alk signaling pathway at developing synapses. Jeb synaptic expression is increased in Alk mutants, consistent with a requirement for Alk receptor function in Jeb uptake. In mtg null mutants, Alk NMJ synaptic levels are reduced and Jeb expression is dramatically increased. NMJ synapse morphology and molecular assembly appear largely normal in jeb and Alk mutants, but larvae exhibit greatly reduced movement, suggesting impaired functional synaptic development. jeb mutant movement is significantly rescued by neuronal Jeb expression. jeb and Alk mutants display normal NMJ postsynaptic responses, but a near loss of patterned, activity-dependent NMJ transmission driven by central excitatory output. We conclude that Jeb-Alk expression and anterograde trans-synaptic signaling are modulated by Mtg and play a key role in establishing functional synaptic connectivity in the developing motor circuit. PMID:20876658

  16. Resting position of the head and malocclusion in a group of patients with cerebral palsy

    PubMed Central

    Martinez-Mihi, Victoria; Orellana, Lorena M.; Silvestre-Rangil, Javier

    2014-01-01

    Cerebral palsy are found as a result of these disorders, along with associated neuromuscular functional alterations that affect the resting position of the head. In this context, the resting position of the head could be responsible for several skeletal and dental occlusal disorders among patients with cerebral palsy. Objective: To assess the presence of malocclusions in patients with cerebral palsy, define the most frequent types of malocclusions, and evaluate how the resting position of the head may be implicated in the development of such malocclusions. Study design: Forty-four patients aged between 12-55 years (18 males and 26 females) were studied. Occlusal conditions, the Dental Aesthetic Index (DAI), changes in the resting position of the head, and breathing and swallowing functions were assessed. Results: Orthodontic treatment was required by 70.8% of the patients, the most frequent malocclusions being molar class II, open bite and high overjet. These individuals showed altered breathing and swallowing functions, as well as habit and postural disorders. The resting position of the head, especially the hyperextended presentation, was significantly correlated to high DAI scores. Conclusions: The results obtained suggest that patients with cerebral palsy are more susceptible to present malocclusions, particularly molar class II malocclusion, increased open bite, and high overjet. Such alterations in turn are more common in patients with a hyperextended position of the head. Key words:Cerebral palsy, malocclusion, head position, disabled patients. PMID:24596627

  17. Patient Positioning Based on a Radioactive Tracer Implanted in Patients With Localized Prostate Cancer: A Performance and Safety Evaluation

    SciTech Connect

    Kruijf, Willy J.M. de; Verstraete, Jan; Neustadter, David; Corn, Benjamin W.; Hol, Sandra; Venselaar, Jack L.M.; Davits, Rob J.; Wijsman, Bart P.; Van den Bergh, Laura; Budiharto, Tom; Oyen, Raymond; Haustermans, Karin; Poortmans, Philip M.P.

    2013-02-01

    Purpose: To evaluate the performance and safety of a radiation therapy positioning system (RealEye) based on tracking a radioactive marker (Tracer) implanted in patients with localized prostate cancer. Methods and Materials: We performed a single-arm multi-institutional trial in 20 patients. The iridium-192 ({sup 192}Ir)-containing Tracer was implanted in the patient together with 4 standard gold seed fiducials. Patient prostate-related symptoms were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Computed tomography (CT) was performed for treatment planning, during treatment, and after treatment to evaluate the migration stability of the Tracer. At 5 treatment sessions, cone beam CT was performed to test the positioning accuracy of the RealEye. Results: The Tracer was successfully implanted in all patients. No device or procedure-related adverse events occurred. Changes in IPSS scores were limited. The difference between the mean change in Tracer-fiducial distance and the mean change in fiducial-fiducial distance was -0.39 mm (95% confidence interval [CI] upper boundary, -0.22 mm). The adjusted mean difference between Tracer position according to RealEye and the Tracer position on the CBCT for all patients was 1.34 mm (95% CI upper boundary, 1.41 mm). Conclusions: Implantation of the Tracer is feasible and safe. Migration stability of the Tracer is good. Prostate patients can be positioned and monitored accurately by using RealEye.

  18. External beam boost irradiation for clinically positive pelvic nodes in patients with uterine cervical cancer

    PubMed Central

    Ariga, Takuro; Toita, Takafumi; Kasuya, Goro; Nagai, Yutaka; Inamine, Morihiko; Kudaka, Wataru; Kakinohana, Yasumasa; Aoki, Youichi; Murayama, Sadayuki

    2013-01-01

    The purpose of this study was to retrospectively analyze the treatment results of boost external beam radiotherapy (EBRT) to clinically positive pelvic nodes in patients with uterine cervical cancer. The study population comprised 174 patients with FIGO stages 1B1–4A cervical cancer who were treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT). Patients with positive para-aortic or common iliac nodes (≥10 mm in the shortest diameter, as evaluated by CT/MRI) were ineligible for the study. Fifty-seven patients (33%) had clinically positive pelvic nodes. The median maximum diameter of the nodes was 15 mm (range, 10–60 mm) and the median number of positive lymph nodes was two (range, one to four). Fifty-two of 57 patients (91%) with positive nodes were treated with boost EBRT (6–10 Gy in three to five fractions). The median prescribed dose of EBRT for nodes was 56 Gy. The median follow-up time for all patients was 66 months (range, 3–142 months). The 5-year overall survival rate, disease-free survival rate and pelvic control rate for patients with positive and negative nodes were 73% and 92% (P = 0.001), 58% and 84% (P < 0.001), and 83% and 92% (P = 0.082), respectively. Five of 57 node-positive patients (9%) developed pelvic node recurrences. All five patients with nodal failure had concomitant cervical failure and/or distant metastases. No significant difference was observed with respect to the incidence or severity of late complications by application of boost EBRT. The current retrospective study demonstrated that boost EBRT to positive pelvic nodes achieves favorable nodal control without increasing late complications. PMID:23365264

  19. Salivary anti-Helicobacter pylori positivity among endoscopy patients with chronic liver disease.

    PubMed

    Feteih, R; Abdel-Salam, M; Jamjoom, H; Akbar, H

    2009-01-01

    In this study, endoscopy patients with and without chronic liver disease (CLD) were examined and tested for Helicobacter pylori infection by detecting the presence of serum and salivary anti-H. pylori antibody. The validity of these measures was compared with Campylobacter-like organism analysis (gold standard) performed on patients requiring gastric biopsy. Among 114 patients with CLD and 50 without, the commonest endoscopy diagnosis was gastritis (27.2%). Salivary H. pylori positivity was significantly associated with older age. Salivary anti-H. pylori antibody positivity showed low sensitivity (36.6%) and high specificity (75.8%) in CLD patients. PMID:20218127

  20. False positive stress-test in a patient with pericardial effusion.

    PubMed

    Mateja, Candice; Mishkin, Joseph; George, Malika; Chheda, Hemant; Guglin, Maya

    2009-10-01

    We report a case of false positive stress test in a patient with cardiac tamponade. After the drainage of pericardial effusion, reversible defect on a stress test resolved. Cardiac catheterization revealed normal coronary arteries. PMID:18768227

  1. Pembrolizumab for HIV-Positive Patients with Recurrent or Refractory Cancer

    Cancer.gov

    In this phase I clinical trial, HIV-positive patients receiving combination antiretroviral therapy who have cancer that has recurred after or has not responded to previous treatment will receive the immune checkpoint inhibitor pembrolizumab.

  2. [Respiratory care with prone position for diffuse atelectasis in critically ill patients].

    PubMed

    Shichinohe, Y; Ujike, Y; Kurihara, M; Yamamoto, S; Oota, K; Tsukamoto, M; Imaizumi, H; Kaneko, M

    1991-01-01

    Diffuse atelectasis often occurs in the dorsal region of the lung of critically ill patients under long term mechanical ventilation. Conventional physical therapies (ex. PEEP, Sigh) have little effect on diffuse dorsal atelectasis. We provided respiratory care with prone position for 7 patients with severe respiratory distress (Two patients were treated twice). Improvement of their Respiratory Indexes (RI, mean 2.97) was obtained in the prone position for 6-163 (mean 35.8) hours. Ventilation efficiency also improved. Static lung compliance didn't change. It was assumed that the prone position was the factor responsible for the improvement of pulmonary V/Q ratio, the change of movement pattern of the diaphragm, and the ease of postural drainage of sputum. There were no complications. We conclude that prone position respiratory care has high utility for critically ill patients with diffuse dorsal atelectasis. PMID:2024073

  3. Sleep Apnea in Patients with Acromegaly. Frequency, Characterization and Positive Pressure Titration

    PubMed Central

    Hernández-Gordillo, Daniel; Ortega-Gómez, María del Rocío; Galicia-Polo, Lourdes; Castorena-Maldonado, Armando; Vergara-López, Alma; Guillén-González, Miguel Ángel; Torre-Bouscoulet, Luis

    2012-01-01

    Objectives: to describe the frequency of sleep apnea in patients with acromegaly;to identify the proportion of candidates for treatment with positive airway pressure;to report our experience with the positive pressure titration process in acromegaly patients. Methods: A cross-sectional study that included the acromegaly cohort at the Centro Medico Nacional “20 de Noviembre” in Mexico City (n=44). A standard polysomnography (PSG) was carried out for each patient. A second PSG was done for purposes of CPAP titration. Results: A total of 35 patients were studied (80% of the cohort, 20 [57%] women). Polysomnography results showed that 34 subjects (97%, 95%CI 91-100%) had apnea hypopnea indexes (AHI) ≥ 5. No patient had central apnea. We identified 19 subjects with AHI ≥5 and Epworth ≥10, for a frequency of obstructive sleep apnea syndrome of 54% (95%CI 36-71%). A total of 31 patients (88%; 95%CI 77-99%) were deemed to be candidates for positive pressure treatment, but only 8 of them accepted CPAP. They required pressures that ranged from 10 to 18 cmH2O. Conclusions: Our results confirm a high prevalence of sleep apnea in patients with acromegaly, and provide evidence that the majority of those patients are candidates for treatment with positive pressure. Contrary to what has been reported, we identified no patients with central apnea. PMID:22754597

  4. The role of AlkB protein in repair of 1,N⁶-ethenoadenine in Escherichia coli cells.

    PubMed

    Maciejewska, Agnieszka M; Sokołowska, Beata; Nowicki, Adam; Kuśmierek, Jarosław T

    2011-05-01

    Etheno (ε) DNA adducts, including 1,N(6)-ethenoadenine (εA), are formed by various bifunctional agents of exogenous and endogenous origin. The AT→TA transversion, the most frequent mutation provoked by the presence of εA in DNA, is very common in critical codons of the TP53 and RAS genes in tumours induced by exposure to carcinogenic vinyl compounds. Here, using a method that allows examination of the mutagenic potency of a metabolite of vinyl chloride, chloroacetaldehyde (CAA), but eliminates its cytotoxicity, we studied the participation of alkA, alkB and mug gene products in the repair of εA in Escherichia coli cells. The test system used comprised the pIF105 plasmid bearing the lactose operon of CC105 origin, which allowed monitoring of Lac(+) revertants that arose by AT→TA substitutions due to the modification of adenine by CAA. The plasmid was CAA-modified in vitro and replicated in E.coli of various genetic backgrounds (wt, alkA, alkB, mug, alkAalkB, alkAmug and alkBmug). To modify the levels of the AlkA and AlkB proteins, mutagenesis was studied in E.coli cells induced or not in adaptive response to alkylating agents. Considering the levels of CAA-induced Lac(+) revertants in strains harbouring the CAA-modified pIF105 plasmid and induced or not in adaptive response, we conclude that the AlkB dioxygenase plays a major role in decreasing the level of AT→TA mutations, thus in the repair of εA in E.coli cells. The observed differences of mutation frequencies in the various mutant strains assayed indicate that Mug glycosylase is also engaged in the repair of εA, whereas the role the AlkA glycosylase in this repair is negligible. PMID:21193516

  5. Relationship between alkaline phosphatase and all-cause mortality in peritoneal dialysis patients.

    PubMed

    Fein, Paul A; Asadi, Sara; Singh, Priyanka; Hartman, William; Stuto, Steven; Chattopadhyay, Jyotiprakas; Avram, Morrell M

    2013-01-01

    Elevated levels of serum alkaline phosphatase (AlkPhos) have been reported to be associated with increased mortality risk in hemodialysis (HD) patients. We examined the association of serum AlkPhos with all-cause mortality in our PD patients. The study enrolled 90 PD patients beginning in 1995. On enrollment, demographics and clinical and biochemical data were recorded. Patients were followed to September 2011. Mean age of the enrollees was 52 years, with 61% being women, and most (81%) being of African descent. Mean and median AlkPhos were 135 U/L and 113 U/L respectively. Mean and maximum follow-up were 2.61 and 16 years respectively. As expected, AlkPhos correlated directly with serum intact parathyroid hormone (r = 0.36, p = 0.003). In a Cox multivariate regression analysis with adjustment for confounding variables, AlkPhos as a continuous (relative risk: 1.016; p = 0.004) anda categorical variable [> 120 U/L and < or = 120 U/L (relative risk: 6.0; p = 0.03)] remained a significant independent predictor of mortality. For each unit increase in enrollment AlkPhos, there was a 1.6% increase in the relative risk of death. Elevated serum AlkPhos is significantly and independently associated with increased mortality risk in our PD patients followed for up to 16 years. AlkPhos should be evaluated prospectively as a potential therapeutic target in clinical practice. PMID:24344494

  6. Cherenkoscopy based patient positioning validation and movement tracking during post-lumpectomy whole breast radiation therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Rongxiao; Andreozzi, Jacqueline M.; Gladstone, David J.; Hitchcock, Whitney L.; Glaser, Adam K.; Jiang, Shudong; Pogue, Brian W.; Jarvis, Lesley A.

    2015-01-01

    To investigate Cherenkov imaging (Cherenkoscopy) based patient positioning and movement tracking during external beam radiation therapy (EBRT). In a phase 1 clinical trial, including 12 patients undergoing post-lumpectomy whole breast irradiation, Cherenkov emission was imaged with a time-gated ICCD camera synchronized to the LINAC pulse output, during different fractions of the treatment. Patients were positioned with the aid of the AlignRT system in the beginning of each treatment session. Inter-fraction setup variation was studied by rigid image registrations between images acquired at individual treatments to the average image from all imaged treatment fractions. The amplitude of respiratory motion was calculated from the registration of each frame of Cherenkov images to the reference. A Canny edge detection algorithm was utilized to highlight the beam field edges and biological features provided by major blood vessels apparent in the images. Real-time Cherenkoscopy can monitor the treatment delivery, patient motion and alignment of the beam edge to the treatment region simultaneously. For all the imaged fractions, the patient positioning discrepancies were within our clinical tolerances (3 mm in shifts and 3 degree in pitch angle rotation), with 4.6% exceeding 3 mm but still within 4 mm in shifts. The average discrepancy of repetitive patient positioning was 1.22 mm in linear shift and 0.34 degrees in rotational pitch, consistent with the accuracy reported by the AlignRT system. The edge detection algorithm enhanced features such as field edges and blood vessels. Patient positioning discrepancies and respiratory motion retrieved from rigid image registration were consistent with the edge enhanced images. Besides positioning discrepancies caused by globally inaccurate setups, edge enhanced blood vessels indicate the existence of deformations within the treatment region, especially for large patients. Real-time Cherenkoscopy imaging during EBRT is a

  7. Cherenkoscopy based patient positioning validation and movement tracking during post-lumpectomy whole breast radiation therapy.

    PubMed

    Zhang, Rongxiao; Andreozzi, Jacqueline M; Gladstone, David J; Hitchcock, Whitney L; Glaser, Adam K; Jiang, Shudong; Pogue, Brian W; Jarvis, Lesley A

    2015-01-01

    To investigate Cherenkov imaging (Cherenkoscopy) based patient positioning and movement tracking during external beam radiation therapy (EBRT). In a phase 1 clinical trial, including 12 patients undergoing post-lumpectomy whole breast irradiation, Cherenkov emission was imaged with a time-gated ICCD camera synchronized to the LINAC pulse output, during different fractions of the treatment. Patients were positioned with the aid of the AlignRT system in the beginning of each treatment session. Inter-fraction setup variation was studied by rigid image registrations between images acquired at individual treatments to the average image from all imaged treatment fractions. The amplitude of respiratory motion was calculated from the registration of each frame of Cherenkov images to the reference. A Canny edge detection algorithm was utilized to highlight the beam field edges and biological features provided by major blood vessels apparent in the images. Real-time Cherenkoscopy can monitor the treatment delivery, patient motion and alignment of the beam edge to the treatment region simultaneously. For all the imaged fractions, the patient positioning discrepancies were within our clinical tolerances (3 mm in shifts and 3 degree in pitch angle rotation), with 4.6% exceeding 3 mm but still within 4 mm in shifts. The average discrepancy of repetitive patient positioning was 1.22 mm in linear shift and 0.34 degrees in rotational pitch, consistent with the accuracy reported by the AlignRT system. The edge detection algorithm enhanced features such as field edges and blood vessels. Patient positioning discrepancies and respiratory motion retrieved from rigid image registration were consistent with the edge enhanced images. Besides positioning discrepancies caused by globally inaccurate setups, edge enhanced blood vessels indicate the existence of deformations within the treatment region, especially for large patients. Real-time Cherenkoscopy imaging during EBRT is a

  8. Abundance and diversity of n-alkane-degrading bacteria in a forest soil co-contaminated with hydrocarbons and metals: a molecular study on alkB homologous genes.

    PubMed

    Pérez-de-Mora, Alfredo; Engel, Marion; Schloter, Michael

    2011-11-01

    Unraveling functional genes related to biodegradation of organic compounds has profoundly improved our understanding of biological remediation processes, yet the ecology of such genes is only poorly understood. We used a culture-independent approach to assess the abundance and diversity of bacteria catalyzing the degradation of n-alkanes with a chain length between C(5) and C(16) at a forest site co-contaminated with mineral oil hydrocarbons and metals for nearly 60 years. The alkB gene coding for a rubredoxin-dependent alkane monooxygenase enzyme involved in the initial activation step of aerobic aliphatic hydrocarbon metabolism was used as biomarker. Within the area of study, four different zones were evaluated: one highly contaminated, two intermediately contaminated, and a noncontaminated zone. Contaminant concentrations, hydrocarbon profiles, and soil microbial respiration and biomass were studied. Abundance of n-alkane-degrading bacteria was quantified via real-time PCR of alkB, whereas genetic diversity was examined using molecular fingerprints (T-RFLP) and clone libraries. Along the contamination plume, hydrocarbon profiles and increased respiration rates suggested on-going natural attenuation at the site. Gene copy numbers of alkB were similar in contaminated and control areas. However, T-RFLP-based fingerprints suggested lower diversity and evenness of the n-alkane-degrading bacterial community in the highly contaminated zone compared to the other areas; both diversity and evenness were negatively correlated with metal and hydrocarbon concentrations. Phylogenetic analysis of alkB denoted a shift of the hydrocarbon-degrading bacterial community from Gram-positive bacteria in the control zone (most similar to Mycobacterium and Nocardia types) to Gram-negative genotypes in the contaminated zones (Acinetobacter and alkB sequences with little similarity to those of known bacteria). Our results underscore a qualitative rather than a quantitative response of

  9. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK

    SciTech Connect

    Sun, Hui-Yong; Ji, Feng-Qin

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer The study revealed the detailed resistance mechanism of the non-active mutation C1156Y in ALK. Black-Right-Pointing-Pointer C1156Y leads to crizotinib displacement and conformational changes in the binding cavity. Black-Right-Pointing-Pointer The conformations cause a decline in the vdW and electrostatic energy between crizotinib and ALK. -- Abstract: Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.

  10. Chromosomal radiosensitivity of human immunodeficiency virus positive/negative cervical cancer patients in South Africa

    PubMed Central

    HERD, OLIVIA; FRANCIES, FLAVIA; KOTZEN, JEFFREY; SMITH, TRUDY; NXUMALO, ZWIDE; MULLER, XANTHENE; SLABBERT, JACOBUS; VRAL, ANNE; BAEYENS, ANS

    2016-01-01

    Cervical cancer is the second most common cancer amongst South African women and is the leading cause of cancer-associated mortality in this region. Several international studies on radiation-induced DNA damage in lymphocytes of cervical cancer patients have remained inconclusive. Despite the high incidence of cervical cancer in South Africa, and the extensive use of radiotherapy to treat it, the chromosomal radiosensitivity of South African cervical cancer patients has not been studied to date. Since a high number of these patients are human immunodeficiency virus (HIV)-positive, the effect of HIV infection on chromosomal radiosensitivity was also investigated. Blood samples from 35 cervical cancer patients (20 HIV-negative and 15 HIV-positive) and 20 healthy controls were exposed to X-rays at doses of 6 MV of 2 and 4 Gy in vitro. Chromosomal radiosensitivity was assessed using the micronucleus (MN) assay. MN scores were obtained using the Metafer 4 platform, an automated microscopic system. Three scoring methods of the MNScore module of Metafer were applied and compared. Cervical cancer patients had higher MN values than healthy controls, with HIV-positive patients having the highest MN values. Differences between groups were significant when using a scoring method that corrects for false positive and false negative MN. The present study suggested increased chromosomal radiosensitivity in HIV-positive South African cervical cancer patients. PMID:26549042

  11. Prone positioning improves survival in severe ARDS: a pathophysiologic review and individual patient meta-analysis.

    PubMed

    Gattinoni, L; Carlesso, E; Taccone, P; Polli, F; Guérin, C; Mancebo, J

    2010-06-01

    Prone positioning has been used for over 30 years in the management of patients with acute respiratory distress syndrome (ARDS). This maneuver has consistently proven capable of improving oxygenation in patients with acute respiratory failure. Several mechanisms can explain this observation, including possible intervening net recruitment and more homogeneously distributed alveolar inflation. It is also progressively becoming clear that prone positioning may reduce the nonphysiological stress and strain associated with mechanical ventilation, thus decreasing the risk of ventilator-induced lung injury, which is known to adversely impact patient survival. The available randomized clinical trials, however, have failed to demonstrate that prone positioning improves the outcomes of patients with ARDS overall. In contrast, the individual patient meta-analysis of the four major clinical trials available clearly shows that with prone positioning, the absolute mortality of severely hypoxemic ARDS patients may be reduced by approximately 10%. On the other hand, all data suggest that long-term prone positioning may expose patients with less severe ARDS to unnecessary complications. PMID:20473258

  12. Prevalence survey of infection with Treponema pallidum among HIV-positive patients in Tehran

    PubMed Central

    Badie; Yavari, Zeinab; Esmaeeli, Shooka; Paydary, Koosha; Emamzadeh-Fard, Sahra; SeyedAlinaghi, SeyedAhmad; Rasoulinejad, Mehrnaz

    2013-01-01

    Objective To identify the frequency of syphilis among Iranian HIV-positive patients. Methods A cross-sectional study on the prevalence of syphilis and HIV co-infection among 450 patients diagnosed with HIV infection was conducted between 2004 and 2008 at Imam Khomeini hospital, Tehran, Iran. The lab tests including CD4 cell count, cerebrospinal fluid, veneral disease research laboratory (VDRL), fluorescent treponema antibody-absorption (FTA-Abs) and viral load were performed for all the patients. Data regarding medical history and their demographics were also collected. Results Of all 450 HIV-positive patients, 24 (5.3%) had a positive VDRL test and only two men had a FTA-Abs positive test which means 0.45% of them had a definite co-infection of syphilis. 65.3% of the HIV-positive patients were injection drug users that the co-infection prevalence of them was 0.7%. We did not find any patient with neurosyphilis. Conclusions Considering the increasing prevalence of HIV and also extensive use of highly active antiretroviral therapy in developing nations, the diagnosis of syphilis should be timely established using screening tests among such patients. PMID:23620862

  13. S100-Negative, CD1a-Positive Cutaneous Histiocytosis in a Patient with S100-Positive, CD1a-Positive Pulmonary Histiocytosis.

    PubMed

    Mask-Bull, Lisa; Crowson, Neil A; John, Andrew; Mask, Neal A

    2015-08-01

    In the diagnostic approach to histiocytic proliferations, immunohistochemistry may be a source of both confusion and clarification. We present a case of a 60-year-old man with a generalized pruritic eruption that demonstrated positive staining for CD1a, but negative staining for langerin and S100 protein. This immunophenotype is neither representative nor characteristic of any recognized dendritic cell tumor but has been previously described in 3 cases of skin-limited histiocytosis. However, our patient also demonstrated pulmonary histiocytic infiltrates that were positive for both CD1a and S100 proteins. This differing expression of S100 protein witnessed in 2 separate organ systems affords us insight into the pathophysiology of these histiocytic proliferations. PMID:25321083

  14. Gender Reassignment Surgery in Human Immunodeficiency Virus-Positive Patients: A Report of Two Cases

    PubMed Central

    Choi, Ji-An; Kim, Myung-Hoon; Kim, Min-Su; Lee, Keun-Cheol

    2015-01-01

    It is believed that surgery on human immunodeficiency virus (HIV)-positive patients is dangerous and should be avoided due to the possibility of postoperative infection of the patients or HIV occupational transmission to the medical staff. We discuss here the preparations and measures needed to conduct surgery safely on HIV-positive patients, based on our experience. We performed sex reassignment surgery on two HIV-positive patients from January 2013 to January 2015. Both of them were receiving highly active antiretroviral therapy and were asymptomatic, with a normal CD4 count (>500 cells/µL). The HIV-RNA was undetectable within the bloodstream. All the staff wore protective clothing, glasses, and three pairs of protective gloves in the operating room because of the possibility of transmission. Prophylactic antibiotics were administered to the patients, and antiviral therapy was performed during their perioperative course. Neither of the patients had postoperative complications, and none of the medical staff experienced accidental exposure. Both patients had satisfactory surgery outcomes without complications. HIV-positive patients can undergo surgery safely without increased risk of postoperative complications or HIV transmission to the staff through the proper use of antibiotics, active antiretroviral therapy, and supplemental protective measures with post-exposure prophylaxis for the staff in case of HIV exposure. PMID:26618127

  15. Gender Reassignment Surgery in Human Immunodeficiency Virus-Positive Patients: A Report of Two Cases.

    PubMed

    Kim, Seok-Kwun; Choi, Ji-An; Kim, Myung-Hoon; Kim, Min-Su; Lee, Keun-Cheol

    2015-11-01

    It is believed that surgery on human immunodeficiency virus (HIV)-positive patients is dangerous and should be avoided due to the possibility of postoperative infection of the patients or HIV occupational transmission to the medical staff. We discuss here the preparations and measures needed to conduct surgery safely on HIV-positive patients, based on our experience. We performed sex reassignment surgery on two HIV-positive patients from January 2013 to January 2015. Both of them were receiving highly active antiretroviral therapy and were asymptomatic, with a normal CD4 count (>500 cells/µL). The HIV-RNA was undetectable within the bloodstream. All the staff wore protective clothing, glasses, and three pairs of protective gloves in the operating room because of the possibility of transmission. Prophylactic antibiotics were administered to the patients, and antiviral therapy was performed during their perioperative course. Neither of the patients had postoperative complications, and none of the medical staff experienced accidental exposure. Both patients had satisfactory surgery outcomes without complications. HIV-positive patients can undergo surgery safely without increased risk of postoperative complications or HIV transmission to the staff through the proper use of antibiotics, active antiretroviral therapy, and supplemental protective measures with post-exposure prophylaxis for the staff in case of HIV exposure. PMID:26618127

  16. Positioning of the anaesthetised patient during robotically assisted laparoscopic surgery: perioperative staff experiences.

    PubMed

    Mangham, M

    2016-03-01

    Safe, patient centred care is a large part of our trust values at the Royal Wolverhampton NHS Trust. Robotic assisted laparoscopic surgery (RALS) is still in its infancy within our trust, and we decided to look at what we have learned so far regarding patient positioning during robotic surgery for gynae-oncology and uro-gynae procedures. We also considered what we believe needs to be achieved in order to deliver high standards of care in positioning patients during robotic surgery, not only now, but also for the future of robotic surgery. PMID:27149834

  17. SU-E-J-15: Automatically Detect Patient Treatment Position and Orientation in KV Portal Images

    SciTech Connect

    Qiu, J; Yang, D

    2015-06-15

    Purpose: In the course of radiation therapy, the complex information processing workflow will Result in potential errors, such as incorrect or inaccurate patient setups. With automatic image check and patient identification, such errors could be effectively reduced. For this purpose, we developed a simple and rapid image processing method, to automatically detect the patient position and orientation in 2D portal images, so to allow automatic check of positions and orientations for patient daily RT treatments. Methods: Based on the principle of portal image formation, a set of whole body DRR images were reconstructed from multiple whole body CT volume datasets, and fused together to be used as the matching template. To identify the patient setup position and orientation shown in a 2D portal image, the 2D portal image was preprocessed (contrast enhancement, down-sampling and couch table detection), then matched to the template image so to identify the laterality (left or right), position, orientation and treatment site. Results: Five day’s clinical qualified portal images were gathered randomly, then were processed by the automatic detection and matching method without any additional information. The detection results were visually checked by physicists. 182 images were correct detection in a total of 200kV portal images. The correct rate was 91%. Conclusion: The proposed method can detect patient setup and orientation quickly and automatically. It only requires the image intensity information in KV portal images. This method can be useful in the framework of Electronic Chart Check (ECCK) to reduce the potential errors in workflow of radiation therapy and so to improve patient safety. In addition, the auto-detection results, as the patient treatment site position and patient orientation, could be useful to guide the sequential image processing procedures, e.g. verification of patient daily setup accuracy. This work was partially supported by research grant from

  18. Axillary dissection in melanoma. Prognostic variables in node-positive patients.

    PubMed Central

    Bevilacqua, R G; Coit, D G; Rogatko, A; Younes, R N; Brennan, M F

    1990-01-01

    We evaluated the importance of 14 clinical and pathologic variables as determinants of prognosis in patients with malignant melanoma and positive regional lymph nodes at axillary dissection. The records of 197 patients operated on between 1974 and 1984 were reviewed. Univariate analysis indicated as prognostically significant the number (p less than 0.001) and percentage (p less than 0.001) of positive nodes, highest nodal status (p less than 0.001), macroscopic or microscopic nodal metastases (p = 0.002), presence or absence of extranodal disease (p = 0.003), clinical stage (III versus less than III, p = 0.015), and site (considered as trunk versus other locations, p = 0.02). However, by multivariate analysis, only three variables were shown to be independent determinants of survival: percentage of positive nodes (p = 0.004), presence or absence of extranodal disease (p = 0.012), and site (trunk versus other locations, p = 0.019). Combining these three variables, subsets of patients with markedly different prognoses could be generated. It is possible to predict a favorable outcome for patients with less than 10% positive nodes, no extranodal disease, and a primary lesion at a site other than the trunk. It is also possible to recognize that the prognosis is very poor for patients with extranodal disease and truncal primary lesions, regardless of the percentage of positive lymph nodes. Finally it was verified that the prognosis is always unfavorable when the percentage of positive lymph nodes is very high. PMID:2375645

  19. Kappa angles in different positions in patients with myopia during LASIK

    PubMed Central

    Qi, Hui; Jiang, Jing-Jing; Jiang, Yan-Ming; Wang, Li-Qiang; Huang, Yi-Fei

    2016-01-01

    AIM To investigate the difference in kappa angle between sitting and supine positions during laser-assisted in situ keratomileusis (LASIK). METHODS A retrospective study was performed on 395 eyes from 215 patients with myopia that received LASIK. Low, moderate, and high myopia groups were assigned according to diopters. The horizontal and vertical components of kappa angle in sitting position were measured before the operation, and in supine position during the operation. The data from the two positions were compared and the relationship between kappa angle and diopters were analyzed. RESULTS Two hundred and twenty-three eyes (56.5%) in sitting position and 343 eyes (86.8%) in supine position had positive kappa angles. There were no significant differences in horizontal and vertical components of kappa angle in the sitting position or horizontal components of kappa angle in the supine position between the three groups (P>0.05). A significant difference in the vertical components of kappa angle in the supine position was seen in the three groups (P<0.01). Differences in both horizontal and vertical components of kappa angles were significant between the sitting and supine positions. Positive correlations in both horizontal and vertical components of kappa angles (P<0.05) were found and vertical components of kappa angle in sitting and supine positions were negatively correlated with the degree of myopia (sitting position: r=-0.109; supine position: r=-0.172; P<0.05). CONCLUSION There is a correlation in horizontal and vertical components of kappa angle in sitting and supine positions. Positive correlations in both horizontal and vertical components of kappa angle in sitting and supine positions till the end of the results. This result still needs further observation. Clinicians should take into account different postures when excimer laser surgery needs to be performed. PMID:27162734

  20. American Society for Pain Management Nursing Position Statement: Pain Management in Patients with Substance Use Disorders

    PubMed Central

    Oliver, June; Coggins, Candace; Compton, Peggy; Hagan, Susan; Matteliano, Deborah; Stanton, Marsha; St. Marie, Barbara; Strobbe, Stephen; Turner, Helen N.

    2013-01-01

    The American Society for Pain Management Nursing (ASPMN) has updated its position statement on managing pain in patients with substance use disorders. This position statement is endorsed by the International Nurses Society on Addictions (IntNSA) and includes clinical practice recommendations based on current evidence. It is the position of ASPMN and IntNSA that every patient with pain, including those with substance use disorders, has the right to be treated with dignity, respect, and high quality pain assessment and management. Failure to identify and treat the concurrent conditions of pain and substance use disorders will compromise the ability to treat either condition effectively. Barriers to caring for these patients include stigmatization, misconceptions, and limited access to providers skilled in these two categories of disorders. Topics addressed in this position statement include the scope of substance use and related disorders, conceptual models of addiction, ethical considerations, addiction risk stratification, and clinical recommendations. PMID:22929604

  1. American Society for Pain Management Nursing Position Statement: Pain Management in Patients with Substance Use Disorders

    PubMed Central

    Oliver, June; Coggins, Candace; Compton, Peggy; Hagan, Susan; Matteliano, Deborah; Stanton, Marsha; St. Marie, Barbara; Strobbe, Stephen

    2014-01-01

    The American Society for Pain Management Nursing (ASPMN) has updated its position statement on managing pain in patients with substance use disorders. This position statement is endorsed by the International Nurses Society on Addictions (IntNSA) and includes clinical practice recommendations based on current evidence. It is the position of ASPMN and IntNSA that every patient with pain, including those with substance use disorders, has the right to be treated with dignity, respect, and high quality pain assessment and management. Failure to identify and treat the concurrent conditions of pain and substance use disorders will compromise the ability to treat either condition effectively. Barriers to caring for these patients include stigmatization, misconceptions, and limited access to providers skilled in these two categories of disorders. Topics addressed in this position statement include the scope of substance use and related disorders, conceptual models of addiction, ethical considerations, addiction risk stratification, and clinical recommendations. PMID:24335741

  2. Multimodality Treatment for Patients with Node-Positive Prostate Cancer: the Role of Radiation Therapy.

    PubMed

    Ochiai, Satoru; Nomoto, Yoshihito; Kobayashi, Shigeki; Yamashita, Yasufumi; Watanabe, Yui; Toyomasu, Yutaka; Kawamura, Tomoko; Takada, Akinori; Ii, Noriko; Sakuma, Hajime

    2016-01-01

    Prostate cancer is the secondary most frequently diagnosed cancer in the world. Although numerous prospective randomized trial have been conducted to guide the management of patients with localized or locally advanced prostate cancer, few clinical trials targeting node-positive prostate cancer have been reported. Therefore, there are still controversies in the optimal management of node-positive prostate cancer. Recently, efficacy of multimodality treatment, including radiation therapy (RT), for such patients has been reported in several articles. The results indicate potential benefit of RT both in adjuvant therapy after prostatectomy and in definitive therapy for node-positive prostate cancer. The aim in this article was to summarize the current evidence for RT and evaluate the role in multimodality treatment for patients with node-positive prostate cancer. PMID:27221830

  3. Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review.

    PubMed

    Koulouras, Vasilios; Papathanakos, Georgios; Papathanasiou, Athanasios; Nakos, Georgios

    2016-05-01

    Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the "sponge lung" - and the "shape matching" -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients' response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort. PMID:27152255

  4. Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors

    PubMed Central

    Daldrup-Link, Heike E.; Mohanty, Suchismita; Ansari, Celina; Lenkov, Olga; Shaw, Aubie; Ito, Ken; Hong, Su Hyun; Hoffmann, Matthias; Pisani, Laura; Boudreau, Nancy; Gambhir, Sanjiv Sam; Coussens, Lisa M.

    2016-01-01

    Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies. PMID:27182558

  5. Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients

    PubMed Central

    V, Vijay; Shekhanawar, M.S.; Rajeshwari; M, Amareshwaras; D, Shantala

    2014-01-01

    Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART. Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India. Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat). Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed. PMID:25478335

  6. An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core.

    PubMed

    Song, Zilan; Xia, Zongjun; Ji, Yinchun; Xing, Li; Gao, Yinglei; Ai, Jing; Geng, Meiyu; Zhang, Ao

    2016-08-01

    Our early structure-activity relationship study has identified benzo[b]carbazolone 6 as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that 6 is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with 6 in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound 6 is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor. PMID:27131066

  7. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond*

    PubMed Central

    Fedeles, Bogdan I.; Singh, Vipender; Delaney, James C.; Li, Deyu; Essigmann, John M.

    2015-01-01

    The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli “adaptive response” protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1–8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins. PMID:26152727

  8. Occurrence of diverse alkane hydroxylase alkB genes in indigenous oil-degrading bacteria of Baltic Sea surface water.

    PubMed

    Viggor, Signe; Jõesaar, Merike; Vedler, Eve; Kiiker, Riinu; Pärnpuu, Liis; Heinaru, Ain

    2015-12-30

    Formation of specific oil degrading bacterial communities in diesel fuel, crude oil, heptane and hexadecane supplemented microcosms of the Baltic Sea surface water samples was revealed. The 475 sequences from constructed alkane hydroxylase alkB gene clone libraries were grouped into 30 OPFs. The two largest groups were most similar to Pedobacter sp. (245 from 475) and Limnobacter sp. (112 from 475) alkB gene sequences. From 56 alkane-degrading bacterial strains 41 belonged to the Pseudomonas spp. and 8 to the Rhodococcus spp. having redundant alkB genes. Together 68 alkB gene sequences were identified. These genes grouped into 20 OPFs, half of them being specific only to the isolated strains. Altogether 543 diverse alkB genes were characterized in the brackish Baltic Sea water; some of them representing novel lineages having very low sequence identities with corresponding genes of the reference strains. PMID:26541986

  9. In silico studies on the interaction between bioactive ligands and ALK5, a biological target related to the cancer treatment.

    PubMed

    Almeida, Michell O; Trossini, Gustavo H G; Maltarollo, Vinícius G; Silva, Danielle da C; Honorio, Kathia M

    2016-09-01

    Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-βRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors. PMID:26524124

  10. 3D-QSAR and molecular fragment replacement study on diaminopyrimidine and pyrrolotriazine ALK inhibitors

    NASA Astrophysics Data System (ADS)

    Ke, Zhipeng; Lu, Tao; Liu, Haichun; Yuan, Haoliang; Ran, Ting; Zhang, Yanmin; Yao, Sihui; Xiong, Xiao; Xu, Jinxing; Xu, Anyang; Chen, Yadong

    2014-06-01

    Over expression of anaplastic lymphoma kinase (ALK) has been found in many types of cancer, and ALK is a promising therapeutic target for the treatment of cancer. To obtain new potent inhibitors of ALK, we conducted lead optimization using 3D-QSAR modeling and molecular docking investigation of 2,4-diaminopyrimidines and 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine-based compounds. Three favorable 3D-QSAR models (CoMFA with q2, 0.555; r2, 0.939; CoMSIA with q2, 0.625; r2, 0.974; Topomer CoMFA with q2, 0.557; r2 0.756) have been developed to predict the biological activity of novel compounds. Topomer Search was utilized for virtual screening to obtain suitable fragments. The novel compounds generated by molecular fragment replacement (MFR) were evaluated by Topomer CoMFA prediction, Glide (docking) and further evaluated with CoMFA and CoMSIA prediction. 25 novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine derivatives as potential ALK inhibitors were finally obtained. In this paper, a combination of CoMFA, CoMSIA and Topomer CoMFA could obtain favorable 3D-QSAR models and suitable fragments for ALK inhibitors optimization. The work flow which comprised 3D-QSAR modeling, Topomer Search, MFR, molecular docking and evaluating criteria could be applied to de novo drug design and the resulted compounds initiate us to further optimize and design new potential ALK inhibitors.

  11. Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options

    PubMed Central

    Desai, Arpita; Menon, Smitha P.; Dy, Grace K.

    2016-01-01

    During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway. PMID:27144064

  12. Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options.

    PubMed

    Desai, Arpita; Menon, Smitha P; Dy, Grace K

    2016-03-01

    During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway. PMID:27144064

  13. Management of the node-positive neck in the patient with HPV-associated oropharyngeal cancer

    PubMed Central

    Garden, Adam S.; Gunn, Gary B.; Hessel, Amy; Beadle, Beth M.; Ahmed, Salmaan; El-naggar, Adel; Fuller, Clifton D.; Byers, Lauren A.; Phan, Jack; Frank, Steven J.; Morrison, William H.; Kies, Merill S.; Rosenthal, David I.; Sturgis, Erich M.

    2014-01-01

    Background The goal of this study was to assess the rates of recurrence in the neck for node-positive patients with HPV-associated oropharynx cancer treated with definitive radiation (with or without chemotherapy). Methods This is a single institutional retrospective study. Methodology included database search, and statistical testing including frequency analysis, Kaplan-Meier tests, and comparative tests including chi-square, logistic regression and log-rank. Results The cohort consisted of 401 node-positive patients irradiated between 2006 – June 2012. Three hundred eighty eight patients had CT restaging, and 251 had PET and/or US as a component of their post radiation staging. Eighty patients (20%) underwent neck dissection, and 21 (26%) had a positive specimen. The rate of neck dissection increased with increasing nodal stage, and was lower in patients who had PET scans or ultrasound in addition to CT restaging. The median follow-up was 30 months. The 2-year actuarial neck recurrence rate was 7% and 5% in all patients and those with local control, respectively. Nodal recurrence rates were greater in current smokers (p=.008). There was no difference in nodal recurrences rates in patients who did or did not have a neck dissection (p = .4) Conclusions A treatment strategy of (chemo)radiation with neck dissection performed based on response resulted in high rates of regional disease control in patients with HPV-associated oropharyngeal cancer. PMID:24898672

  14. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins.

    PubMed

    Zdżalik, Daria; Domańska, Anna; Prorok, Paulina; Kosicki, Konrad; van den Born, Erwin; Falnes, Pål Ø; Rizzo, Carmelo J; Guengerich, F Peter; Tudek, Barbara

    2015-06-01

    AlkB proteins are evolutionary conserved Fe(II)/2-oxoglutarate-dependent dioxygenases, which remove alkyl and highly promutagenic etheno(ɛ)-DNA adducts, but their substrate specificity has not been fully determined. We developed a novel assay for the repair of ɛ-adducts by AlkB enzymes using oligodeoxynucleotides with a single lesion and specific DNA glycosylases and AP-endonuclease for identification of the repair products. We compared the repair of three ɛ-adducts, 1,N(6)-ethenoadenine (ɛA), 3,N(4)-ethenocytosine (ɛC) and 1,N(2)-ethenoguanine (1,N(2)-ɛG) by nine bacterial and two human AlkBs, representing four different structural groups defined on the basis of conserved amino acids in the nucleotide recognition lid, engaged in the enzyme binding to the substrate. Two bacterial AlkB proteins, MT-2B (from Mycobacterium tuberculosis) and SC-2B (Streptomyces coelicolor) did not repair these lesions in either double-stranded (ds) or single-stranded (ss) DNA. Three proteins, RE-2A (Rhizobium etli), SA-2B (Streptomyces avermitilis), and XC-2B (Xanthomonas campestris) efficiently removed all three lesions from the DNA substrates. Interestingly, XC-2B and RE-2A are the first AlkB proteins shown to be specialized for ɛ-adducts, since they do not repair methylated bases. Three other proteins, EcAlkB (Escherichia coli), SA-1A, and XC-1B removed ɛA and ɛC from ds and ssDNA but were inactive toward 1,N(2)-ɛG. SC-1A repaired only ɛA with the preference for dsDNA. The human enzyme ALKBH2 repaired all three ɛ-adducts in dsDNA, while only ɛA and ɛC in ssDNA and repair was less efficient in ssDNA. ALKBH3 repaired only ɛC in ssDNA. Altogether, we have shown for the first time that some AlkB proteins, namely ALKBH2, RE-2A, SA-2B and XC-2B can repair 1,N(2)-ɛG and that ALKBH3 removes only ɛC from ssDNA. Our results also suggest that the nucleotide recognition lid is not the sole determinant of the substrate specificity of AlkB proteins. PMID:25797601

  15. Positive predictive values of the coding for bisphosphonate therapy among cancer patients in the Danish National Patient Registry

    PubMed Central

    Nielsson, Malene Schou; Erichsen, Rune; Frøslev, Trine; Taylor, Aliki; Acquavella, John; Ehrenstein, Vera

    2012-01-01

    Background The purpose of this study was to estimate the positive predictive value (PPV) of the coding for bisphosphonate treatment in selected cancer patients from the Danish National Patient Registry (DNPR). Methods Through the DNPR, we identified all patients with recorded cancer of the breast, prostate, lung, kidney, and with multiple myeloma. We restricted the study sample to patients with bisphosphonate treatment recorded during an admission to Aalborg Hospital, Denmark, from 2005 through 2009. We retrieved and reviewed medical records of these patients from the initial cancer diagnosis onwards to confirm or rule out bisphosphonate therapy. We calculated the PPV of the treatment coding as the proportion of patients with confirmed bisphosphonate treatment. Results We retrieved and reviewed the medical records of 60 cancer patients with treatment codes corresponding to bisphosphonate therapy. Recorded code corresponded to treatment administered intravenously for 59 of 60 patients, corresponding to a PPV of 98.3% (95% confidence interval 92.5–99.8). In the remaining patient, bisphosphonate treatment was also confirmed but was an orally administered bisphosphonate; thus, the treatment for any bisphosphonate regardless of administration was confirmed for all 60 patients (PPV of 100%, 95% confidence interval 95.9–100.0). Conclusion The PPV of bisphosphonate treatment coding among cancer patients in the DNPR is very high and the recorded treatment nearly always corresponds to intravenous administration. PMID:22977313

  16. Positive Psychological Interventions for Patients with Type 2 Diabetes: Rationale, Theoretical Model, and Intervention Development

    PubMed Central

    Huffman, Jeff C.; DuBois, Christina M.; Millstein, Rachel A.; Celano, Christopher M.; Wexler, Deborah

    2015-01-01

    Most patients with type 2 diabetes (T2D) have suboptimal adherence to recommended diet, physical activity, and/or medication. Current approaches to improve health behaviors in T2D have been variably effective, and successful interventions are often complex and intensive. It is therefore vital to develop interventions that are simple, well-accepted, and applicable to a wide range of patients who suffer from T2D. One approach may be to boost positive psychological states, such as positive affect or optimism, as these constructs have been prospectively and independently linked to improvements in health behaviors. Positive psychology (PP) interventions, which utilize systematic exercises to increase optimism, well-being, and positive affect, consistently increase positive states and are easily delivered to patients with chronic illnesses. However, to our knowledge, PP interventions have not been formally tested in T2D. In this paper, we review a theoretical model for the use of PP interventions to target health behaviors in T2D, describe the structure and content of a PP intervention for T2D patients, and describe baseline data from a single-arm proof-of-concept (N = 15) intervention study in T2D patients with or without depression. We also discuss how PP interventions could be combined with motivational interviewing (MI) interventions to provide a blended psychological-behavioral approach. PMID:26064980

  17. Analysis of couch position tolerance limits to detect mistakes in patient setup.

    PubMed

    Hadley, Scott W; Balter, James M; Lam, Kwok L

    2009-01-01

    This work investigates the use of the tolerance limits on the treatment couch position to detect mistakes in patient positioning and warn users of possible treatment errors. Computer controlled radiotherapy systems use the position of the treatment couch as a surrogate for patient position and a tolerance limit is applied against a planned position. When the couch is out of tolerance a warning is sent to a user to indicate a possible mistake in setup. A tight tolerance may catch all positioning mistakes while as the same time sending too many warnings; while a loose tolerance will not catch all mistakes. We develop a statistical model of the absolute position for the three translational axes of the couch. The couch position for any fraction is considered a random variable x(i). The ideal planned couch position x(p) is unknown before a patient starts treatment and must be estimated from the daily positions x(i). As such x(p) is also a random variable. The tolerance, tol, is applied to the difference between the daily and planned position, d(i) = x(i) - x(p). The di is a linear combination of random variables and therefore the density of di is the convolution of distributions of xi and xp. Tolerance limits are based on the standard deviation of d(i) such that couch positions that are more than 2 standard deviation away are considered out of tolerance. Using this framework we investigate two methods of setting x(p) and tolerance limits. The first, called first day acquire (FDA), is to take couch position on the first day as the planned position. The second is to use the cumulative average (CumA) over previous fractions as the planned position. The standard deviation of d(i) shrinks as more samples are used to determine x(p) and so the tolerance limit shrinks as a function of fraction number when a CumA technique is used. The metrics of sensitivity and specificity were used to characterize the performance of the two methods to correctly identify a couch position as in

  18. Laparoscopic sigmoidectomy for a patient with situs inversus totalis: effect of changing operator position.

    PubMed

    Yaegashi, Mizunori; Kimura, Toshimoto; Sakamoto, Takashi; Sato, Tadao; Kawasaki, Yuichiro; Otsuka, Koki; Wakabayashi, Go

    2015-04-01

    Situs inversus totalis (SIT) is a rare congenital condition in which the abdominal and thoracic organs are on the opposite sides to their normal anatomic positions. Reports of laparoscopic surgery for colorectal cancer with SIT are very few. Due to the mirror-image transposition of organs and vascular abnormalities, laparoscopic surgery for patients with SIT is technically complicated. Therefore, it has been reported as easier for left-handed surgeons. This report presents that operative procedures can be conducted as usual by changing the positions of the operator and assistants, even if the operator is right-handed. A 71-year-old woman visited our hospital with a 2-month history of hematochezia. Colonoscopy revealed an ulcerative tumor in the sigmoid colon and biopsy confirmed well-differentiated adenocarcinoma. Laparoscopic sigmoidectomy radical lymphadenectomy was performed. The operating time was 189 minutes and blood loss was 13 mL. The patient was discharged on postoperative day 7, without any complications. We report that complicated surgical procedures for patients with SIT can be simplified by changing viewpoints. Due to the altered anatomy in SIT, the positions of the operator and assistants are very important. Location of the pelvis is almost the same as in orthotopic patients, by moving the operator from the left side to the right side of the patient. Changing the position of the operator to the right side seems to be effective for patients with SIT during pelvic procedures. PMID:25875545

  19. Laparoscopic Sigmoidectomy for a Patient With Situs Inversus Totalis: Effect of Changing Operator Position

    PubMed Central

    Yaegashi, Mizunori; Kimura, Toshimoto; Sakamoto, Takashi; Sato, Tadao; Kawasaki, Yuichiro; Otsuka, Koki; Wakabayashi, Go

    2015-01-01

    Situs inversus totalis (SIT) is a rare congenital condition in which the abdominal and thoracic organs are on the opposite sides to their normal anatomic positions. Reports of laparoscopic surgery for colorectal cancer with SIT are very few. Due to the mirror-image transposition of organs and vascular abnormalities, laparoscopic surgery for patients with SIT is technically complicated. Therefore, it has been reported as easier for left-handed surgeons. This report presents that operative procedures can be conducted as usual by changing the positions of the operator and assistants, even if the operator is right-handed. A 71-year-old woman visited our hospital with a 2-month history of hematochezia. Colonoscopy revealed an ulcerative tumor in the sigmoid colon and biopsy confirmed well-differentiated adenocarcinoma. Laparoscopic sigmoidectomy radical lymphadenectomy was performed. The operating time was 189 minutes and blood loss was 13 mL. The patient was discharged on postoperative day 7, without any complications. We report that complicated surgical procedures for patients with SIT can be simplified by changing viewpoints. Due to the altered anatomy in SIT, the positions of the operator and assistants are very important. Location of the pelvis is almost the same as in orthotopic patients, by moving the operator from the left side to the right side of the patient. Changing the position of the operator to the right side seems to be effective for patients with SIT during pelvic procedures. PMID:25875545

  20. Next-Generation Sequencing Identifies Deregulation of MicroRNAs Involved in Both Innate and Adaptive Immune Response in ALK+ ALCL

    PubMed Central

    Steinhilber, Julia; Bonin, Michael; Walter, Michael; Fend, Falko; Bonzheim, Irina; Quintanilla-Martinez, Leticia

    2015-01-01

    Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPβ-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPβ, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL. PMID:25688981

  1. Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

    PubMed Central

    Koulouras, Vasilios; Papathanakos, Georgios; Papathanasiou, Athanasios; Nakos, Georgios

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the “sponge lung” - and the “shape matching” -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients’ response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort. PMID:27152255

  2. Comparison of planned and achieved implant position in total knee arthroplasty with patient-specific positioning guides

    PubMed Central

    van Leeuwen, Justin A M J; Grøgaard, Bjarne; Nordsletten, Lars; Röhrl, Stephan M

    2015-01-01

    Background and purpose Intraoperatively, patient-specific positioning guides (PSPGs) represent the preoperatively planned alignment. We investigated the degree of correlation between preoperative planning and the alignment achieved postoperatively with the PSPG technique. Patients and methods TKAs performed with the PSPG technique between 2009 and 2011 were included. 39 patients (42 TKAs) volunteered for a postoperative CT scan. 2 independent observers performed the postoperative CT measurements. Preoperative component angles (target angles) in the coronal and axial planes were defined as 0 degrees, and in the sagittal plane on average 2.8 degrees for the femoral component and 3 degrees for the tibial component. A postoperative full-length standing anteroposterior radiograph was carried out in 41 TKAs. Results The femoral component was on average 1.2 (SD 1.5) degrees in varus, 4.4 (SD 4.0) degrees in flexion, and 0.5 (SD 1.4) degrees in external rotation. The tibial component was on average 0.4 (SD 2.5) degrees in varus and 3.7 (SD 2.3) degrees in flexion. A statistically significant difference between the target (preoperative software plan) and postoperative CT measurement was found for the femoral component angle in the frontal plane (p < 0.001; CI: 0.8–1.7), the sagittal plane (p = 0.01; CI –5.6 to –3.1), and the axial plane (p = 0.03; CI: 0.04–0.88). HKA angles were greater than 3 degrees from the neutral axis in 10 of the 41 cases. Interpretation We found our postoperative component alignment angles to be close to the software plan, especially for the tibial component. However, we found outliers in all planes and we cannot therefore conclude that the PSPG technique is a method that reproduces preoperatively planned alignment in a consistent manner. PMID:25386738

  3. Predictive Factors of Spontaneous Bacterial Peritonitis Caused by Gram-Positive Bacteria in Patients With Cirrhosis

    PubMed Central

    Kim, Jung Ho; Jeon, Yong Duk; Jung, In Young; Ahn, Mi Young; Ahn, Hea Won; Ahn, Jin Young; Ku, Nam Su; Han, Sang Hoon; Choi, Jun Yong; Ahn, Sang Hoon; Song, Young Goo; Han, Kwang Hyub; Kim, June Myung

    2016-01-01

    Abstract Spontaneous bacterial peritonitis (SBP) in patients with cirrhosis is typically caused by gram-negative bacteria. However, the number of SBP cases due to gram-positive bacteria is steadily increasing. To date, little is known about the predictive factors involved in SBP infections. We performed a retrospective cohort study of patients (>18 years) with SBP due to gram-positive and -negative bacteria who were enrolled from January 2006 to December 2013 at Severance Hospital in Seoul, Korea where the incidences of hepatitis B virus associated chronic liver disease, cirrhosis, and hepatocellular carcinoma are high. Only the 1st SBP episode for each patient within the study period was included in our analysis. We identified 77 patients with cirrhosis and SBP. Of these, 27 patients (35%) had gram-positive bacterial infections and 50 patients (65%) had gram-negative bacterial infections. Our univariate analysis revealed that an early stage of cirrhosis (P = 0.004), lower creatinine level (P = 0.011), lower Sequential Organ Failure Assessment (SOFA) score (P = 0.001), lower Model for End-Stage Liver Disease score (P = 0.005), and use of systemic antibiotics within 30 days before SBP diagnosis (P = 0.03) were significantly associated with gram-positive bacterial infections. Our multivariate analysis indicated that the use of systemic antibiotics within 30 days before SBP diagnosis (odds ratio, 3.94; 95% CI, 1.11–13.96; P = 0.033) and a lower SOFA score (odds ratio, 0.56; 95% CI, 0.37–0.86; P = 0.007) were independent predictive factors of SBP caused by gram-positive bacterial infections in patients with cirrhosis. However, we did not observe a statistically significant difference in the 28-day mortality between the gram-positive and -negative bacterial infection groups (40.7% vs 46.0%, respectively; P = 0.407). In this study, the incidence rate of SBP caused by gram-positive bacteria in patients with cirrhosis was similar to the

  4. Comparison of length of stay and outcomes of patients with positive versus negative blood culture results

    PubMed Central

    Hozhabri, Neda S. T.; Armstrong, Kris; Puthottile, Jason; Benavides, Raul; Beal, Stacy

    2015-01-01

    In the United States, sepsis is the leading cause of death in critically ill patients. The fatality rate for severe sepsis is about 40%, and treatment costs over $16 billion annually. It is critical to identify and treat the source of sepsis. While there are varying guidelines determining when to draw blood for culture, at Baylor University Medical Center at Dallas, blood cultures are ordered for patients with new onset of fever, immunosuppression, or a suspicion of an underlying infectious etiology. We conducted a retrospective study of patients who had blood cultures after hospital admission or in the emergency department in December 2013. We compared length of stay and outcomes of patients with positive versus negative blood cultures. There was no significant difference for length of stay or outcomes among patients with positive and negative blood cultures. For patients admitted from the emergency department, there was a longer length of stay for patients with positive cultures; however, the overall prognosis was not worse. PMID:25552786

  5. Uveitis secondary to leishmaniasis immune reconstitution syndrome in a HIV-positive patient.

    PubMed

    Davies, Olubanke; Allen, Felicity; Gruener, Anna M; Simons, Rebecca; Graham, Elizabeth M; Larbalestier, Nick

    2016-06-01

    We describe the case of a HIV-positive patient treated for visceral leishmaniasis who developed uveitis as part of a leishmaniasis immune reconstitution syndrome. Visceral leishmaniasis is increasingly found in HIV-positive adults. Its ophthalmic manifestations can range from relatively minor to complicated anterior uveitis, leading to secondary glaucoma and loss of vision. Clinicians caring for people living with HIV should be alert to the complications of leishmaniasis that can occur before and during treatment. PMID:26002317

  6. Endotracheal cuff pressure changes with change in position in neurosurgical patients

    PubMed Central

    Athiraman, UmeshKumar; Gupta, Rohit; Singh, Georgene

    2015-01-01

    Background: Placement of a cuffed endotracheal tube for the administration of general anesthesia is routine. The cuff of the endotracheal tube is inflated with air to achieve an adequate seal to prevent micro-aspiration. Over inflation of the cuff can decrease the mucosal perfusion, leading to pressure necrosis and nerve palsies. Inadequate seal can lead to micro aspiration. So the cuff pressure has to be monitored and kept within the prescribed limits of 20-30 cms of water. Aim of the Study: To observe the effect of different positions on the endotracheal cuff pressure in patients undergoing neurosurgical procedures. Materials and Methods: This is an observational study conducted on 70 patients undergoing neurosurgical procedures in various positions. After intubation, the cuff pressure was checked with a cuff pressure manometer, Endotest (Teleflex Medical, Rush) and adjusted to be within the allowable pressure limits as is the routine practice. The cuff pressure was checked again at three time points after achieving the final position with the head on pins, at the end of the procedure and before extubation. Various factors such as the age, position, duration of surgery were studied. There were no major complications like aspiration, stridor or hoarseness of voice post extubation in any of the patients. Results: A significant decline in the cuff pressures were noted from the initial supine position to extubation (P < .001) in the supine group. Also a significant decline in the cuff pressures were found in the prone group from their initial intubated supine position to all the other three corresponding time points namely after final positioning (P < .001), at the end of the procedure (P < .001) and before extubation (P < .001). Conclusion: Cuff pressure has to be checked after achieving the final positioning of the patient and adjusted to the prescribed limits to prevent micro aspiration. PMID:26807392

  7. Patient positioning and the accuracy of pulmonary artery pressure measurements (180f).

    PubMed

    Shih, F J

    1999-12-01

    The measurement of pulmonary artery pressure (PAP) is a common nursing practice in hemodynamic monitoring of patients in the emergency room and intensive care unit. Several researchers have proposed that PAP should be measured with the patient in a supine position with legs horizontal in order to promote a relaxed state. The most widely used reference point is the phlebostatic axis, which is located at the intersection of the fourth intercostal space and the midchest level. However, this positioning requirement is in conflict with one of the goals of nursing care, which is to achieve comfortable positioning of the patient without compromising respiratory or cardiovascular function. In addition, since frequent readings are necessary, critically ill patients can lose valuable sleep time. The existing literature still fails to justify the validity of the phlebostatic axis as an external reference point for leveling the pressure transducer. In addition, findings on the accuracy of readings obtained in the supine, Fowler's and lateral recumbent positions are also in conflict. This paper reviewed research related to measurement of PAP in the supine, various Fowler's, and lateral positions in order to clarify the major factors which might have resulted in the conflicts in data on PAP measurements. Suggestions are also provided for nurse clinicians to obtain more accurate PAP measurements. PMID:10576120

  8. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.

    PubMed

    Rousselot, Philippe; Coudé, Marie Magdelaine; Gokbuget, Nicola; Gambacorti Passerini, Carlo; Hayette, Sandrine; Cayuela, Jean-Michel; Huguet, Françoise; Leguay, Thibaut; Chevallier, Patrice; Salanoubat, Celia; Bonmati, Caroline; Alexis, Magda; Hunault, Mathilde; Glaisner, Sylvie; Agape, Philippe; Berthou, Christian; Jourdan, Eric; Fernandes, José; Sutton, Laurent; Banos, Anne; Reman, Oumedaly; Lioure, Bruno; Thomas, Xavier; Ifrah, Norbert; Lafage-Pochitaloff, Marina; Bornand, Anne; Morisset, Laure; Robin, Valérie; Pfeifer, Heike; Delannoy, Andre; Ribera, Josep; Bassan, Renato; Delord, Marc; Hoelzer, Dieter; Dombret, Herve; Ottmann, Oliver G

    2016-08-11

    Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy. PMID:27121472

  9. Is SLN Biopsy Alone Safe in SLN Positive Breast Cancer Patients?

    PubMed

    van la Parra, Raquel F D; de Wilt, Johannes H W; Mol, Suzanne J J; Mulder, Andries H; de Roos, Wilfred K; Bosscha, Koop

    2015-01-01

    The Z0011 trial demonstrated no difference in overall survival (OS) and locoregional recurrence in breast cancer patients with a positive sentinel lymph node (SLN) randomized to axillary lymph node dissection (ALND) or no further surgery. The aim of this study was to evaluate locoregional recurrence in a nonrandomized group of SLN positive patients, in whom cALND was not performed, that were retrospectively categorized by the Z0011 eligibility criteria. From two hospital breast cancer databases consisting of 656 consecutive SLN positive breast cancer patients, 88 patients, who did not undergo cALND, were identified. This population was categorized by the Z0011 inclusion criteria (e.g., eligible versus ineligible) and the groups were compared. Thirty-four patients (38.6%) were retrospectively eligible for omitting cALND according to the Z0011 criteria and 54 (61.4%) were not. The median number of SLNs removed in both groups was 1 (range 1-5). The number of positive SLNs did not differ between the groups. Tumor size was slightly larger in the ineligible group (21 mm versus 19 mm) and 76% of patients in the ineligible group underwent a mastectomy. At a median follow-up of 26 months (range 1-84 months), one axillary recurrence was observed in the ineligible group versus 0 in the eligible group. Axillary recurrence was low, even in patients who did not meet the Z0011 inclusion criteria. Future trials that randomize Z0011 ineligible patients are needed to investigate long-term results. PMID:26391102

  10. Horizontal canal benign paroxysmal positional vertigo: diagnosis and treatment of 37 patients.

    PubMed

    Maranhão, Eliana Teixeira; Maranhão Filho, Péricles

    2015-06-01

    Benign paroxysmal positional vertigo (BPPV), the most frequent cause of vertigo is associated with high morbidity in the elderly population. The most common form is linked to debris in the posterior semicircular canal. However, there has been an increasing number of reported BPPV cases involving the horizontal canals. The purpose of this article is to highlight the clinical features, diagnosis, and treatment in 37 patients with horizontal canal BPPV; twenty-six with geotropic nystagmus, and eleven with the apogeotropic form. Treatment consisted of the Gufoni manoeuver in eighteen patients (48.6%), the barbecue 360° maneuver in twelve patients (32.4%), both manoeuvers in four patients (10.8%), both manoeuvers plus head shaking in one patient (2.7%), and the Gufoni maneuver plus head shaking in two patients. Cupulolithiasis patients were asked to sleep in a forced prolonged position. We obtained a complete resolution of vertigo and nystagmus in 30 patients (81.0%) on the initial visit. PMID:26083883

  11. Spontaneous ocular positioning during visual imagery in patients with hemianopia and/or hemineglect.

    PubMed

    Fourtassi, Maryam; Rode, Gilles; Tilikete, Caroline; Pisella, Laure

    2016-06-01

    Spontaneous eye movements during imagery are not random and can be used to study and reveal mental visualization processes (Fourtassi et al., 2013; Johansson et al. 2006). For example, we previously showed that during memory recall of French towns via imagery healthy individuals looks straight ahead when recalling Paris and their subsequent gaze positions are significantly correlated with the real GPS coordinates of the recalled towns. This correlation suggests that memory retrieval is done via depictive representations as it is never found when the towns are recalled using verbal fluency. In the present paper we added to this finding by showing that the mental image is spontaneously centered on the head or body midline. In order to investigate the capacities of visual imagery in patients, and by extension, the role of primary visual cortex and fronto-parietal cortex in spatial visual imagery, we recorded gaze positions during memory recall of French towns in an imagery task, a non-imagery task (verbal fluency), and a visually-guided task in five patients with left or right hemianopia and in four patients with hemineglect (two with left hemianopia and two without). The correlation between gaze position and real GPS coordinates of the recalled towns was significant in all hemianopic patients, but in patients with hemineglect this was only the case for towns located on the right half of the map of France. This suggests hemianopic patients can perform spatially consistent mental imagery despite direct or indirect unilateral lesions of the primary visual cortex. In contrast, the left-sided towns recalled by hemineglect patients, revealed that they have some spatial inconsistency or representational difficulty. Hemianopic patients positioned and maintained their gaze in their contralesional hemispace, suggesting that their mental map was not centered on their head or body midline. This contralesional gaze positioning appeared to be a general compensation strategy and

  12. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions

    PubMed Central

    Reshetnyak, Andrey V.; Murray, Phillip B.; Shi, Xiarong; Mo, Elizabeth S.; Mohanty, Jyotidarsini; Tome, Francisco; Bai, Hanwen; Gunel, Murat; Lax, Irit; Schlessinger, Joseph

    2015-01-01

    Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-α (AUG-α), as a ligand for ALK. AUG-α binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-α binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-β) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-α stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states. PMID:26630010

  13. Processing of Positive and Negative Feedback in Patients with Cerebellar Lesions.

    PubMed

    Rustemeier, Martina; Koch, Benno; Schwarz, Michael; Bellebaum, Christian

    2016-08-01

    It is well accepted that the cerebellum plays a crucial role in the prediction of the sensory consequences of movements. Recent findings of altered error processing in patients with selective cerebellar lesions led to the hypothesis that feedback processing and feedback-based learning might be affected by cerebellar damage as well. Thus, the present study investigated learning from and processing of positive and negative feedback in 12 patients with selective cerebellar lesions and healthy control subjects. Participants performed a monetary feedback learning task. The processing of positive and negative feedback was assessed by means of event-related potentials (ERPs) during the learning task and during a separate task in which the frequencies of positive and negative feedback were balanced. Patients did not show a general learning deficit compared to controls. Relative to the control group, however, patients with cerebellar lesions showed significantly higher ERP difference wave amplitudes (rewards-losses) in a time window between 250 and 450 ms after feedback presentation, possibly indicating impaired outcome prediction. The analysis of the original waveforms suggested that patients and controls primarily differed in their pattern of feedback-related negativity and P300 amplitudes. Our results add to recent findings on altered performance monitoring associated with cerebellar damage and demonstrate, for the first time, alterations of feedback processing in patients with cerebellar damage. Unaffected learning performance appears to suggest that chronic cerebellar lesions can be compensated in behaviour. PMID:26208703

  14. Positive psychological states and health behaviors in acute coronary syndrome patients: A qualitative study.

    PubMed

    Huffman, Jeff C; DuBois, Christina M; Mastromauro, Carol A; Moore, Shannon V; Suarez, Laura; Park, Elyse R

    2016-06-01

    Positive psychological states are linked to superior cardiac outcomes, possibly mediated through increased participation in health behaviors. Trained study staff conducted in-depth semi-structured interviews in the hospital and 3 months later for 34 patients diagnosed with an acute coronary syndrome. These interviews focused on positive psychological states, cardiac health behaviors, and their connection; the interviews were transcribed and independently coded using directed content analysis. Both optimism and positive affect were associated with completion of physical activity and healthy eating in a bidirectional manner. In contrast, gratitude, while common, was infrequently linked to completion of health behaviors. PMID:25114026

  15. Predicting Likelihood of Having Four or More Positive Nodes in Patient With Sentinel Lymph Node-Positive Breast Cancer: A Nomogram Validation Study

    SciTech Connect

    Unal, Bulent; Gur, Akif Serhat; Beriwal, Sushil; Tang Gong; Johnson, Ronald; Ahrendt, Gretchen; Bonaventura, Marguerite; Soran, Atilla

    2009-11-15

    Purpose: Katz suggested a nomogram for predicting having four or more positive nodes in sentinel lymph node (SLN)-positive breast cancer patients. The findings from this formula might influence adjuvant radiotherapy decisions. Our goal was to validate the accuracy of the Katz nomogram. Methods and Materials: We reviewed the records of 309 patients with breast cancer who had undergone completion axillary lymph node dissection. The factors associated with the likelihood of having four or more positive axillary nodes were evaluated in patients with one to three positive SLNs. The nomogram developed by Katz was applied to our data set. The area under the curve of the corresponding receiver operating characteristics curve was calculated for the nomogram. Results: Of the 309 patients, 80 (25.9%) had four or more positive axillary lymph nodes. On multivariate analysis, the number of positive SLNs (p < .0001), overall metastasis size (p = .019), primary tumor size (p = .0001), and extracapsular extension (p = .01) were significant factors predicting for four or more positive nodes. For patients with <5% probability, 90.3% had fewer than four positive nodes and 9.7% had four or more positive nodes. The negative predictive value was 91.7%, and sensitivity was 80%. The nomogram was accurate and discriminating (area under the curve, .801). Conclusion: The probability of four or more involved nodes is significantly greater in patients who have an increased number of positive SLNs, increased overall metastasis size, increased tumor size, and extracapsular extension. The Katz nomogram was validated in our patients. This nomogram will be helpful to clinicians making adjuvant treatment recommendations to their patients.

  16. Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma.

    PubMed

    Yoon, Harry H; Lewis, Mark A; Foster, Nathan R; Sukov, William R; Khan, Maliha; Sattler, Christopher A; Wiktor, Anne E; Wu, Tsung-Teh; Jenkins, Robert B; Sinicrope, Frank A

    2016-10-01

    Although HER2-positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2-positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2-targeted therapies that penetrate the blood-brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative-intent surgery during a time period (1980-1997) when no patient received HER2-targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow-up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2-positive (vs -negative) primary tumors showed a higher 5-year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases. PMID:27198655

  17. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action.

    PubMed

    Lorente, M; Torres, S; Salazar, M; Carracedo, A; Hernández-Tiedra, S; Rodríguez-Fornés, F; García-Taboada, E; Meléndez, B; Mollejo, M; Campos-Martín, Y; Lakatosh, S A; Barcia, J; Guzmán, M; Velasco, G

    2011-06-01

    Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas. PMID:21233844

  18. Atractylodin Inhibits Interleukin-6 by Blocking NPM-ALK Activation and MAPKs in HMC-1.

    PubMed

    Chae, Hee-Sung; Kim, Young-Mi; Chin, Young-Won

    2016-01-01

    Atractylodin is one of the major constituents of the rhizome of Atractylodes lancea, which is widely used in Korean traditional medicine as a remedy for the treatment of gastritis and gastric ulcers. Despite of a major constituent of widely used botanical to treat inflammatory responses little is known about anti-inflammatory effect of atractylodin in the human mast cell (HMC-1). Hence, we evaluated the effect of atractylodin on the release of IL-6, the involvement of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) and mitogen-activated protein kinases (MAPKs) in phorbol-12-myristate-13-acetate and A23187-induced HMC-1. In addition, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), phospholipase C (PLC) gamma 1, and AKT phosphorylation relevant to NPM-ALK signal pathway were assessed. IL-6 levels in the HMC-1 stimulated by phorbol-12-myristate-13-acetate and A23187 were apparently decreased by the treatment of atractylodin. Concurrently, atractylodin not only inhibited the phosphorylation of NPM-ALK, but also suppressed the phosphorylation of JAK2, STAT3, PLC gamma 1, and AKT. Furthermore, the activated mitogen-activated protein kinases (MAPKs) by phorbol-12-myristate-13-acetate and A23187 were inhibited by atractylodin. These results suggested that atractylodin might have a potential regulatory effect on inflammatory mediator expression through blockade of both the phosphorylation of MAPKs and the NPM-ALK signaling pathway. PMID:27598116

  19. A mapping of people's positions regarding the breaking of bad news to patients.

    PubMed

    Igier, Valérie; Muñoz Sastre, María Teresa; Sorum, Paul Clay; Mullet, Etienne

    2015-01-01

    The objective of this study was to map people's positions regarding the breaking of bad news to patients. One hundred forty adults who had in the past received bad medical news or whose elderly relatives had in the past received bad news, 25 nurses, and 28 nurse's aides indicated the acceptability of physicians' conduct in 72 vignettes of giving bad news to elderly patients. Vignettes were all combinations of five factors: (a) the severity of the disease (severe but not lethal, extremely severe and possibly lethal, or incurable), (b) the patient's wishes (insists on knowing the full truth vs. does not insist), (c) the level of social support during hospitalization, (d) the patient's psychological robustness, and (e) the physician's decision about communicating bad news (tell the patient that the illness is not severe and minimize the severity of the illness when talking to the patient's relatives, tell the full truth to her relatives, or tell the full truth to both the elderly patient and her relatives). Four qualitatively different positions were found. Twenty-eight percent of participants preferred the full truth to be told; 36% preferred the truth to be told but understood that the physician would inform the family first; 13% did not think that telling the full truth is best for patients; and 23% understood that the full truth would be told in some cases and not in others, depending on the physician's perception of the situation. The present mapping could be used to detect the position held by each patient and act accordingly. This would be made easier if breaking bad news was conceived as a communication process involving a range of health care professionals, rather than as a single occurrence in time. PMID:25186427

  20. Evaluation of upper limb sense of position in healthy individuals and patients after stroke.

    PubMed

    Cusmano, I; Sterpi, I; Mazzone, A; Ramat, S; Delconte, C; Pisano, F; Colombo, R

    2014-01-01

    The aims of this study were to develop and evaluate reliability of a quantitative assessment tool for upper limb sense of position on the horizontal plane. We evaluated 15 healthy individuals (controls) and 9 stroke patients. A robotic device passively moved one arm of the blindfolded participant who had to actively move his/her opposite hand to the mirror location in the workspace. Upper-limb's position was evaluated by a digital camera. The position of the passive hand was compared with the active hand's 'mirror' position. Performance metrics were then computed to measure the mean absolute errors, error variability, spatial contraction/expansion, and systematic shifts. No significant differences were observed between dominant and non-dominant active arms of controls. All performance parameters of the post-stroke group differed significantly from those of controls. This tool can provide a quantitative measure of upper limb sense of position, therefore allowing detection of changes due to rehabilitation. PMID:24918181

  1. Effects of changes in intracellular iron pool on AlkB-dependent and AlkB-independent mechanisms protecting E.coli cells against mutagenic action of alkylating agent.

    PubMed

    Sikora, Anna; Maciejewska, Agnieszka M; Poznański, Jarosław; Pilżys, Tomasz; Marcinkowski, Michał; Dylewska, Małgorzata; Piwowarski, Jan; Jakubczak, Wioletta; Pawlak, Katarzyna; Grzesiuk, Elżbieta

    2015-08-01

    An Escherichia coli hemH mutant accumulates protoporphyrin IX, causing photosensitivity of cells to visible light. Here, we have shown that intracellular free iron in hemH mutants is double that observed in hemH(+) strain. The aim of this study was to recognize the influence of this increased free iron concentration on AlkB-directed repair of alkylated DNA by analyzing survival and argE3 → Arg(+) reversion induction after λ>320 nm light irradiation and MMS-treatment in E. coli AB1157 hemH and alkB mutants. E.coli AlkB dioxygenase constitutes a direct single-protein repair system using non-hem Fe(II) and cofactors 2-oxoglutarate (2OG) and oxygen (O2) to initiate oxidative dealkylation of DNA/RNA bases. We have established that the frequency of MMS-induced Arg(+) revertants in AB1157 alkB(+)hemH(-)/pMW1 strain was 40 and 26% reduced comparing to the alkB(+)hemH(-) and alkB(+)hemH(+)/pMW1, respectively. It is noteworthy that the effect was observed only when bacteria were irradiated with λ>320 nm light prior MMS-treatment. This finding indicates efficient repair of alkylated DNA in photosensibilized cells in the presence of higher free iron pool and AlkB concentrations. Interestingly, a 31% decrease in the level of Arg(+) reversion was observed in irradiated and MMS-treated hemH(-)alkB(-) cells comparing to the hemH(+)alkB(-) strain. Also, the level of Arg(+) revertants in the irradiated and MMS treated hemH(-) alkB(-) mutant was significantly lower (by 34%) in comparison to the same strain but MMS-treated only. These indicate AlkB-independent repair involving Fe ions and reactive oxygen species. According to our hypothesis it may be caused by non-enzymatic dealkylation of alkylated dNTPs in E. coli cells. In in vitro studies, the absence of AlkB protein in the presence of iron ions allowed etheno(ϵ) dATP and ϵdCTP to spontaneously convert to dAMP and dCMP, respectively. Thus, hemH(-) intra-cellular conditions may favor Fe-dependent dealkylation of modified d

  2. Equal 3-Year Outcomes for Kidney Transplantation Alone in HCV-Positive Patients With Cirrhosis

    PubMed Central

    Parsikia, Afshin; Campos, Stalin; Khanmoradi, Kamran; Pang, John; Balasubramanian, Manjula; Zaki, Radi; Ortiz, Jorge

    2015-01-01

    Kidney transplantation alone in clinically compensated patients with cirrhosis is not well documented. Current guidelines list cirrhosis as a contraindication for kidney transplantation alone. This is an Institutional Review Board–approved retrospective study. We report our experience with a retrospective comparison between transplants in hepatitis C virus–positive (HCV+) patients without cirrhosis and HCV+ patients with cirrhosis. All of the patients were followed for at least a full 3-year period. All of the deaths and graft losses were recorded and analyzed using Kaplan-Meier methodology. One- and three-year cumulative patient survival rates for noncirrhotic patients were 91% and 82%, respectively. For cirrhotic patients, one- and three-year cumulative patient survival rates were 100% and 83%, respectively (P = NS). One- and three-year cumulative graft survival rates censored for death were 94% and 81%, and 95% and 82% for the noncirrhosis and cirrhosis groups, respectively (P = NS). Comparable patient and allograft survival rates were observed when standard kidney allograft recipients were analyzed separately. This study is the longest follow-up document in the literature showing that HCV+ clinically ompensated patients with cirrhosis may undergo kidney transplantation alone as a safe and viable practice. PMID:25594655

  3. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

    PubMed Central

    Richards, Mark W.; Law, Edward W. P.; Rennalls, La’Verne P.; Busacca, Sara; O’Regan, Laura; Fry, Andrew M.; Fennell, Dean A.; Bayliss, Richard

    2014-01-01

    Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners. PMID:24706829

  4. Treatment outcome of new smear positive pulmonary tuberculosis patients in Penang, Malaysia

    PubMed Central

    2014-01-01

    Background According to the World Health Organization’s recent report, in Malaysia, tuberculosis (TB) treatment success rate for new smear positive pulmonary tuberculosis (PTB) patients is still below the global success target of 85%. In this study, we evaluated TB treatment outcome among new smear positive PTB patients, and identified the predictors of unsuccessful treatment outcome and longer duration of treatment (i.e., > 6 months). Methods The population in this study consisted of all new smear positive PTB patients who were diagnosed at the chest clinic of Penang General Hospital between March 2010 and February 2011. During the study period, a standardized data collection form was used to obtain socio-demographic, clinical and treatment related data of the patients from their medical charts and TB notification forms (Tuberculosis Information System; TBIS). These data sources were reviewed at the time of the diagnosis of the patients and then at the subsequent follow-up visits until their final treatment outcomes were available. The treatment outcomes of the patients were reported in line with six outcome categories recommended by World Health Organization. Multiple logistic regression analysis was used to find the independent risk factors for unsuccessful treatment outcome and longer treatment duration. Data were analyzed using the PASW (Predictive Analysis SoftWare, version 19.0. Armonk, NY: IBM Corp). Results Among the 336 PTB patients (236 male and 100 female) notified during the study period, the treatment success rate was 67.26% (n = 226). Out of 110 patients in unsuccessful outcome category, 30 defaulted from the treatment, 59 died and 21 were transferred to other health care facilities. The mean duration of TB treatment was 8.19 (SD 1.65) months. In multiple logistic regression analysis, risk factors for unsuccessful treatment outcome were foreign nationality, male gender and being illiterate. Similarly, risk factors for mortality due to TB

  5. Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins?

    SciTech Connect

    Chan, Linda W.; Rabban, Joseph; Hwang, E. Shelley; Bevan, Alison; Alvarado, Michael; Ewing, Cheryl; Esserman, Laura; Fowble, Barbara

    2011-05-01

    Purpose: Resection margin status is one of the most significant factors for local recurrence in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery with or without radiation. However, its impact on chest wall recurrence in patients treated with mastectomy is unknown. The purpose of this study was to determine chest wall recurrence rates in women with DCIS and close (<5 mm) or positive mastectomy margins in order to evaluate the potential role of radiation therapy. Methods and Materials: Between 1985 and 2005, 193 women underwent mastectomy for DCIS. Fifty-five patients had a close final margin, and 4 patients had a positive final margin. Axillary surgery was performed in 17 patients. Median follow-up was 8 years. Formal pathology review was conducted to measure and verify margin status. Nuclear grade, architectural pattern, and presence or absence of necrosis was recorded. Results: Median pathologic size of the DCIS in the mastectomy specimen was 4.5 cm. Twenty-two patients had DCIS of >5 cm or diffuse disease. Median width of the close final margin was 2 mm. Nineteen patients had margins of <1 mm. One of these 59 patients experienced a chest wall recurrence with regional adenopathy, followed by distant metastases 2 years following skin-sparing mastectomy. The DCIS was high-grade, 4 cm, with a 5-mm deep margin. A second patient developed an invasive cancer in the chest wall 20 years after her mastectomy for DCIS. This cancer was considered a new primary site arising in residual breast tissue. Conclusions: The risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high-grade DCIS. One out of 20 (5%) patients undergoing skin sparing or total skin-sparing mastectomy experienced a chest wall recurrence. This risk of a chest wall recurrence appears sufficiently low not to warrant a recommendation for postmastectomy radiation therapy for patients with margins of <5 mm. There were too few patients

  6. Is patient confidentiality compromised with the electronic health record?: a position paper.

    PubMed

    Wallace, Ilse M

    2015-02-01

    In order for electronic health records to fulfill their expected benefits, protection of privacy of patient information is key. Lack of trust in confidentiality can lead to reluctance in disclosing all relevant information, which could have grave consequences. This position paper contemplates whether patient confidentiality is compromised by electronic health records. The position that confidentiality is compromised was supported by the four bioethical principles and argued that despite laws and various safeguards to protect patients' confidentiality, numerous data breaches have occurred. The position that confidentiality is not compromised was supported by virtue ethics and a utilitarian viewpoint and argued that safeguards keep information confidential and the public feels relatively safe with the electronic health record. The article concludes with an ethically superior position that confidentiality is compromised with the electronic health record. Although organizational and governmental ways of enhancing the confidentiality of patient information within the electronic health record facilitate confidentiality, the ultimate responsibility of maintaining confidentiality rests with the individual end-users and their ethical code of conduct. The American Nurses Association Code of Ethics for nurses calls for nurses to be watchful with data security in electronic communications. PMID:25532832

  7. The Patient Protection and Affordable Care Act: The Role of the School Nurse. Position Statement

    ERIC Educational Resources Information Center

    Combe, Laurie G.; Sharpe, Susan; Feeser, Cynthia Jo; Ondeck, Lynnette; Fekaris, Nina

    2015-01-01

    It is the position of the National Association of School Nurses (NASN) that the registered professional school nurse (hereinafter referred to as school nurse) serves a vital role in the delivery of health care to our nation's students within the healthcare system reshaped by the Patient Protection and Affordable Care Act of 2010, commonly known as…

  8. Patient Positioning and Skin Sequelae: Ischemic Epidermal Necrosis from Tight Padding During Cardiac Surgery.

    PubMed

    Sadeghpour, Mona; Au, Jeremiah; Ho, Jonhan; Hyman, Jaime; Patton, Timothy

    2016-05-15

    Careful positioning and padding of pressure points during surgery are recommended to prevent pressure ulcers, vascular injury, and nerve damage in an immobilized patient. However, overpadding may have unintended consequences. We report a case of ischemia-induced full-thickness epidermal necrosis secondary to tight foam padding during a cardiac surgery. PMID:26934606

  9. Assessing Riverside Community College Nursing Student Attitudes toward Exposure to AIDS/HIV-Positive Patients.

    ERIC Educational Resources Information Center

    Kross, Carolyn Sue

    In fall 1990, a study was conducted to assess the attitudes of nursing students who were attending Riverside Community College (RCC), in California, toward exposure to Acquired Immune Deficiency Syndrome/Human Immunodeficiency Virus (AIDS/HIV) positive patients in a hospital setting. All students enrolled in RCC's associate degree nursing program…

  10. Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma

    PubMed Central

    Marino, Federica Zito; Liguori, Giuseppina; Aquino, Gabriella; La Mantia, Elvira; Bosari, Silvano; Ferrero, Stefano; Rosso, Lorenzo; Gaudioso, Gabriella; De Rosa, Nicla; Scrima, Marianna; Martucci, Nicola; La Rocca, Antonello; Normanno, Nicola; Morabito, Alessandro; Rocco, Gaetano; Botti, Gerardo; Franco, Renato

    2015-01-01

    Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be ‘major’, characterized by a single tumor showing two different histologic types, and ‘minor’, due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes. PMID:26422230

  11. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer

    PubMed Central

    Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

    2013-01-01

    Introduction: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. Methods: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Results: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57

  12. Clinical value of anaerobic blood culture: a retrospective analysis of positive patient episodes

    PubMed Central

    James, P.; Al-Shafi, K.

    2000-01-01

    Aim—To investigate the clinical value of anaerobic blood culture. Methods—Blood culture bottles (n = 25 185) submitted for culture over a two year period were reviewed. Results—The bottles yielded 1992 positive patient episodes, a positive rate of 14.4/1000 hospital admissions. Significantly more isolations were obtained from aerobic than from anaerobic bottles. Twelve of the 38 anaerobic episodes were detected in aerobic bottles. Clinical management was influenced in one of 24 patients whose cultures yielded anaerobes from anaerobic bottles only. For a further six patients it was unlikely that the result had any effect on clinical management. Conclusions—If aerobic bottles were substituted for the anaerobic bottles, detection of positive patient episodes would increase by at least 6%. A higher yield would be achieved by using two aerobic bottles for routine culture and using anaerobic bottles only for patients where anaerobic culture may influence clinical management. Key Words: blood culture • anaerobes • BacT/Alert PMID:10823145

  13. Positioning patient-perceived medical services to develop a marketing strategy.

    PubMed

    Jung, Minsoo; Hong, Myung-Sun

    2012-01-01

    In today's medical market, marketing philosophy is being rapidly transformed from customer searching to patient satisfaction and service improvement. The principal objective of this study was to contribute to the establishment of a desirable medical marketing strategy, through the factors of customer satisfaction and the positioning of patients' perceptions by marketing institutions. The data were collected from 282 students of the College of Public Health and Medicine in Seoul. The survey tools were developed using the SERVQUAL scale. Analysis in this study involved both statistical and network analysis. The former was used to verify the determinants of service satisfaction as perceived by respondents, via factor analysis and multiple regression analysis. The latter was obtained using a positioning map and 2-mode network analysis with the matrix data converted from raw data. The determining factors for patient satisfaction were identified as facilities, accessibility, process, physicians, and medical staff. The regression equation was significant (R = 0.606), and the most influential variable was the service quality of physicians (β = .569). According to multidimensional scaling, the positioning of medical institutions indicated that patients' perceptions were affected by hospital size and specialization. By recognizing and managing patient satisfaction, medical institutions are able to foster customer loyalty and, in turn, to enhance service quality. It is necessary to develop an adequate marketing mix to provide better medical services and to overcome medical competition among institutions. PMID:22281998

  14. The HIV-positive dentist: balancing the rights of the health care worker and the patient.

    PubMed

    Gardam, M A; Flanagan, W F; Salit, I E

    2001-06-12

    We describe a hypothetical case of an HIV-positive dentist without cognitive impairment who uses proper infection control procedures. The dentist's physician notifies the medical officer of health without the dentist's consent. Although HIV-positive health care workers, including dentists, have been identified in the past, proven HIV transmission to patients is very rare. Most authorities recommend that an HIV-positive health care worker be monitored by an expert panel, which could then, if necessary, refer to the regulatory body to revoke or restrict the person's license to practice. Mandatory HIV testing is not required for health care workers because they generally do not pose a risk for infecting their patients; they are, however, ethically and legally obligated to report their HIV status to their profession's regulatory body. PMID:11450216

  15. Study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients.

    PubMed

    Mounier, R; Adrie, C; Français, A; Garrouste-Orgeas, M; Cheval, C; Allaouchiche, B; Jamali, S; Dinh-Xuan, A T; Goldgran-Toledano, D; Cohen, Y; Azoulay, E; Timsit, J-F; Ricard, J-D

    2010-04-01

    The aim of the present study was to examine whether prone positioning (PP) affects ventilator associated-pneumonia (VAP) and mortality in patients with acute lung injury/adult respiratory distress syndrome. 2,409 prospectively included patients were admitted over 9 yrs (2000-2008) to 12 French intensive care units (ICUs) (OUTCOMEREA). The patients required invasive mechanical ventilation (MV) and had arterial oxygen tension/inspiratory oxygen fraction ratios <300 during the first 48 h. Controls were matched to PP patients on the PP propensity score (+/-10%), MV duration longer than that in PP patients before the first turn prone, and centre. VAP incidence was similar in the PP and control groups (24 versus 13 episodes.1,000 patient-days MV(-1) respectively, p = 0.14). After adjustment, PP did not decrease VAP occurrence (HR 1.64 (95% CI 0.70-3.84); p = 0.25) but significantly delayed hospital mortality (HR 0.56 (95% CI 0.39-0.79); p = 0.001), without decreasing 28-day mortality (37% in both groups). Post hoc analyses indicated that PP did not protect against VAP but, when used for >1 day, might decrease mortality and benefit the sickest patients (Simplified Acute Physiology Score >50). In ICU patients with hypoxaemic acute respiratory failure, PP had no effect on the risk of VAP. PP delayed mortality without decreasing 28-day mortality. PP >1 day might decrease mortality, particularly in the sickest patients. PMID:19741030

  16. Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma

    ClinicalTrials.gov

    2014-06-26

    Peripheral T-cell Lymphoma (Not Otherwise Specified); Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma Nasal Type; Enteropathy- Type T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Anaplastic Large Cell Lymphoma (ALCL) (ALK-1 Negative); Relapsed ALCL (ALK-1 Positive) Post Autologous Transplant

  17. Comparison of Gait Aspects According to FES Stimulation Position Applied to Stroke Patients

    PubMed Central

    Mun, Byeong-mu; Kim, Tae-ho; Lee, Jin-hwan; Lim, Jin-youg; Seo, Dong-kwon; Lee, Dong-jin

    2014-01-01

    [Purpose] This study sought to identify the gait aspects according to the FES stimulation position in stroke patients during gait training. [Subjects and Methods] To perform gait analysis, ten stroke patients were grouped based on 4 types of gait conditions: gait without FES stimulation (non-FES), gait with FES stimulation on the tibialis anterior (Ta), gait with FES stimulation on the tibialis anterior and quadriceps (TaQ), and gait with FES stimulation on the tibialis anterior and gluteus medius (TaGm). [Results] Based on repeated measures analysis of variance of measurements of gait aspects comprised of gait speed, gait cycle, and step length according to the FES stimulation position, the FES stimulation significantly affected gait aspects. [Conclusion] In conclusion, stimulating the tibialis anterior and quadriceps and stimulating the tibialis anterior and gluteus medius are much more effective than stimulating only the tibialis anterior during gait training in stroke patients using FES. PMID:24764634

  18. High Mortality among Patients with Positive Blood Cultures at a Children's Hospital in Tbilisi, Georgia

    PubMed Central

    Schaffner, Jami; Chochua, Sopio; Kourbatova, Ekaterina V.; Barragan, Maribel; Wang, Yun F; Blumberg, Henry M; Rio, Carlos del; Walker, H. Kenneth; Leonard, Michael K.

    2010-01-01

    Background The etiology and outcomes of blood stream infections (BSI) among pediatric patients is not well described in resource-limited countries including Georgia. Methods Patients with positive blood cultures at the largest pediatric hospital in the country of Georgia were identified by review of medical and laboratory records for patients who had blood cultures obtained between 01/2004-06/2006. Results Of 1,693 blood cultures obtained during the study period, 338 (20%) were positive; 299 were included in our analysis. The median age was 14 days (range 2 days -14 years) and 178 (60%) were male; 53% of patients with a positive culture were admitted to Neonatal Intensive Care Unit (NICU). Gram-negative bacilli (GNB) were representing 165 (55%) of 299 cultures. Further speciation of 135 (82%) of 165 GNR was not possible because of lack of laboratory capacity. Overall mortality was 30% (90 of 299). Among the 90 children who died, 80 (89%) were neonates and 68 (76%) had BSI caused by Gram-negative organism. In multivariate analysis, independent risk factors for in-hospital mortality included age <30 days (OR=4.00, 95% CI 1.89-8.46) and having a positive blood culture for a Gram-negative BSI (OR=2.38, 95% CI 1.32-4.29). Conclusions A high mortality was seen among children, particularly neonates, with positive blood cultures at the largest pediatric hospital in Georgia. Because of limited laboratory capacity microbiological identification of common organisms known to cause BSI in children was not possible and susceptibility testing was not performed. Improving the infrastructure of diagnostic microbiology laboratories in resource limited countries is critical in order to improve patient care and clinical outcomes and from a public health standpoint to improve surveillance activities. PMID:19759489

  19. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.

    PubMed

    Weissberg, Itai; Wood, Lydia; Kamintsky, Lyn; Vazquez, Oscar; Milikovsky, Dan Z; Alexander, Allyson; Oppenheim, Hannah; Ardizzone, Carolyn; Becker, Albert; Frigerio, Federica; Vezzani, Annamaria; Buckwalter, Marion S; Huguenard, John R; Friedman, Alon; Kaufer, Daniela

    2015-06-01

    Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE. PMID:25836421

  20. Electromagnetic Tracking of Intrafraction Prostate Displacement in Patients Externally Immobilized in the Prone Position

    SciTech Connect

    Bittner, Nathan; Wallner, Kent E.; Merrick, Gregory S.

    2010-06-01

    Purpose: To evaluate intrafraction prostate displacement among patients immobilized in the prone position using real-time monitoring of implanted radiofrequency transponders. Methods and Materials: The Calypso localization system was used to track prostate motion in patients receiving external beam radiation therapy (XRT) for prostate cancer. All patients were treated in the prone position and immobilized with a thermoplastic immobilization device. Real-time measurement of prostate displacement was recorded for each treatment fraction. These measurements were used to determine the duration and magnitude of displacement along the three directional axes. Results: The calculated centroid of the implanted transponders was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 38.0%, 13.9%, and 4.5% of the time. In the lateral dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 2.7%, 0.4%, and 0.06% of the time. In the superior-inferior dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 16.1%, 4.7%, and 1.5% of the time, respectively. In the anterior-posterior dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 13.4%, 3.0%, and 0.5% of the time. Conclusions: Intrafraction prostate displacement in the prone position is comparable to that in the supine position. For patients with large girth, in whom the supine position may preclude accurate detection of implanted radiofrequency transponders, treatment in the prone position is a suitable alternative.

  1. Patient position verification in ion-beam therapy using ion-beam radiography and fiducial markers

    NASA Astrophysics Data System (ADS)

    Huber, Lucas; Telsemeyer, Julia; Martišíková, Mária; Jäkel, Oliver

    2011-11-01

    The basic rationale for radiation therapy using ion-beams is its high local precision of dose deposition. Therefore accurate patient positioning prior to and during beam application is a crucial part of the therapy. The current standard position verification procedure uses X-ray based imaging before each beam application. The patient is assumed to remain in his position throughout irradiation. Currently there is no monitoring of the patient position or organ movement during treatment. The aim of this study is to investigate the possibility of verifying the position of a fiducial marker during therapy using ion radiography. Some modern ion therapy facilities like the Heidelberg Ion-Beam Therapy Center (HIT), where our measurements were carried out, use scanning pencil beams to apply dose. Exploiting them for imaging allows to solely irradiate regions of interest in the patient's body, e.g. tissue containing medical markers. The advantage of this technique is that it can be performed quickly in turn with therapeutic beam application and irradiates only very little tissue. For our measurements we used conventional medical metal markers embedded in phantom material mimicking body tissue. To image the residual beam we use a Perkin Elmer RID256-L flat panel detector. In an idealized setup the marker contrast was measured to be as high as 60%, which was reduced by a factor of 2-2.5 when the marker was placed at distances to the detector in the phantom material larger than 10 cm. It was shown that applying 2ṡ105 carbon ions suffices to make the markers' position visible in a setup of realistic material thickness and marker depth. While the dose is comparable to X-ray imaging, the irradiated volume and, consequently, also the integral dose is considerably reduced. However, in realistic geometries there are large particle range differences in lateral direction yielding steep signal gradients in the radiography. Thus, the useful image area with unambiguous signal

  2. Learning from positively deviant wards to improve patient safety: an observational study protocol

    PubMed Central

    Baxter, Ruth; Taylor, Natalie; Kellar, Ian; Lawton, Rebecca

    2015-01-01

    Introduction Positive deviance is an asset-based approach to improvement which has recently been adopted to improve quality and safety within healthcare. The approach assumes that solutions to problems already exist within communities. Certain groups or individuals identify these solutions and succeed despite having the same resources as others. Within healthcare, positive deviance has previously been applied at individual or organisational levels to improve specific clinical outcomes or processes of care. This study explores whether the positive deviance approach can be applied to multidisciplinary ward teams to address the broad issue of patient safety among elderly patients. Methods and analysis Preliminary work analysed National Health Service (NHS) Safety Thermometer data from 34 elderly medical wards to identify 5 ‘positively deviant’ and 5 matched ‘comparison’ wards. Researchers are blinded to ward status. This protocol describes a multimethod, observational study which will (1) assess the concurrent validity of identifying positively deviant elderly medical wards using NHS Safety Thermometer data and (2) generate hypotheses about how positively deviant wards succeed. Patient and staff perceptions of safety will be assessed on each ward using validated surveys. Correlation and ranking analyses will explore whether this survey data aligns with the routinely collected NHS Safety Thermometer data. Staff focus groups and researcher fieldwork diaries will be completed and qualitative thematic content analysis will be used to generate hypotheses about the strategies, behaviours, team cultures and dynamics that facilitate the delivery of safe patient care. The acceptability and sustainability of strategies identified will also be explored. Ethics and dissemination The South East Scotland Research Ethics Committee 01 approved this study (reference: 14/SS/1085) and NHS Permissions were granted from all trusts. Findings will be published in peer

  3. Survival in patients with human papillomavirus positive tonsillar cancer in relation to treatment.

    PubMed

    Attner, Per; Näsman, Anders; Du, Juan; Hammarstedt, Lalle; Ramqvist, Torbjörn; Lindholm, Johan; Munck-Wikland, Eva; Dalianis, Tina; Marklund, Linda

    2012-09-01

    The incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases have increased in the last decades. In parallel, treatment for tonsillar cancer has been intensified e.g., by accelerated radiotherapy, and chemotherapy, resulting in more side effects. Patients with HPV-positive tonsillar cancer have better prognosis than those with HPV-negative tumors, and the former group could hypothetically benefit from reduced, less-toxic treatment without compromising survival. Here, we therefore evaluated possible differences in overall and disease-specific survival after different oncological treatments in 153 patients with HPV DNA- and P16-positive tonsillar cancer who were diagnosed and treated with intent to cure between 2000 and 2007, in Stockholm, Sweden. Of these patients, 86 were treated with conventional radiotherapy, 40 were treated with accelerated radiotherapy and 27 were treated with chemoradiotherapy. There were no significant differences in overall or disease-free survival between the groups. However, there was a trend, implying a beneficial effect of the intensified treatment, with chemoradiotherapy being better than radiotherapy despite that more patients had stage IV disease in the former group; and accelerated radiotherapy being better than conventional radiotherapy. This needs to be followed further in larger more homogenous groups of patients. In conclusion, patients with HPV-positive tonsillar cancer treated with conventional- or accelerated radiotherapy or chemoradiotherapy disclosed similar survival rates. The trend for better survival and less metastasis after intensified treatment underlines the need for large prospective studies comparing less intense to more intense treatment (chemoradiotherapy). PMID:22038860

  4. Influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient satisfaction

    PubMed Central

    Pellicer-Chover, Hilario; Cervera-Ballester, Juan; Peñarrocha-Oltra, David; Bagán, Leticia; Peñarrocha-Diago, María

    2016-01-01

    Background To assess the influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient comfort and stability, speech, functionality and overall satisfaction. Material and Methods A retrospective clinical study was made of patients subjected to rehabilitation of atrophic maxilla with complete maxillary implant-supported fixed prostheses involving a minimum of two zygomatic implants (one on each side) in conjunction with premaxillary implants, and with 12 months of follow-up after implant loading. Subjects used a VAS to score general satisfaction, comfort and stability, speech and functionality, and the results were analyzed in relation to the prosthetic arm length of the zygomatic implants 12 months after prosthetic delivery. Results Twenty-two patients participated in the study, receiving 22 prostheses anchored on 148 implants (44 were zygomatic and 94 were conventional implants). The mean right and left prosthetic arm length was 5.9±2.4 mm and 6.1±2.7 mm, respectively, with no statistically significant differences between them (p=0.576). The mean scores referred to comfort/retention, speech, functionality and overall satisfaction were high - no correlation being found between prosthetic arm length and patient satisfaction (p=0.815). Conclusions No relationship could be identified between prosthetic arm length (palatal position) and patient satisfaction. Key words:Zygomatic implants, patient satisfaction, zygomatic prosthesis, prosthetic arm length. PMID:26946206

  5. Which patients with sentinel node-positive breast cancer can avoid axillary dissection?

    PubMed

    Ho, Alice Y; Cody, Hiram S

    2013-01-01

    Sentinel lymph node (SLN) biopsy is standard care for patients with cN0 breast cancer. An extensive literature, including seven randomized trials, has established that patients with negative SLN do not require axillary dissection (ALND), that axillary local recurrence after a negative SLN biopsy is rare, that disease-free and overall survival are unaffected by the addition of ALND to SLN biopsy, and that the morbidity of SLN biopsy is substantially less than that of ALND. It is now clear that many patients with positive SLN do not require ALND. In ACOSOG Z0011, 6-year locoregional control and survival were equivalent with versus without the performance of ALND in cT1-2N0 patients with ≤2 positive SLN treated by breast conservation with whole breast radiation therapy. A small but growing body of data now suggests that ALND may not be required for selected patients outside the Z0011 eligibility criteria, specifically those treated by mastectomy (without post-mastectomy radiation therapy), by partial breast irradiation, and by neoadjuvant chemotherapy. Looking ahead, the principal goals of axillary staging, prognostication, and local control will be accomplished by SLN biopsy for a substantial majority of patients, and the role of ALND will continue to diminish. PMID:23714457

  6. Toxicity of Head-and-Neck Radiation Therapy in Human Immunodeficiency Virus-Positive Patients

    SciTech Connect

    Sanfilippo, Nicholas J.; Mitchell, James; Grew, David; DeLacure, Mark

    2010-08-01

    Purpose: To examine the acute morbidity of high dose head and neck RT and CRT in patients with infected with HIV. Methods and Materials: All HIV-positive patients who underwent radiation therapy for head and neck cancer in our department between 2004 and 2008 were reviewed. Treatment related data were examined. All treatments were delivered with megavoltage photon beams or electron beams. Patients were evaluated by an attending radiation oncologist for toxicity and response on a weekly basis during therapy and monthly after treatment in a multidisciplinary clinic. Acute toxicities were recorded using the Radiation Therapy and Oncology Group (RTOG) common toxicity criteria. Response to treatment was based on both physical exam as well as post-treatment imaging as indicated. Results: Thirteen patients who underwent RT with a diagnosis of HIV were identified. Median age was 53 years and median follow-up was 22 months. Twelve had squamous cell carcinoma and one had lymphoproliferative parotiditis. Median radiation dose was 66.4 Gy and median duration of treatment was 51 days. The median number of scheduled radiotherapy days missed was zero (range 0 to 7). One patient (8%) developed Grade 4 confluent moist desquamation. Eight patients (61%) developed Grade 3 toxicity. Conclusion: Based on our results, HIV-positive individuals appear to tolerate treatment for head and neck cancer, with toxicity similar to that in HIV-negative individuals.

  7. SU-C-19A-04: Evaluation of Patient Positioning Reproducibility with Three Supine Breast Boards

    SciTech Connect

    Zhang, Y; Brinkmann, D; Pafundi, D; Park, S; Yan, E; Choo, R; Petersen, I; Childs, S; Pisansky, T; Remmes, N; Mutter, R

    2014-06-15

    Purpose: To evaluate positioning reproducibility using three commercially available breast board immobilization systems for whole breast radiation therapy. Methods: Weekly pre-treatment cone beam CT images from 18 free-breathing breast radiotherapy patients, each immobilized with one of three breast boards, were retrospectively registered to the planning CT. Relative shifts between breast tissue and sternum/chest wall (CW), and breast tissue and spine compared to planning CT were obtained for each board. Positioning reproducibility, inter-patient variation and intra-patient variation were evaluated by group mean (M), standard deviation of group mean (Σ) and standard deviation of random shift (σ). Margins to account for setup uncertainties were calculated based on shift uncertainties in x, y, and z directions. Results: For breast positioning relative to sternum/CW, the average shift from planned positioning was 4.5mm (95% CI: 3.5 – 5.3), 3.3mm (CI: 2.9 - 3.8) and 2.6mm (CI: 1.8 - 3.5) for Breast Boards I, II, and III, respectively. The respective numbers for breast positioning relative to spine were 7.2 mm (CI: 4.1 – 10.3), 6.4 mm (CI: 4.3 – 8.3) and 4.3 mm (CI: 2.5 – 6.2). Localizing to the sternum/CW as a surrogate for the breast tissue, margins for setup uncertainties were 5.7mm, 5.5mm, and 6.0mm for Breast Board I, 5.0mm, 4.0mm and 4.3mm for Breast Board II, and 3.8mm, 3.5mm and 4.8mm for Breast Board III, in the lateral, anterior/posterior, and superior/inferior directions, respectively. Conclusion: Better patient positioning reproducibility was observed with Boards II and III compared to Board I. Inter- and intra-patient set-up uncertainties were also improved with Boards II and III, which requires smaller PTV margins. Independent of breast board, breast cancer patient positioning to the sternum/CW is a better surrogate than the spine. Our findings have potential dosimetric consequences from set-up uncertainties when employing IMRT or proton

  8. Development and clinical application of a patient-position monitoring system

    NASA Astrophysics Data System (ADS)

    Gerig, Lee H.; El-Hakim, Sabry F.; Szanto, Janos; Salhani, Doug; Girard, A.

    1994-10-01

    We have developed and clinically tested a computer vision system capable of real time monitoring of the position of an oncology (cancer) patient undergoing radiation therapy. The system is able to report variations in patient setup from day to day, as well as patient motion during an individual treatment. The system consists of two CCD cameras mounted in the treatment room and focused on the treatment unit isocenter. The cameras are interfaced to a PC via a two channel video board. Special targets, placed on the patient surface are automatically recognized and extracted by our 3D vision software. The three coordinates of each target are determined using a triangulation algorithm. System accuracy, stability and reproducibility were tested in the laboratory as well as in the radiation therapy room. Beside accuracy, the system must ensure the highest reliability and safety in the actual application environment. In this paper we also report on the results of clinical testing performed on a total of 23 patients having various treatment sites and techniques. The system in its present configuration is capable of measuring multiple targets placed on the patient surface during radiation therapy. In the clinical environment the system has an accuracy and repeatability of better than 0.5 mm in Cartesian space over extended periods (> 1 month). The system can measure and report patient position in less than 5 seconds. Clinically we have found that the system can easily and accurately detect patient motion during treatment as well as variations in patient setup from day to day. A brief description of the system and detailed analysis of its performance in the laboratory and in the clinic are presented.

  9. SU-E-J-184: Stereo Time-Of-Flight System for Patient Positioning in Radiotherapy

    SciTech Connect

    Wentz, T; Gilles, M; Visvikis, D; Le Fur, E; Pradier, O

    2014-06-01

    Purpose: The objective of this work is to test the advantage of using the surface acquired by two stereo Time-of-Flight (ToF) cameras in comparison of the use of one camera only for patient positioning in radiotherapy. Methods: A first step consisted on validating the use of a stereo ToFcamera system for positioning management of a phantom mounted on a linear actuator producing very accurate and repeatable displacements. The displacements between two positions were computed from the surface point cloud acquired by either one or two cameras thanks to an iterative closest point algorithm. A second step consisted on determining the displacements on patient datasets, with two cameras fixed on the ceiling of the radiotherapy room. Measurements were done first on voluntary subject with fixed translations, then on patients during the normal clinical radiotherapy routine. Results: The phantom tests showed a major improvement in lateral and depth axis for motions above 10 mm when using the stereo-system instead of a unique camera (Fig1). Patient measurements validate these results with a mean real and measured displacement differences in the depth direction of 1.5 mm when using one camera and 0.9 mm when using two cameras (Fig2). In the lateral direction, a mean difference of 1 mm was obtained by the stereo-system instead of 3.2 mm. Along the longitudinal axis mean differences of 5.4 and 3.4 mm with one and two cameras respectively were noticed but these measurements were still inaccurate and globally underestimated in this direction as in the literature. Similar results were also found for patient subjects with a mean difference reduction of 35%, 7%, and 25% for the lateral, depth, and longitudinal displacement with the stereo-system. Conclusion: The addition of a second ToF-camera to determine patient displacement strongly improved patient repositioning results and therefore insures better radiation delivery.

  10. Novel Approach to Simulate Sleep Apnea Patients for Evaluating Positive Pressure Therapy Devices.

    PubMed

    Isetta, Valentina; Montserrat, Josep M; Santano, Raquel; Wimms, Alison J; Ramanan, Dinesh; Woehrle, Holger; Navajas, Daniel; Farré, Ramon

    2016-01-01

    Bench testing is a useful method to characterize the response of different automatic positive airway pressure (APAP) devices under well-controlled conditions. However, previous models did not consider the diversity of obstructive sleep apnea (OSA) patients' characteristics and phenotypes. The objective of this proof-of-concept study was to design a new bench test for realistically simulating an OSA patient's night, and to implement a one-night example of a typical female phenotype for comparing responses to several currently-available APAP devices. We developed a novel approach aimed at replicating a typical night of sleep which includes different disturbed breathing events, disease severities, sleep/wake phases, body postures and respiratory artefacts. The simulated female OSA patient example that we implemented included periods of wake, light sleep and deep sleep with positional changes and was connected to ten different APAP devices. Flow and pressure readings were recorded; each device was tested twice. The new approach for simulating female OSA patients effectively combined a wide variety of disturbed breathing patterns to mimic the response of a predefined patient type. There were marked differences in response between devices; only three were able to overcome flow limitation to normalize breathing, and only five devices were associated with a residual apnea-hypopnea index of <5/h. In conclusion, bench tests can be designed to simulate specific patient characteristics, and typical stages of sleep, body position, and wake. Each APAP device behaved differently when exposed to this controlled model of a female OSA patient, and should lead to further understanding of OSA treatment. PMID:26978077

  11. Positive psychology group intervention for breast cancer patients: a randomised trial.

    PubMed

    Victoria Cerezo, M; Ortiz-Tallo, Margarita; Cardenal, Violeta; De La Torre-Luque, Alejandro

    2014-08-01

    This study assessed the effects of a psychological group intervention based on positive psychology in women with breast cancer. 175 women were randomly assigned either to an experimental group, receiving the 14-session intervention (n = 87), or to a wait list group (n = 88) that did not receive any type of intervention. For treatment, a group intervention was applied, based on improving psychological strengths and enhancing positive psychology-based styles of coping. Strength-related outcomes, self-esteem, well-being, and happiness were assessed before and after the intervention. The experimental group showed higher scores on all of the study variables after the intervention. Participants reported improved self-esteem, emotional intelligence-related abilities, resilience, and optimism, as well as positive affectivity, well-being, and happiness. The results show a beneficial effect of this psychological intervention based on positive psychology on female breast cancer patients' psychological health. PMID:25153949

  12. Increased CD4+/CD8+ Double-Positive T Cells in Chronic Chagasic Patients

    PubMed Central

    Giraldo, Nicolas A.; Bolaños, Natalia I.; Cuellar, Adriana; Guzman, Fanny; Uribe, Ana Maria; Bedoya, Astrid; Olaya, Natalia; Cucunubá, Zulma M.; Roa, Nubia; Rosas, Fernando; Velasco, Víctor; Puerta, Concepción J.; González, John M.

    2011-01-01

    Background CD4+/CD8+ double positive (DP) T cells have been described in healthy individuals as well as in patients with autoimmune and chronic infectious diseases. In chronic viral infections, this cell subset has effector memory phenotype and displays antigen specificity. No previous studies of double positive T cells in parasite infections have been carried out. Methodology/Principal Findings Seventeen chronic chagasic patients (7 asymptomatic and 10 symptomatic) and 24 non-infected donors, including 12 healthy and 12 with non-chagasic cardiomyopathy donors were analyzed. Peripheral blood was stained for CD3, CD4, CD8, HLA-DR and CD38, and lymphocytes for intracellular perforin. Antigen specificity was assessed using HLA*A2 tetramers loaded with T. cruzi K1 or influenza virus epitopes. Surface expression of CD107 and intracellular IFN-γ production were determined in K1-specific DP T cells from 11 chagasic donors. Heart tissue from a chronic chagasic patient was stained for both CD8 and CD4 by immunochemistry. Chagasic patients showed higher frequencies of DP T cells (2.1%±0.9) compared with healthy (1.1%±0.5) and non-chagasic cardiomyopathy (1.2%±0.4) donors. DP T cells from Chagasic patients also expressed more HLA-DR, CD38 and perforin and had higher frequencies of T. cruzi K1-specific cells. IFN-γ production in K1-specific cells was higher in asymptomatic patients after polyclonal stimulation, while these cells tended to degranulate more in symptomatic donors. Immunochemistry revealed that double positive T cells infiltrate the cardiac tissue of a chagasic donor. Conclusions Chagasic patients have higher percentages of circulating double positive T cells expressing activation markers, potential effector molecules and greater class I antigenic specificity against T. cruzi. Although K1 tetramer positive DP T cell produced little IFN-γ, they displayed degranulation activity that was increased in symptomatic patients. Moreover, K1-specific DP T cells can

  13. Stochastic formulation of patient positioning using linac-mounted cone beam imaging with prior knowledge

    SciTech Connect

    Hoegele, W.; Loeschel, R.; Dobler, B.; Hesser, J.; Koelbl, O.; Zygmanski, P.

    2011-02-15

    Purpose: In this work, a novel stochastic framework for patient positioning based on linac-mounted CB projections is introduced. Based on this formulation, the most probable shifts and rotations of the patient are estimated, incorporating interfractional deformations of patient anatomy and other uncertainties associated with patient setup. Methods: The target position is assumed to be defined by and is stochastically determined from positions of various features such as anatomical landmarks or markers in CB projections, i.e., radiographs acquired with a CB-CT system. The patient positioning problem of finding the target location from CB projections is posed as an inverse problem with prior knowledge and is solved using a Bayesian maximum a posteriori (MAP) approach. The prior knowledge is three-fold and includes the accuracy of an initial patient setup (such as in-room laser and skin marks), the plasticity of the body (relative shifts between target and features), and the feature detection error in CB projections (which may vary depending on specific detection algorithm and feature type). For this purpose, MAP estimators are derived and a procedure of using them in clinical practice is outlined. Furthermore, a rule of thumb is theoretically derived, relating basic parameters of the prior knowledge (initial setup accuracy, plasticity of the body, and number of features) and the parameters of CB data acquisition (number of projections and accuracy of feature detection) to the expected estimation accuracy. Results: MAP estimation can be applied to arbitrary features and detection algorithms. However, to experimentally demonstrate its applicability and to perform the validation of the algorithm, a water-equivalent, deformable phantom with features represented by six 1 mm chrome balls were utilized. These features were detected in the cone beam projections (XVI, Elekta Synergy) by a local threshold method for demonstration purposes only. The accuracy of estimation

  14. Dental age in patients with impacted maxillary canines related to the position of the impacted teeth.

    PubMed

    Rozylo-Kalinowska, Ingrid; Kolasa-Raczka, Anna; Kalinowski, Pawel

    2011-10-01

    The aim of the study was to determine whether there are differences in dental age (DA) using the method of Demirjian, in patients with impacted buccal or palatal maxillary canines in relation to unaffected controls. DA was estimated using Demirjian's method on panoramic radiographs of two groups of Caucasian patients. The study group consisted of 116 patients aged from 12 to 16 years (80 females and 36 males) that was further divided into 54 patients with unilateral or bilateral palatally impacted maxillary canines and 62 patients with buccally positioned canines. The control group of 116 subjects without canine impaction was matched to the study group by age and gender. Calculated DAs and differences between dental and chronological age (CA) were compared between the groups. Statistical analysis was performed using Shapiro-Wilk, Mann-Whitney U, and Student's t-test. DA was significantly lower in patients with impacted maxillary canines than in healthy controls and also when palatal or buccal ectopia was considered. The rate of dental development in patients with palatally impacted canines did not differ from that of subjects with buccal canine displacement. The differences between DA and CA were higher in healthy controls (increase in DA) than in patients with impacted maxillary canines. DA estimation using Demirjian's method may be lower than expected in subjects with maxillary canine impaction. PMID:21262933

  15. Positive Contrast MRI Techniques for Visualization of Iron-Loaded Hernia Mesh Implants in Patients

    PubMed Central

    Ciritsis, Alexander; Truhn, Daniel; Hansen, Nienke L.; Otto, Jens; Kuhl, Christiane K.; Kraemer, Nils A.

    2016-01-01

    Object In MRI, implants and devices can be delineated via susceptibility artefacts. To discriminate susceptibility voids from proton-free structures, different positive contrast techniques were implemented. The purpose of this study was to evaluate a pulse sequence-based positive contrast technique (PCSI) and a post-processing susceptibility gradient mapping algorithm (SGM) for visualization of iron loaded mesh implants in patients. Material and Methods Five patients with iron-loaded MR-visible inguinal hernia mesh implants were examined at 1.5 Tesla. A gradient echo sequence (GRE; parameters: TR: 8.3ms; TE: 4.3ms; NSA:2; FA:20°; FOV:350mm²) and a PCSI sequence (parameters: TR: 25ms; TE: 4.6ms; NSA:4; FA:20°; FOV:350mm²) with on-resonant proton suppression were performed. SGM maps were calculated using two algorithms. Image quality and mesh delineation were independently evaluated by three radiologists. Results On GRE, the iron-loaded meshes generated distinct susceptibility-induced signal voids. PCSI exhibited susceptibility differences including the meshes as hyperintense signals. SGM exhibited susceptibility differences with positive contrast. Visually, the different algorithms presented no significant differences. Overall, the diagnostic value was rated best in GRE whereas PCSI and SGM were barely “sufficient”. Conclusion Both “positive contrast” techniques depicted implanted meshes with hyperintense signal. SGM comes without additional acquisition time and can therefore be utilized in every patient. PMID:27192201

  16. Oral ranula in an HIV-positive patient: case report and literature review

    PubMed Central

    Kinshuck, Andrew Jon; Schober, Marianne; Kokai, George; Clarke, Ray

    2012-01-01

    We describe the presentation and treatment of an HIV-positive patient with an oral ranula, and review the literature. Ranulas are mucoceles or retention cysts formed by the extravasation of mucus from the sublingual gland, presumably due to continued production of saliva in the presence of ductal obstruction. Oral ranulas in children are rare and the overall prevalence of mucoceles has been reported as 0.08% in children aged 0–12 years. However, there has been a documented increased occurrence in HIV-positive patients. This has been attributed to a blockage of the salivary gland by inflammation and peri-ductal fibrosis following HIV-associated salivary gland disease. Oral lesions may indicate infection with HIV and can also predict progression of HIV to AIDS. The most common oral manifestation is oral candidiasis occurring in 67% of children with HIV. Following this salivary gland disease, periodontal and gingival disease and herpes simplex are the next most common. The exact prevalence of ranulas in an HIV population is not known but the occurrence of a paediatric patient with HIV having at least one oral lesion has been documented as high as 63% and salivary gland disease at 50%. The true extent of the relationship between HIV and ranula is as yet unknown. This represents the only reported case of oral ranula in an HIV-positive patient in the UK. PMID:22783004

  17. Oral ranula in an HIV-positive patient: case report and literature review.

    PubMed

    Kinshuck, Andrew Jon; Schober, Marianne; Kokai, George; Clarke, Ray

    2012-01-01

    We describe the presentation and treatment of an HIV-positive patient with an oral ranula, and review the literature. Ranulas are mucoceles or retention cysts formed by the extravasation of mucus from the sublingual gland, presumably due to continued production of saliva in the presence of ductal obstruction. Oral ranulas in children are rare and the overall prevalence of mucoceles has been reported as 0.08% in children aged 0-12 years. However, there has been a documented increased occurrence in HIV-positive patients. This has been attributed to a blockage of the salivary gland by inflammation and peri-ductal fibrosis following HIV-associated salivary gland disease. Oral lesions may indicate infection with HIV and can also predict progression of HIV to AIDS. The most common oral manifestation is oral candidiasis occurring in 67% of children with HIV. Following this salivary gland disease, periodontal and gingival disease and herpes simplex are the next most common. The exact prevalence of ranulas in an HIV population is not known but the occurrence of a paediatric patient with HIV having at least one oral lesion has been documented as high as 63% and salivary gland disease at 50%. The true extent of the relationship between HIV and ranula is as yet unknown. This represents the only reported case of oral ranula in an HIV-positive patient in the UK. PMID:22783004

  18. Exogenous Magnesium Chloride Reduces the Activated Partial Thromboplastin Times of Lupus Anticoagulant-Positive Patients

    PubMed Central

    Tokutake, Takayoshi; Baba, Hisami; Shimada, Yuji; Takeda, Wataru; Sato, Keijiro; Hiroshima, Yuki; Kirihara, Takehiko; Shimizu, Ikuo; Nakazawa, Hideyuki; Kobayashi, Hikaru; Ishida, Fumihiro

    2016-01-01

    The activated partial thromboplastin time (APTT) assay is a basic hemostatic assay based on the time it takes for clots to form in plasma samples after the addition of calcium chloride. It is used to screen for various coagulation disorders. Several previous reports have suggested that magnesium (Mg) might contribute to coagulation reactions by binding to specific coagulation proteins. We investigated the effects of Mg on the APTT. In healthy controls, the APTT was significantly prolonged in proportion to the increase in the concentration of magnesium chloride in the range from 2.1 to 16.7 mmol/L. Among eight samples from patients with various disorders that exhibited prolonged APTT, two samples demonstrated shorter APTT when Mg was added, both of which were from patients that were positive for lupus anticoagulant. When we examined 206 clinical APTT samples, we found that Mg shortened the APTT of two samples. These two samples were also from lupus anticoagulant-positive patients (p-value: <0.003). Our findings regarding the unique effects of exogenous Mg on the APTT of lupus anticoagulant-positive patients might shed light on the role of Mg in APTT assays and lead to the development of a novel screening method for lupus anticoagulant. PMID:27355205

  19. Positive predictive value of diagnosis coding for hemolytic anemias in the Danish National Patient Register

    PubMed Central

    Hansen, Dennis Lund; Overgaard, Ulrik Malthe; Pedersen, Lars; Frederiksen, Henrik

    2016-01-01

    Purpose The nationwide public health registers in Denmark provide a unique opportunity for evaluation of disease-associated morbidity if the positive predictive values (PPVs) of the primary diagnosis are known. The aim of this study was to evaluate the predictive values of hemolytic anemias registered in the Danish National Patient Register. Patients and methods All patients with a first-ever diagnosis of hemolytic anemia from either specialist outpatient clinic contact or inpatient admission at Odense University Hospital from January 1994 through December 2011 were considered for inclusion. Patients with mechanical reason for hemolysis such as an artificial heart valve, and patients with vitamin-B12 or folic acid deficiency were excluded. Results We identified 412 eligible patients: 249 with a congenital hemolytic anemia diagnosis and 163 with acquired hemolytic anemia diagnosis. In all, hemolysis was confirmed in 359 patients, yielding an overall PPV of 87.1% (95% confidence interval [CI]: 83.5%–90.2%). A diagnosis could be established in 392 patients of whom 355 patients had a hemolytic diagnosis. Diagnosis was confirmed in 197 of the 249 patients with congenital hemolytic anemia, yielding a PPV of 79.1% (95% CI: 73.5%–84.0%). Diagnosis of acquired hemolytic anemia could be confirmed in 136 of the 163 patients, resulting in a PPV of 83.4% (95% CI: 76.8%–88.8%). For hemoglobinopathy PPV was 84.1% (95% CI: 77.4%–89.4%), for hereditary spherocytosis PPV was 80.6% (95% CI: 69.5%–88.9%), and for autoimmune hemolytic anemia PPV was 78.4% (95% CI: 70.4%–85.0%). Conclusion The PPV of hemolytic anemias was moderately high. The PPVs were comparable in the three main categories of overall hemolysis, and congenital and acquired hemolytic anemia. PMID:27445504

  20. Dental Health Status of HIV-Positive Patients and Related Variables in Southeast Iran

    PubMed Central

    Saravani, Shirin; Nosrat Zehi, Tahereh; Kadeh, Hamideh; Mir, Sarvar

    2016-01-01

    Background Different factors can be responsible for the increased prevalence of dental caries and missing teeth in HIV-positive patients. Objectives This study evaluates dental health status and its relationship with social, behavioral, and medical factors in HIV-positive patients under the coverage of Zahedan University of Medical Sciences in Southeast Iran. Patients and Methods In a cross-sectional study, the dental health status of 119 HIV-positive patients was assessed in accordance with WHO indices and included decayed, missing, and filled teeth (DMFT). A questionnaire on different social, behavioral, and medical variables was filled out for every case and the relationship and correlation of the variables to dental health status were investigated using One-way ANOVA, the Kruskal Wallis test, the t-test, the Mann-Whitney test, Spearman’s rho correlation coefficient, and Pearson correlation. Results The mean value of DMFT index was 11.87 ± 8.08, where the mean values of decayed and missing teeth were 8.42 ± 5.44 and 3.43 ± 4.07, respectively. DMFT index, decayed, and missing teeth correlated only with age (P < 0.0001, P = 0.009, P < 0.0001) and duration of HIV involvement (P = 0.004, P = 0.031, P = 0.007). Conclusions The dental health status of HIV-positive patients in this region was almost inappropriate. Most social, behavioral, and medical factors had no influence on dental health; only a correlation between dental health, age, and duration of HIV involvement was observed. PMID:27622173

  1. Clinical pilot study: efficacy of triple antibiotic therapy in Blastocystis positive irritable bowel syndrome patients

    PubMed Central

    2014-01-01

    Background Blastocystis species are common human enteric parasites. Carriage has been linked to Irritable Bowel Syndrome (IBS). Treatment of Blastocystis spp. with antimicrobials is problematic and insensitive diagnostic methods and re-infection complicate assessment of eradication. We investigated whether triple antibiotic therapy comprising diloxanide furoate, trimethoprim/sulfamethoxazole and secnidazole (TAB) given to diarrhoea-predominant IBS (D-IBS) patients positive for Blastocystis would achieve eradication. Methods In a longitudinal, prospective case study 10 D-IBS Blastocystis-positive patients took 14 days of diloxanide furoate 500 mg thrice daily, trimethoprim/sulfamethoxazole 160/80 mg twice daily and secnidazole 400 mg thrice daily. Faecal specimens were collected at baseline, day 15 and 4 weeks after completion of TAB. Specimens were analysed using faecal smear, culture and polymerase chain reaction (PCR) of the 16 SSU rRNA. Patients kept a concurrent clinical diary. Results Six (60%) patients cleared Blastocystis spp. after TAB, including three who had failed previous therapy. Subtypes detected were ST3 (60%), ST4 (40%), ST1 (20%) and ST7, 8 (10%); four patients had mixed ST infections. Serum immunoglobulin A (IgA) levels were low in 40% of patients. Higher rates of Blastocystis clearance were observed in patients symptomatic for less than a year (Mann–Whitney, p = 0.032, 95% confidence) with no associations found with age, previous antibiotic therapy, faecal parasite load, ST, IgA level or clinical improvement. Conclusions Clearance of Blastocystis spp. was achieved with TAB in 60% of D-IBS patients, an improvement over conventional monotherapy. Higher clearance rates are needed to facilitate investigation of the relevance of this parasite in clinically heterogenous IBS. PMID:25349629

  2. Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis.

    PubMed

    Andersson, Olov; Reissmann, Eva; Ibáñez, Carlos F

    2006-08-01

    Growth differentiation factor 11 (GDF11) contributes to regionalize the mouse embryo along its anterior-posterior axis by regulating the expression of Hox genes. The identity of the receptors that mediate GDF11 signalling during embryogenesis remains unclear. Here, we show that GDF11 can interact with type I receptors ALK4, ALK5 and ALK7, but predominantly uses ALK4 and ALK5 to activate a Smad3-dependent reporter gene. Alk5 mutant embryos showed malformations in anterior-posterior patterning, including the lack of expression of the posterior determinant Hoxc10, that resemble defects found in Gdf11-null mutants. A heterozygous mutation in Alk5, but not in Alk4 or Alk7, potentiated Gdf11(-/-)-like phenotypes in vertebral, kidney and palate development in an Acvr2b(-/-) background, indicating a genetic interaction between the two receptor genes. Thus, the transforming growth factor-beta (TGF-beta) receptor ALK5, which until now has only been associated with the biological functions of TGF-beta1 to TGF-beta3 proteins, mediates GDF11 signalling during embryogenesis. PMID:16845371

  3. Depression and diagnosis of neurocognitive impairment in HIV-positive patients.

    PubMed

    Pinheiro, C A T; Souza, L D M; Motta, J V S; Kelbert, E F; Souza, M S; Martins, C S R; Coelho, F M C; Pinheiro, K A T; Pinheiro, R T

    2016-01-01

    Neurocognitive impairment (NCI) is frequently observed in patients infected with human immunodeficiency virus (HIV) and results from the compromise of subcortical brain structures by the virus. The manifestations of NCI range from asymptomatic impairment to dementia. In addition to cognitive impairment resulting from HIV infection, other factors such as depression are associated with the loss of cognitive functions. The aim of this study was to estimate the prevalence of NCI in HIV-positive patients in a city in southern Brazil and to establish possible associations for the prevalence of NCI with HIV-related and other risk factors. This cross-sectional study of HIV-positive outpatients was conducted in a specialized care service in the city of Pelotas in Southern Brazil. Sociodemographic data and HIV-related information were collected, and all patients underwent psychiatric and neurocognitive evaluations. The prevalence of NCI among the 392 patients was 54.1% when tracked using the IHDS (International HIV Dementia Scale) and 36.2% when the IHDS was associated with a battery of complementary tests. A bivariate analysis suggested an association of NCI with gender, age, educational level, depression, current CD4 count and lowest CD4 count. The association of NCI with depression remained in the Poisson regression (PR=1.96, 95%CI=1.12-3.42). The prevalence of cognitive impairment in HIV-positive patients estimated in this study is in accordance with international and Brazilian data. Of the factors analyzed, depression showed the greatest evidence of association with neurocognitive loss. Based on our findings, the inclusion of instruments to evaluate depression in our services for patients with HIV and acquired immunodeficiency syndrome (AIDS) is recommended. PMID:27626305

  4. [Psychotherapy of positive symptoms in the treatment of patients with schizophrenia psychosis].

    PubMed

    Wiedemann, G; Klingberg, S

    2003-01-01

    While the treatment of positive symptoms of patients with schizophrenic psychosis appeared until recently to be solely pharmacotherapeutic, new research findings show the efficacy of cognitive-behavioural psychotherapy (CBT) on positive symptoms in chronic psychotic patients. In addition, the effectiveness even in acute and recent-onset psychosis could be shown in some studies. The effects of CBT and standard care in psychosis compared to standard care alone and to other psychosocial interventions plus standard care are reviewed. The results of several studies and one meta-analysis show that CBT in schizophrenia patients has a direct effect on psychotic symptoms such as hallucinations as well as on relapse prevention. In routine settings,however,CBT has until now only rarely been delivered to these patients. In so-called large pragmatic trials, which might be subsumed as phase IIIb studies, the effects are tested. The therapeutic approach with the components of CBT for psychosis are described: building a therapeutic relationship, cognitive-behavioural coping strategies, developing an understanding of the experience of psychosis,working on hallucinations and delusions, addressing negative self-evaluations, anxiety, and depression,managing risk of relapse and social disability. Further clinical implications are described (capability of learning the therapeutic strategies, deliverability in broader clinical settings, acceptability by patients, combination with atypical neuroleptic drugs,and treatment of choice in risk populations). PMID:12596031

  5. Electromyography of symmetrical trunk movements and trunk position sense in chronic stroke patients

    PubMed Central

    Liao, Chien-Fen; Liaw, Lih-Jiun; Wang, Ray-Yau; Su, Fong-Chin; Hsu, Ar-Tyan

    2015-01-01

    [Purpose] To explore the differences in bilateral trunk muscle activation between chronic stroke patients and healthy controls, this study investigated the symmetry index and cross-correlation of trunk muscles during trunk flexion and extension movements. This study also assessed the differences in trunk reposition error between groups and the association between trunk reposition error and bilateral trunk muscle activation. [Subjects and Methods] Fifteen stroke patients and 15 age- and gender-matched healthy subjects participated. Bilateral trunk muscle activations were collected by electromyography during trunk flexion and extension. Trunk reposition errors in trunk flexion and extension directions were recorded by a Qualisys motion capture system. [Results] Compared with the healthy controls, the stroke patients presented lower symmetrical muscle activation of the bilateral internal oblique and lower cross-correlation of abdominal muscles during trunk flexion, and lower symmetry index and cross-correlation of erector spinae in trunk extension. They also showed a larger trunk extension reposition error. A smaller trunk reposition error was associated with higher cross-correlation of bilateral trunk muscles during trunk movements in all subjects. [Conclusion] Trunk muscle function during symmetrical trunk movements and trunk reposition sense were impaired in the chronic stroke patients, and trunk position sense was associated with trunk muscle functions. Future studies should pay attention to symmetrical trunk movements as well as trunk extension position sense for patients with chronic stroke. PMID:26504267

  6. First-Line Treatment Patterns and Clinical Outcomes in Patients With HER2-Positive and Hormone Receptor-Positive Metastatic Breast Cancer From registHER

    PubMed Central

    Kaufman, Peter A.; Brufsky, Adam M.; Mayer, Musa; Yood, Marianne Ulcickas; Yoo, Bongin; Quah, Cheng; Yardley, Denise; Rugo, Hope S.

    2013-01-01

    Background. Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. Methods. registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. Results. HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89). Conclusions. These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged

  7. Indoor patient position estimation using particle filtering and wireless body area networks.

    PubMed

    Ren, Hongliang; Meng, Max Q H; Xu, Lisheng

    2007-01-01

    Wireless Body Area Network (WBAN) has been recently promoted to monitor the physiological parameters of patient in an unobtrusive and natural way. This paper towards to make advantage of those ongoing wireless communication links between the body sensors to provide estimated position information of patients or particular body area networks, which make daily activity surveillance possible for further analysis. The proposed particle filtering based localization algorithm just picks up the received radio signal strength information from beacons or its neighbors to infer its own pose, which do not require additional hardware or instruments. Theoretical analysis and simulation experiments are presented to examine the performance of location estimating method. PMID:18002445

  8. Bloodstream Infections Are an Improbable Cause of Positive Serum (1,3)-β-d-Glucan in Hematology Patients

    PubMed Central

    Mikulska, M.; Del Bono, V.; Guolo, F.; Minetto, P.; Gobbi, M.; Ghiso, A.; Bacigalupo, A.; Viscoli, C.

    2014-01-01

    Ninety-one serum samples from 51 hematology patients with bacteremia infections were tested for (1,3)-β-d-glucan (BG). Eleven samples (15%) from 7 patients (14%) were positive for BG. Of these 7 patients with positive BG results, 4 (8%) had invasive aspergillosis and 3 (6%) had no invasive fungal disease. Bacteremia was an unlikely cause of the false-positive BG results. PMID:24990906

  9. [Ophthalmic manifestations of toxoplasmosis in a human immunodeficiency virus-positive patient. Description of a case].

    PubMed

    Hermida Pérez, J A; Bermejo Hernandez, Á; Sobenes Gutierrez, R

    2014-03-01

    Toxoplasmosis is an infection of worldwide distribution caused by Toxoplasma gondii, and infects a large proportion of the world population. Only under certain circumstances of severe immunosuppression can the parasite reactivate and cause disease. The most common form of presentation of this pathology in patients with positive HIV is the brain abscess. One of the extra-cerebral forms is toxoplasmic chorioretinitis, which could lead to a chronic active form of a slowly progressive retinitis. Diagnosis is made by observing the eye fundus and confirmed by the scarring obtained after specific treatment. We report a case of a patient with diabetes and positive HIV, in whom a toxoplasmic scar injury was detected in the annual retinography follow-up. A conservative therapeutic approach was decided, with regular check-ups for possible detection of disease activation. PMID:23566559

  10. Novel Alkane Hydroxylase Gene (alkB) Diversity in Sediments Associated with Hydrocarbon Seeps in the Timor Sea, Australia▿

    PubMed Central

    Wasmund, Kenneth; Burns, Kathryn A.; Kurtböke, D. Ipek; Bourne, David G.

    2009-01-01

    Hydrocarbon seeps provide inputs of petroleum hydrocarbons to widespread areas of the Timor Sea. Alkanes constitute the largest proportion of chemical components found in crude oils, and therefore genes involved in the biodegradation of these compounds may act as bioindicators for this ecosystem's response to seepage. To assess alkane biodegradation potential, the diversity and distribution of alkane hydroxylase (alkB) genes in sediments of the Timor Sea were studied. Deduced AlkB protein sequences derived from clone libraries identified sequences only distantly related to previously identified AlkB sequences, suggesting that the Timor Sea maybe a rich reservoir for novel alkane hydroxylase enzymes. Most sequences clustered with AlkB sequences previously identified from marine Gammaproteobacteria though protein sequence identities averaged only 73% (with a range of 60% to 94% sequence identities). AlkB sequence diversity was lower in deep water (>400 m) samples off the continental slope than in shallow water (<100 m) samples on the continental shelf but not significantly different in response to levels of alkanes. Real-time PCR assays targeting Timor Sea alkB genes were designed and used to quantify alkB gene targets. No correlation was found between gene copy numbers and levels of hydrocarbons measured in sediments using sensitive gas chromatography-mass spectrometry techniques, probably due to the very low levels of hydrocarbons found in most sediment samples. Interestingly, however, copy numbers of alkB genes increased substantially in sediments exposed directly to active seepage even though only low or undetectable concentrations of hydrocarbons were measured in these sediments in complementary geochemical analyses due to efficient biodegradation. PMID:19820158

  11. Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy

    PubMed Central

    Cao, Lu; Cai, Gang; Xu, Fei; Yang, Zhao-Zhi; Yu, Xiao-Li; Ma, Jin-Li; Zhang, Qian; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi

    2016-01-01

    Abstract The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2–positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT. Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed. At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor–positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR−/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07–15.35; P = 0.039). Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID:27512838

  12. A software tool of digital tomosynthesis application for patient positioning in radiotherapy.

    PubMed

    Yan, Hui; Dai, Jian-Rong

    2016-01-01

    Digital Tomosynthesis (DTS) is an image modality in reconstructing tomographic images from two-dimensional kV projections covering a narrow scan angles. Comparing with conventional cone-beam CT (CBCT), it requires less time and radiation dose in data acquisition. It is feasible to apply this technique in patient positioning in radiotherapy. To facilitate its clinical application, a software tool was developed and the reconstruction processes were accelerated by graphic process-ing unit (GPU). Two reconstruction and two registration processes are required for DTS application which is different from conventional CBCT application which requires one image reconstruction process and one image registration process. The reconstruction stage consists of productions of two types of DTS. One type of DTS is reconstructed from cone-beam (CB) projections covering a narrow scan angle and is named onboard DTS (ODTS), which represents the real patient position in treatment room. Another type of DTS is reconstructed from digitally reconstructed radiography (DRR) and is named reference DTS (RDTS), which represents the ideal patient position in treatment room. Prior to the reconstruction of RDTS, The DRRs are reconstructed from planning CT using the same acquisition setting of CB projections. The registration stage consists of two matching processes between ODTS and RDTS. The target shift in lateral and longitudinal axes are obtained from the matching between ODTS and RDTS in coronal view, while the target shift in longitudinal and vertical axes are obtained from the matching between ODTS and RDTS in sagittal view. In this software, both DRR and DTS reconstruction algorithms were implemented on GPU environments for acceleration purpose. The comprehensive evaluation of this software tool was performed including geometric accuracy, image quality, registration accuracy, and reconstruction efficiency. The average correlation coefficient between DRR/DTS generated by GPU-based algorithm

  13. Factors Associated With Smoking Status among HIV-Positive Patients in Routine Clinical Care

    PubMed Central

    Zyambo, Cosmas M; Willig, James H; Cropsey, Karen L; Carson, April P; Wilson, Craig; Tamhane, Ashutosh R; Westfall, Andrew O; Burkholder, Greer A

    2015-01-01

    Background Treatment-related reductions in morbidity and mortality among human immunodeficiency virus (HIV)-positive patients have been attenuated by cigarette smoking, which increases risk of cardiovascular, respiratory, and neoplastic diseases. This study investigated factors associated with smoking status among HIV-positive patients. Methods This cross-sectional study included 2,464 HIV-positive patients attending the HIV Clinic at the University of Alabama at Birmingham between April 2008 and December 2013. Smoking status (current, former, never), psychosocial factors, and clinical characteristics were assessed. Multinomial logistic regression was used to obtain unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of the various factors with smoking status. Results Among HIV-positive patients (mean age 45 years, 75% male, 55% African-American), the majority reported a history of smoking (39% current and 22% former smokers). In adjusted models, patient characteristics associated with increased odds of current smoking were male gender (OR for heterosexual men, 1.8 [95% CI: 1.3–2.6]; for men who have sex with men, 1.5 [1.1–1.9]), history of respiratory diseases (1.5 [1.2–1.9]), unsuppressed HIV viral load (>50 copies/mL) (1.5 [1.1–1.9]), depression (1.6 [1.3–2.0]), anxiety (1.6 [1.2–2.1]), and prior and current substance abuse (4.7 [3.6–6.1] and 8.3 [5.3–13.3] respectively). Male gender, anxiety, and substance abuse were also associated with being a former smoker. Conclusions Smoking was common among HIV-positive patients, with several psychosocial factors associated with current and former smoking. This suggests smoking cessation programs in HIV clinic settings may achieve greater impact by integrating interventions that also address illicit substance abuse and mental health. PMID:26767146

  14. Isolated penile Kaposi's sarcoma in a HIV-positive patient stable on treatment for three years.

    PubMed

    Lebari, Dornubari; Gohil, Jesal; Patnaik, Lipsita; Wasef, Wafaa

    2014-07-01

    Kaposi's sarcoma (KS) is an AIDS-defining condition. Typically, KS affects the skin with or without visceral involvement. The extensive use of antiretroviral therapy (ART) has decreased the incidence of KS amongst the HIV-positive population. We report a case of a 40-year-old man with HIV-1 infection with CD4 count of 551 cells/mm(3)and an undetectable viral load who presented with two skin-coloured KS lesions on the prepuce of the penis. Diagnosis was confirmed by histopathology. He had been commenced on ART three years earlier with a nadir CD4 count of 255 cells/mm(3) He had achieved and maintained viral suppression since commencing ART. The patient was initially treated with cryotherapy and 5% imiquimod as the lesions were presumed to be warts. The lack of response to treatment prompted further investigation. We carried out a literature search of published cases of penile KS over the past 10 years. The majority of articles regarding penile KS were published in the pre-ART era and involved patients with AIDS. Over the past 10 years, published cases of penile KS have almost exclusively been in HIV-negative men. We found 10 published cases of penile KS in HIV-negative men and only one other published case of penile KS in a HIV-positive man, who had severe immune suppression with CD4 count below 200 cells/mm(3) This is the first case report to describe a HIV-positive patient stable on ART with a CD4 count above 200 cells/mm(3)and suppressed HIV-1 viral load, to develop two KS lesions on the penis. Clinicians have to remain suspicious of penile lesions and appreciate the crucial role a biopsy with histopathological analysis plays in confirming a diagnosis. In addition, this case illustrates that unusual presentations of KS can still occur in treated HIV-positive patients with sustained immune recovery. PMID:24492851

  15. Genetic Diversity of Pneumocystis carinii Isolated from Human Immunodeficiency Virus-Positive Patients in Turin, Italy

    PubMed Central

    Volpe, Gisella; Sbaiz, Luca; Avanzini, Claudio; Caramello, Pietro; Savoia, Dianella

    2001-01-01

    By DNA sequence analysis we identified two new strain types and five novel sporadic variations among 25 isolates of Pneumocystis carinii f. sp. hominis obtained from 19 human immunodeficiency virus-positive patients. Of these, 13 were infected with a single strain and 6 were coinfected. Fifteen different combination types were identified among the 18 strains for which complete molecular typing was accomplished. PMID:11474032

  16. Positional convulsant syncope in a pacemaker patient following insulation break of the right ventricular lead

    PubMed Central

    Ben Lassoued, Mehdi; Baatour, Makram; Haggui, Abdeddayem; Lamine, Khaled

    2014-01-01

    In spite of the advances made in the technology of pacemakers which resulted in a decrease in the incidence of pacemaker lead fracture, the latter remains a potential complication of implanted pacemakers manufactured in the early days. In this report, we present a case of fracture of the unipolar electrode diagnosed by an emergency physician in a patient on a pacemaker for 10 years who presented to the emergency department with positional convulsant syncopes. PMID:24827652

  17. Diffuse Cerebral Vasculopathy in a HIV-Positive Patient with Recurrent Strokes.

    PubMed

    Kao, Hung-Wen; Chen, Cheng-Yu; Hsueh, Chun-Jen; Lo, Chung-Ping; Juan, Chun-Jung; Chang, Wei-Chou; Huang, Guo-Shu

    2008-02-18

    The causes of ischemic stroke in the young adult are diverse. Human immunodeficiency virus (HIV) infection-related vasculopathy is usually not included in the list of differential diagnoses. HIV-positive patients may present with acute neurologic dysfunction of different causes, among which cerebral infarction is an uncommon one. Herein, we report a HIV-infected young man who suffered from recurrent ischemic strokes with evidence of cerebral vasculopathy on serial magnetic resonance images. PMID:24256749

  18. Patients Respond More Positively to Physicians Who Focus on Their Ideal Affect

    PubMed Central

    Sims, Tamara; Tsai, Jeanne L.

    2014-01-01

    Previous findings suggest that patients choose physicians whose affective focus matches how they ideally want to feel (Sims et al., 2014). For instance, the more people wanted to feel excitement, the more likely they were to hypothetically choose a new physician who promoted excitement. What remains unknown is whether this match shapes how patients actually respond to physicians after being assigned to them (i.e., whether they adhere to physicians’ recommendations more and evaluate physicians more positively). To this end, community adults reported their global ideal affect and actual affect (how they ideally want to feel and actually feel during a typical week, respectively), and were randomly assigned to receive health recommendations from either a physician who expressed and promoted high arousal positive states (HAP) (e.g., excitement), or one who expressed and promoted low arousal positive states (LAP) (e.g., calm). For the next five days, participants reported their daily adherence to the recommendations and their daily ideal and actual affect. At the end of the week, participants evaluated their physician. As predicted, the more participants wanted to feel HAP, the more they adhered to the “HAP-focused” physician’s recommendations, and the more participants wanted to feel LAP, the more they adhered to the “LAP-focused” physician’s recommendations. Participants also evaluated their physician more positively when his affective focus matched their ideal affect. Neither global nor daily actual affect systematically predicted how patients responded to their physicians. These findings suggest that patients respond better to physicians whose affective focus matches their ideal affect. PMID:25313670

  19. False-positive indium-111 labeled leukocyte scintigram in a patient with a painful hip prosthesis

    SciTech Connect

    Feldman, N.; Makler, P.T. Jr.; Alavi, A.

    1986-01-01

    A Tronzo hip prosthesis is designed to elicit an inflammatory reaction in order to promote prosthesis stability. A three-phased bone scan and Ga-67 imaging in conjunction with physical examination and laboratory findings failed to demonstrate evidence for osteomyelitis in a patient with a painful hip prosthesis, in whom images obtained with In-111-labeled leukocytes were positive. This observation demonstrated that the interpretation of the latter technique in demonstrating inflammation can cause a false impression of an infectious process.

  20. Positional convulsant syncope in a pacemaker patient following insulation break of the right ventricular lead.

    PubMed

    Ben Lassoued, Mehdi; Baatour, Makram; Haggui, Abdeddayem; Lamine, Khaled

    2014-01-01

    In spite of the advances made in the technology of pacemakers which resulted in a decrease in the incidence of pacemaker lead fracture, the latter remains a potential complication of implanted pacemakers manufactured in the early days. In this report, we present a case of fracture of the unipolar electrode diagnosed by an emergency physician in a patient on a pacemaker for 10 years who presented to the emergency department with positional convulsant syncopes. PMID:24827652

  1. Psychometric Evaluation of the Fear of Positive Evaluation Scale in Patients With Social Anxiety Disorder

    PubMed Central

    Weeks, Justin W.; Heimberg, Richard G.; Rodebaugh, Thomas L.; Goldin, Philippe R.; Gross, James J.

    2014-01-01

    The Fear of Positive Evaluation Scale (FPES; Weeks, Heimberg, & Rodebaugh, 2008) was designed to assess fear of positive evaluation, a proposed cognitive component of social anxiety. Although previous findings on the psychometric properties of the FPES have been highly encouraging, only one previous study has examined the psychometric profile of the FPES in a sample of patients with social anxiety disorder (Fergus et al., 2009). The primary purpose of the present study was to conduct a large multi-site examination of the psychometric profile of the FPES among patients with a principal diagnosis of social anxiety disorder (n = 226; generalized subtype: 97.8%). Responses of non-anxious control participants (n = 42) were also examined. The factorial validity, internal consistency, test-retest reliability, construct validity, and treatment sensitivity of the FPES were strongly supported by our findings. Furthermore, an FPES cutoff score was identified for distinguishing levels of fear of positive evaluation characteristic of patients with social anxiety disorder from those characteristic of the control group. Results provide additional support for the psychometric properties of the FPES in clinical samples. PMID:21966932

  2. Assessment of interfractional prostate motion in patients immobilized in the prone position using a thermoplastic shell

    PubMed Central

    Ikeda, Itaru; Mizowaki, Takashi; Sawada, Yohei; Nakata, Manabu; Norihisa, Yoshiki; Ogura, Masakazu; Hiraoka, Masahiro

    2014-01-01

    The aim of this study was to evaluate the interfractional prostate motion of patients immobilized in the prone position using a thermoplastic shell. A total of 24 patients with prostate calcifications detectable using a kilo-voltage X-ray image-guidance system (ExacTrac X-ray system) were examined. Daily displacements of the calcification within the prostate relative to pelvic bony structures were calculated by the ExacTrac X-ray system. The average displacement and standard deviation (SD) in each of the left–right (LR), anterior–posterior (AP), and superior–inferior (SI) directions were calculated for each patient. Based on the results of interfractional prostate motion, we also calculated planning target volume (PTV) margins using the van Herk formula and examined the validity of the PTV margin of our institute (a 9-mm margin everywhere except posteriorly, where a 6-mm margin was applied). In total, 899 data measurements from 24 patients were obtained. The average prostate displacements ± SD relative to bony structures were 2.8 ± 3.3, −2.0 ± 2.0 and 0.2 ± 0.4 mm, in the SI, AP and LR directions, respectively. The required PTV margins were 9.7, 6.1 and 1.4 mm in the SI, AP and LR directions, respectively. The clinical target volumes of 21 patients (87.5%) were located within the PTV for 90% or more of all treatment sessions. Interfractional prostate motion in the prone position with a thermoplastic shell was equivalent to that reported for the supine position. The PTV margin of our institute is considered appropriate for alignment, based on bony structures. PMID:23860549

  3. Inter- and Intrafractional Positional Uncertainties in Pediatric Radiotherapy Patients With Brain and Head and Neck Tumors

    SciTech Connect

    Beltran, Chris; Krasin, Matthew J.; Merchant, Thomas E.

    2011-03-15

    Purpose: To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies. Methods: Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board-approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds. Results: The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively. Conclusion: On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU.

  4. Novel Approach to Simulate Sleep Apnea Patients for Evaluating Positive Pressure Therapy Devices

    PubMed Central

    Isetta, Valentina; Montserrat, Josep M.; Santano, Raquel; Wimms, Alison J.; Ramanan, Dinesh; Woehrle, Holger; Navajas, Daniel; Farré, Ramon

    2016-01-01

    Bench testing is a useful method to characterize the response of different automatic positive airway pressure (APAP) devices under well-controlled conditions. However, previous models did not consider the diversity of obstructive sleep apnea (OSA) patients’ characteristics and phenotypes. The objective of this proof-of-concept study was to design a new bench test for realistically simulating an OSA patient’s night, and to implement a one-night example of a typical female phenotype for comparing responses to several currently-available APAP devices. We developed a novel approach aimed at replicating a typical night of sleep which includes different disturbed breathing events, disease severities, sleep/wake phases, body postures and respiratory artefacts. The simulated female OSA patient example that we implemented included periods of wake, light sleep and deep sleep with positional changes and was connected to ten different APAP devices. Flow and pressure readings were recorded; each device was tested twice. The new approach for simulating female OSA patients effectively combined a wide variety of disturbed breathing patterns to mimic the response of a predefined patient type. There were marked differences in response between devices; only three were able to overcome flow limitation to normalize breathing, and only five devices were associated with a residual apnea-hypopnea index of <5/h. In conclusion, bench tests can be designed to simulate specific patient characteristics, and typical stages of sleep, body position, and wake. Each APAP device behaved differently when exposed to this controlled model of a female OSA patient, and should lead to further understanding of OSA treatment. PMID:26978077

  5. [Strengthening the patients' position--a new challenge to public health].

    PubMed

    Jäger, H

    1999-06-01

    Prevention and health promotion are well-established strategies to reduce the demand for health care. Nevertheless efforts to encourage the empowerment of consumers vis-à-vis the providers of health-care are relatively new in Germany. Programmes intended to improve a person's level of confidence in dealing with chronic illness have been shown to lower costs. The potential for reducing demand for unnecessary interventions may save money and increase the quality of provided health care. The views of consumers and their personal experiences are crucial in establishing a more effective quality management in the German health care system in Germany. At present patients are not always sufficiently involved in the process of clinical decision-making and often their knowledge does not enable them to assess the quality of services rendered. In comparison with other European countries the position of German patients is rather weak. The backing of patients' interests by insurance companies is more developed in Belgium, self-organisation of patients is established in Switzerland and, with strong government support, in the Netherlands (Kranich, 1997). However in Germany there is now growing interest in providing support for patients' participation in the choice of treatment, quality of health care and decision-making strategies for health problem management. The German Ministry of Health is currently working on a Patients' Charter to guarantee patients' rights. The Public Health Service could play its role in representing patients' interests more intensively. Health-insurance companies could concentrate more on educating the consumer in order to encourage better informed decisions and to reduce the frequency of unnecessary health care procedures. The benefits yielded by self-management of health problems (not to be confused with self-treatment), of chronic disease or disability are well-documented and may ultimately even lower medical costs. In this article, various approaches

  6. Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism.

    PubMed

    Umakoshi, Hironobu; Naruse, Mitsuhide; Wada, Norio; Ichijo, Takamasa; Kamemura, Kohei; Matsuda, Yuichi; Fujii, Yuichi; Kai, Tatsuya; Fukuoka, Tomikazu; Sakamoto, Ryuichi; Ogo, Atsushi; Suzuki, Tomoko; Nanba, Kazutaka; Tsuiki, Mika

    2016-05-01

    Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per μg/dL;P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA. PMID:26975712

  7. "Intrinsic" positive end-expiratory pressure in stable patients with chronic obstructive pulmonary disease.

    PubMed

    Dal Vecchio, L; Polese, G; Poggi, R; Rossi, A

    1990-01-01

    We have assessed "intrinsic" positive end-expiratory pressure (PEEPi), during quiet breathing in 18 patients with chronic obstructive pulmonary disease (COPD) in stable condition. Ventilatory flow, lung volume, oesophageal (Poes), gastric (Pga), and transdiaphragmatic pressure (Pdi) were measured. PEEPi was measured as the pressure difference (delta Poes) between the onset of the inspiratory effort, indicated by the start of the Pdi swing, and the point corresponding to zero flow. PEEPi was present in all of the 18 COPD patients, and averaged 2.4 +/- 1.6 cmH2O. The maximum transdiaphragmatic pressure (Pdi,max) was also measured and averaged 81.5 +/- 17.4 cmH2O. Following a randomized sequence, ten patients then inhaled an adrenergic agonist (fenoterol 1.6 mg), and eight patients the corresponding placebo. Fenoterol, but not placebo, caused a significant increase in forced expiratory volume in one second (FEV1) (+34%, on average), associated with a significant decrease in PEEPi (-63%, on average) and a significant improvement in Pdi,max (+19%, on average). We conclude that: 1) intrinsic PEEP can be present in stable COPD patients due to increased airflow resistance; 2) fenoterol improved diaphragmatic strength (Pdi,max) in our COPD patients, possibly due to a decrease in lung volume. PMID:2178961

  8. Right iliac fossa lymphoma in an HIV positive patient: A diagnostic dilemma

    PubMed Central

    Sinnott, Joseph; Natin, Danial; Foster, Paul

    2016-01-01

    Lymphoma should be considered early in patients with HIV when there is a history of weight loss. Although B-cell lymphoma is an AIDS-defining cancer, and many reports of lymphoma in HIV positive patients exist in the literature, this case report illustrates that even in patients with well-controlled HIV the diagnosis must be considered, and puts forward an unusual presentation in an otherwise asymptomatic patient. A 52 year old woman presented for a routine HIV follow-up appointment and was found to be experiencing weight loss. An abdominal examination revealed a right iliac fossa mass. Subsequent CT thorax, abdomen, pelvis imaging confirmed a large mass but did not allow determination of the primary source. Serological tumour marker investigations were unyielding. Trans-vaginal ultrasound guided biopsy of the mass demonstrated diffuse large B-cell lymphoma. This case report emphasises the importance of having a high index of suspicion for these cancers even in patients with low viral load who are on anti-retroviral treatment. It also demonstrates the importance of taking a multidisciplinary approach to diagnosis of the condition to enable prompt treatment and thus improve the outcome for the patient. PMID:26971281

  9. Herbal product use in non-HIV and HIV-positive Hispanic patients.

    PubMed Central

    Rivera, José O.; González-Stuart, Armando; Ortiz, Melchor; Rodríguez, José C.; Anaya, Jaime P.; Meza, Armando

    2005-01-01

    PURPOSE: The primary endpoint of this study was to determine the prevalence of herbal product use by a sample of Mexican-American patients in the El Paso, TX region. Even though medicinal plants are popularly assumed to be a safe and natural alternative to conventional medications, some herbal products may pose a potential health risk to the consumer. Currently, there are few studies related to herbal use by Mexican Americans and none in HIV patients living on the U.S./México border. METHODS: A prospective observational study was conducted in hospitals and clinics throughout the El Paso region area. A semistructured interview was conducted by trained bilingual interviewers. A 45-item bilingual questionnaire was used to collect the information. RESULTS: A total of 439 non-HIV patients as well as 35 patients afflicted with HIV participated in the study. Seventy-nine percent (347/439) of non-HIV and 71% (25/35) of HIV patients reported using herbal products. The percentages of herbal use among the two groups did not show any statistically significant differences (p=0.29), and both groups reflected that herbal products are commonly used. CONCLUSIONS: The use of herbal products was very common among non-HIV (79%) and HIV-positive (71%) Mexican-Americans patients in the El Paso region. PMID:16396061

  10. An interesting case of 'diabetic foot ulcer' in an HIV-positive patient.

    PubMed

    Sivaprakasam, Venkat; Chima-Okereke, Catherine

    2015-03-01

    Kaposi sarcoma is a highly vascularised tumour affecting the skin, lymph nodes and viscera. Kaposi sarcoma is most common in HIV-infected homosexual or bisexual men. We present here a 70-year-old white British male patient, who was under the care of the podiatric team for longstanding 'diabetic foot ulcers'. He was later referred to the Dermatology team who took a biopsy; this revealed features of Kaposi sarcoma which prompted an HIV test which was positive. This patient had previously presented to several healthcare professionals with symptoms suggestive of HIV infection. He was started on antiretroviral therapy and the HIV and human herpesvirus-8 viral loads became undetectable in the blood within weeks and he showed significant clinical improvement. This case report is a reminder to clinicians to have a high index of suspicion in patients presenting with symptoms and signs suggestive of HIV infection. PMID:24841196

  11. SU-E-J-21: Setup Variability of Colorectal Cancer Patients Treated in the Prone Position and Dosimetric Comparison with the Supine Position

    SciTech Connect

    Kim, A; Foster, J; Chu, W; Karotki, A

    2015-06-15

    Purpose: Many cancer centers treat colorectal patients in the prone position on a belly board to minimize dose to the small bowel. That may potentially Result in patient setup instability with corresponding impact on dose delivery accuracy for highly conformal techniques such as IMRT/VMAT. Two aims of this work are 1) to investigate setup accuracy of rectum patients treated in the prone position on a belly board using CBCT and 2) to evaluate dosimetric impact on bladder and small bowel of treating rectum patients in supine vs. prone position. Methods: For the setup accuracy study, 10 patients were selected. Weekly CBCTs were acquired and matched to bone. The CBCT-determined shifts were recorded. For the dosimetric study, 7 prone-setup patients and 7 supine-setup patients were randomly selected from our clinical database. Various clinically relevant dose volume histogram values were recorded for the small bowel and bladder. Results: The CBCT-determined rotational shifts had a wide variation. For the dataset acquired at the time of this writing, the ranges of rotational setup errors for pitch, roll, and yaw were [−3.6° 4.7°], [−4.3° 3.2°], and [−1.4° 1.4°]. For the dosimetric study: the small bowel V(45Gy) and mean dose for the prone position was 5.6±12.1% and 18.4±6.2Gy (ranges indicate standard deviations); for the supine position the corresponding dose values were 12.9±15.8% and 24.7±8.8Gy. For the bladder, the V(30Gy) and mean dose for prone position were 68.7±12.7% and 38.4±3.3Gy; for supine position these dose values were 77.1±13.7% and 40.7±3.1Gy. Conclusion: There is evidence of significant rotational instability in the prone position. The OAR dosimetry study indicates that there are some patients that may still benefit from the prone position, though many patients can be safely treated supine.

  12. The Role of Positive Personality Traits in Emotion Regulation of Patients with Irritable Bowel Syndrome (IBS)

    PubMed Central

    MAZAHERI, Mina; NIKNESHAN, Shekoufeh; DAGHAGHZADEH, Hamed; AFSHAR, Hamid

    2015-01-01

    Background: Personality traits and emotion regulation processes play an important role in human health. The purpose of this study was to investigate the role of positive personality traits (psychological hardiness and interpersonal forgiveness) in emotion regulation of patients with Irritable Bowel Syndrome. Methods: The research was a cross-sectional study. Statistical population included all of IBS patients referred to the Subspecialty Center of Psychiatry in Isfahan in 2013. Overall, 123 subjects (100 women, 83.3%, and 30 men, 16.7%) were selected by census method, according to criteria of research and during a particular period. To collect data, the Difficulties in Emotion Regulation Scale (DERS), Lang and Goulet Hardiness Scale (LGHS) and Interpersonal forgiveness Inventory (IFI) were used. Data was analyzed using Pearson’s correlation coefficient and Multivariate and Binary Logistic regression analyses. Results: Mean age of patients was 33.82±10.45 years and 83.3% (100) of them were female. Regression analyses showed that both personality traits of hardiness and forgiveness were as protective factors for emotional dysregulation with OR, 95% CI: 0.93 and 0.96 sequentially, with adjusting demographic variables (age, gender, and education level and disease duration). Conclusion: Patients who are more hardy and forgiving toward others, are likely more successful at adaptive emotion regulation. It emphasizes the positive and beneficial role of the personality traits in regulating of emotional problems of IBS patients. Hence, these variables should be considered as effective factors in the treatment process of the patients. PMID:26056675

  13. A comparative study on the CT effective dose for various positions of the patient's arm

    NASA Astrophysics Data System (ADS)

    Seong, Ji-Hye; Park, Soon-Ki; Kim, Jung-Sun; Jung, Woo-Young; Kim, Ho-Sung; Dong, Kyung-Rae; Chung, Woon-Kwan; Cho, Jae-Hwan; Cho, Young-Kuk

    2012-10-01

    In a whole body PET/CT (positron emission tomography/computed tomography) scan, lifting the patient's arm to improve the image quality is natural. On the other hand, the arms should be placed lower when the lesion is located in the head and neck. This study compared the CT effective dose for each arm position after applying AEC (automatic exposure control). Forty-five patients who had undergone an 18F-FDG (fluorine-18-fluoro deoxy glucose) whole body PET/CT scan were examined using Biograph Truepoint 40, Biograph Sensation 16, and Discovery STe 8 systems. The CT effective dose of 15 patients for each set of equipment was measured and analyzed comparatively in both the arm-lifted and arm-lowered positions. The ImPACT Ver. 1.0 program was used to measure the CT effective dose. A paired t-test (SPSS 18.0 statistic program) was applied for statistical analysis. In the case of the arm-lifted position, the CT effective dose measured for Biograph 40, Biograph 16, and DSTe 8 systems were 6.33 ± 0.93 mSv, 8.01 ± 1.34 mSv, and 9.69 ± 2.32 mSv, respectively. When the arms were located in the lower position, the respective CT effective doses were 6.97 ± 0.76 mSv, 8.95 ± 1.85 mSv, and 13.07 ± 2.87 mSv, respectively. These results revealed 9.2%, 10.5%, and 25.9% improvement in the CT effective doses for the Biograph 40, Biograph 16 and DSTe 8 systems, respectively, when the arms were raised compared to that when they were lowered (p < 0.05). For the whole body PET/CT case, the CT effective dose applying AEC showed a mean 15.2% decrease in the radiation exposure of the patients when the arm was lifted. The patient with no lesion in the head and neck would show fewer artifacts in the objective part and a lower CT effective dose. For a patient with a lesion in the head and neck, the artifacts in the objective part can be reduced by putting the arms down. The fact that the CT effective dose is increased in a whole-body PET/CT scan should be a concern.

  14. A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer

    ClinicalTrials.gov

    2016-08-30

    Non-Small Cell Lung Cancer (ALK-positive); Non-Small Cell Lung Cancer (c-Met Dependent); Non-Small Cell Lung Cancer (ROS Marker Positive); Systemic Anaplastic Large-Cell Lymphoma; Advanced Malignancies (Except Leukemia)

  15. Dihydropteroate synthase gene mutation rates in Pneumocystis jirovecii strains obtained from Iranian HIV-positive and non-HIV-positive patients.

    PubMed

    Sheikholeslami, Maryam-Fatemeh; Sadraei, Javid; Farnia, Parisa; Forozandeh Moghadam, Mehdi; Emadikochak, Hamid

    2015-05-01

    The dihydropteroate sulfate (DHPS) gene is associated with resistance to sulfa/sulfone drugs in Pneumocystis jirovecii. We investigated the DHPS mutation rate in three groups of Iranian HIV-positive and HIV-negative patients by polymerase chain reaction-restricted fragment length polymorphism analysis. Furthermore, an association between P. jirovecii DHPS mutations and strain typing was investigated based on direct sequencing of internal transcribed spacer region 1 (ITS1) and ITS2. The overall P. jirovecii DHPS mutation rate was (5/34; 14.7%), the lowest rate identified was in HIV-positive patients (1/16; 6.25%) and the highest rate was in malignancies patients (3/11; 27.3%). A moderate rate of mutation was detected in chronic obstructive pulmonary disease (COPD) patients (1/7; 14.3%). Most of the isolates were wild type (29/34; 85.3%). Double mutations in DHPS were detected in patients with malignancies, whereas single mutations at codons 55 and 57 were identified in the HIV-positive and COPD patients, respectively. In this study, two new and rare haplotypes were identified with DHPS mutations. Additionally, a positive relationship between P. jirovecii strain genotypes and DHPS mutations was identified. In contrast, no DHPS mutations were detected in the predominant (Eg) haplotype. This should be regarded as a warning of an increasing incidence of drug-resistant P. jirovecii strains. PMID:25631478

  16. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review

    PubMed Central

    2013-01-01

    Abstract Inflammatory myofibroblastic tumors (IMTs) are categorized as intermediate biologic neoplasms, whereas IMTs with genetic features of ran-binding protein 2 (RANBP2) and anaplastic lymphoma kinase (ALK) rearrangement (IMT-RAs) are possibly related to a more aggressive clinical course. However, fewer than 10 cases of IMT-RA have been reported to date. Herein, we present 2 new cases of IMT-RA in which both tumors recurred quickly after primary surgery; one patient died 3 months later from the disease, and the other patient has been living with the disease for 12 months. IMT-RAs are characterized by noncohesive epithelioid and rounded tumoral cell morphology, commonly derived from pelvic and peritoneal cavities, and frequently show larger tumor sizes. The relation between the clinicopathologic features and poor prognosis of IMT-RA is discussed. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3314123381007714 PMID:24034896

  17. Association of alveolar recruitment maneuvers and prone position in acute respiratory disease syndrome patients.

    PubMed

    Costa, Daniela Caetano; Rocha, Eduardo; Ribeiro, Tatiane Flores

    2009-06-01

    The acute respiratory distress syndrome is the clinical presentation of acute lung injury characterized by diffuse alveolar damage and development of non-cardiogenic pulmonary edema due to increased pulmonary alveolar-capillary membrane permeability. Alveolar recruitment maneuvers and prone position can be used in the treatment of acute respiratory distress syndrome. The objective of this review of literature was to identify possible benefits, indications, complications and care of the associated recruitment maneuvers and prone position for treatment of the acute respiratory distress syndrome. This national and international scientific literature review was developed according to the established criteria for searching the databases MedLine, LILACS, SciElo, PubMed, Cochrane, from 1994 to 2008 in Portuguese and English, with the key words: acute respiratory distress syndrome, alveolar recruitment maneuver and prone position. Despite advances in the understanding of acute respiratory distress syndrome pathophysiology, mortality is still expressive. Alveolar recruitment maneuvers and prone position significantly contribute to treatment of acute respiratory distress syndrome patient aiming to improve oxygenation and minimizing complications of refractory hypoxemia and reduction of pulmonary compliance. However,as there are few studies in literature associating alveolar recruitment maneuvers and prone position for treatment of acute respiratory distress syndrome, additional research and evidences of clinical application are required. PMID:25303351

  18. Nonvolatile S-alk(en)ylthio-L-cysteine derivatives in fresh onion (Allium cepa L. cultivar).

    PubMed

    Starkenmann, Christian; Niclass, Yvan; Troccaz, Myriam

    2011-09-14

    The L-cysteine derivatives (R)-2-amino-3-(methyldisulfanyl)propanoic acid (S-methylthio-L-cysteine), (R)-2-amino-3-(propyldisulfanyl)propanoic acid (S-propylthio-L-cysteine), (R)-2-amino-3-(1-propenyldisulfanyl)propanoic acid (S-(1-propenylthio)-L-cysteine), and (R)-2-amino-3-(2-propenyldisulfanyl)propanoic acid (S-allylthio-L-cysteine) were prepared from 3-[(methoxycarbonyl)dithio]-L-alanine, obtained from the reaction of L-cysteine with methoxycarbonylsulfenyl chloride. The occurrence of these S-(+)-alk(en)ylthio-L-cysteine derivatives in onion (Allium cepa L.) was proven by using UPLC-MS-ESI(+) in SRM mode. Their concentrations in fresh onion were estimated to be 0.19 mg/kg S-methylthio-L-cysteine, 0.01 mg/kg S-propylthio-L-cysteine, and 0.56 mg/kg (S-(1-propenyllthio)-L-cysteine, concentrations that are about 3000 times lower than that of isoalliin (S-(1-propenyl-S-oxo-L-cysteine). These compounds were treated with Fusobacterium nucleatum, a microorganism responsible for the formation of mouth malodor. These L-cysteine disulfides were demonstrated to predominantly produce tri- and tetrasulfides. Isoalliin is almost entirely consumed by the plant enzyme alliin lyase (EC 4.4.1.4 S-alk(en)yl-S-oxo-L-cysteine lyase) in a few seconds, but it is not transformed by F. nucleatum. This example of flavor modulation shows that the plant produces different precursors, leading to the formation of the same types of volatile sulfur compounds. Whereas the plant enzyme efficiently transforms S-alk(en)yl-S-oxo-L-cysteine, mouth bacteria are responsible for the transformation of S-alk(en)ylthio-L-cysteine. PMID:21854077

  19. Regulation of the ALK1 ligands, BMP9 and BMP10.

    PubMed

    Li, Wei; Salmon, Richard M; Jiang, He; Morrell, Nicholas W

    2016-08-15

    Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies. PMID:27528761

  20. ALK5-dependent TGF-β signaling is a major determinant of late stage adult neurogenesis

    PubMed Central

    He, Yingbo; Zhang, Hui; Yung, Andrea; Villeda, Saul A; Jaeger, Philipp A; Olayiwola, Oluwatobi; Fainberg, Nina; Wyss-Coray, Tony

    2014-01-01

    The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in central nervous system (CNS) development, but apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration, and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a striking increase in these aspects of neurogenesis and was associated with higher expression of c-fos in newborn neurons and with stronger memory function. Our findings describe a new and unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis which may have implications for changes in neurogenesis during aging and disease. PMID:24859199

  1. Quantitative determination of S-alk(en)ylcysteine-S-oxides by micellar electrokinetic capillary chromatography.

    PubMed

    Kubec, Roman; Dadáková, Eva

    2008-11-28

    A novel method for determination of S-alk(en)ylcysteine-S-oxides by capillary electrophoresis has been developed and validated. The method is based on extraction of these sulfur amino acids by methanol, their derivatization by fluorenylmethyl chloroformate and subsequent separation by micellar electrokinetic capillary chromatography. Main advantages of the new method are simplicity, sensitivity, high specificity and very low running costs, making it suitable for routine analysis of a large number of samples. Employing this method, the content of S-alk(en)ylcysteine-S-oxides was determined in 12 commonly consumed alliaceous and cruciferous vegetables (e.g. garlic, onion, leek, chive, cabbage, radish, cauliflower and broccoli). The total content of these amino acids in the Allium species evaluated varied between 0.59 and 12.3mg g(-1) fresh weight. Whereas alliin was found only in garlic, isoalliin was the major S-alk(en)ylcysteine-S-oxide in onion, leek, chive and shallot. On the other hand, the cruciferous species analyzed contained only methiin in the range of 0.06-2.45mg g(-1) fresh weight. PMID:18952220

  2. Structure of Escherichia coli AlkA in Complex with Undamaged DNA

    SciTech Connect

    Bowman, Brian R.; Lee, Seongmin; Wang, Shuyu; Verdine, Gregory L

    2010-11-22

    Because DNA damage is so rare, DNA glycosylases interact for the most part with undamaged DNA. Whereas the structural basis for recognition of DNA lesions by glycosylases has been studied extensively, less is known about the nature of the interaction between these proteins and undamaged DNA. Here we report the crystal structures of the DNA glycosylase AlkA in complex with undamaged DNA. The structures revealed a recognition mode in which the DNA is nearly straight, with no amino acid side chains inserted into the duplex, and the target base pair is fully intrahelical. A comparison of the present structures with that of AlkA recognizing an extrahelical lesion revealed conformational changes in both the DNA and protein as the glycosylase transitions from the interrogation of undamaged DNA to catalysis of nucleobase excision. Modeling studies with the cytotoxic lesion 3-methyladenine and accompanying biochemical experiments suggested that AlkA actively interrogates the minor groove of the DNA while probing for the presence of lesions.

  3. Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma.

    PubMed

    Ohnishi, Koji; Yamaguchi, Munekage; Erdenebaatar, Chimeddulam; Saito, Fumitaka; Tashiro, Hironori; Katabuchi, Hidetaka; Takeya, Motohiro; Komohara, Yoshihiro

    2016-06-01

    Lymph node (LN) macrophages play critical roles in anti-tumor immunity, which develops via the activation of cytotoxic T cells (CTL) and NK cells. The present study aims to determine the prognostic significance of CD169(+) LN macrophages in patients with endometrial carcinoma (EC). The number of CD169(+) cells or the CD169(+) -to-CD68(+) macrophage ratio in regional LN (RLN), and the number of CD8(+) CTL or CD57(+) NK cells in tumor tissues were investigated by immunohistochemistry in paraffin-embedded tissue samples from 79 patients with EC. A high density of CD169(+) cells in the RLN of patients with EC was correlated with an early clinical stage or no LN metastasis. A high number of CD169(+) cells and a high CD169(+) -to-CD68(+) macrophage ratio were significantly associated with longer overall survival in EC. We also found that the density of CD169(+) macrophages was positively correlated with the number of CD8(+) CTL and CD57(+) NK cells that infiltrated into tumor tissues. A high density of CD57(+) cells in EC tissues was associated with a better prognosis, while a high density of CD8(+) cells was not linked to an altered prognosis. The present study showed that the density of CD169(+) macrophages in RLN was associated with an improved prognosis in EC patients. CD169(+) macrophages in RLN might represent a useful marker for assessing clinical prognoses and monitoring anti-tumor immunity in patients with EC. PMID:26991548

  4. Pattern of mucocutaneous manifestations in human immunodeficiency virus-positive patients in North India

    PubMed Central

    Kore, Sachin D.; Kanwar, Amrinder J.; Vinay, Keshavamurthy; Wanchu, Ajay

    2013-01-01

    Background: Mucocutaneous diseases are among the first-recognized clinical manifestations of acquired immune deficiency syndrome. They function as visual markers in assessing the progression of human immunodeficiency virus (HIV) infection. Given the relative ease of examination of skin, its evaluation remains an important tool in the diagnosis of HIV infection. Objective: To determine the pattern of mucocutaneous manifestations in HIV-positive patients and to correlate their presence with CD4 counts. Materials and Methods: This cross-sectional study included 352 HIV-infected patients seen at PGIMER, Chandigarh, India, over a period of 1 year. The patients were screened for mucocutaneous disorders by an experienced dermatologist. The patients were classified into different stages according to the World Health Organization clinical and immunological staging system. Results: The most prevalent infection was candidiasis, seen in 57 patients (16.2%). Prevalence of candidiasis, dermatophytosis, herpes simplex, herpes zoster, molluscum contagiosum (MC), seborrheic dermatitis, adverse drug reaction, nail pigmentation, xerosis and diffuse hair loss differed statistically according to the clinical stages of HIV infection. There was a statistically significant association between immunological stages of HIV infection and dermatophytosis. Conclusion: Results of our study suggest that mucocutaneous findings occur throughout the course of HIV infection. Dermatoses like MC and dermatophytosis show an inverse relation with CD4 cell count, and these dermatoses can be used as a proxy indicator of advanced immunosuppression to start highly active anti-retroviral therapy in the absence of facilities to carry out CD4 cell count. PMID:23919050

  5. Tailored chemotherapy based on tumour gene expression analysis: breast cancer patients' misinterpretations and positive attitudes.

    PubMed

    Pellegrini, I; Rapti, M; Extra, J-M; Petri-Cal, A; Apostolidis, T; Ferrero, J-M; Bachelot, T; Viens, P; Julian-Reynier, C; Bertucci, F

    2012-03-01

    The aim of this study was to document how breast cancer patients perceive their prognosis and a tailored treatment based on tumour gene expression analysis, and to identify the features of this approach that may impact its clinical application. In-depth interviews were conducted at three French cancer centres with 37 women (35-69 years of age) with node-positive breast cancer undergoing an adjuvant chemotherapy regimen defined on the basis of the genomic signature predicting the outcome after chemotherapy. Several concerns were identified. First, some misconceptions about these methods were identified due to semantic confusions between the terms 'genomic' and 'genetic', which generated anxiety and uncertainty about the future. Second, the 'not done' and 'not interpretable' signatures were misinterpreted by the women and associated with highly negative connotations. However, the use of tumour genomic analysis to adapt the treatment to each patient received most of the patients' approval because it was perceived as an approach facilitating personalised medicine. In conclusion, improving the quality of provider/patient communications should enable patients to play a more active part in the decision making about their treatment. This will ensure that those who agree to have tumour gene analysis have realistic expectations and sound deductions about the final result disclosure process. PMID:22070677

  6. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    PubMed

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients. PMID:27178335

  7. Continuous Positive Airway Pressure Compliance in Patients with Obstructive Sleep Apnea

    PubMed Central

    Afsharpaiman, Shahla; Vahedi, Encieh; Aqaee, Hossein

    2016-01-01

    Background: Obstructive sleep apnea (OSA) is a common condition in adults. In most cases, first-line therapy includes treatment with positive airway pressure devices. However, because of discomfort, continuous positive airway pressure (CPAP) compliance is often poor. To determine the willingness of patients to use CPAP device, the relationship of demographic and polysomnographic variables with tolerance and the willingness to use CPAP, was evaluated. Materials and Methods: In this cross-sectional study, 120 OSA patients who were treated with CPAP in Baqiyatallah Hospital, Tehran, Iran, were selected by convenience sampling. Polysomnographic variables, willingness to use CPAP for short and long periods of time and possible complications were evaluated. Results: One hundred-twenty cases with a mean age of 53±10.3 years were assessed. The mean Epworth Sleepiness Scale (ESS) score was 11.9 ± 6.2 in CPAP users versus 11.8±6.1 in patients who did not use CPAP. The willingness to use CPAP for short-term was significantly different between the two groups (P=0.008). The average minimum oxygen saturation rate of patients was 75.21% in CPAP users versus 71.63% in non CPAP users. Also, the average desaturation index was higher in CPAP users (54.5 vs. 44.98). The mean ESS was 14.03 ± 6.19 in those who accepted long-term treatment versus 8.85 ± 4.89 (P=0.003). Skin wounds and rhinitis were reported in 4.1% and 4.1% of patients, respectively. Conclusion: It is concluded that high CPAP compliance rates are achievable through comprehensive CPAP therapy.

  8. Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients: A pilot observational study.

    PubMed

    Heng, Lei; Wang, Ming-Yu; Sun, Hou-Liang; Zhu, Shan-Shan

    2016-08-01

    Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia.Sixty-two patients (ASA physical status I-II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance.Fifty-eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self-positioning, which were tolerable.These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID:27512858

  9. [Therapy with somatostatin analogs in patient with orbitopathy and positive Octreoscan].

    PubMed

    Pichler, R; Maschek, W; Holzinger, C

    2001-01-01

    We prospectively evaluated 28 persons with active endocrine ophthalmopathy and positive sonographic criteria (A-mode) on extraocular eye muscles. To evaluate somatostatin-receptor status SPECT of the orbits was performed with a double-headed rotating gamma camera after application of 110 MBq 111-In-Pentreotide. 9 patients (12/56 eyes respectively) showed a marked uptake ratio (> 2 in circular ROIs by semiquantitative calculation) and were selected for lanreotide (30 mg i.m. every 14 d) treatment. 5 individuals had control scan after clinical progression which became positive in two of them. All but one tolerated modest side-effects of lanreotide treatment (diarrhea). Therapy was discontinued after 3-10 months when thyroid eye disease had lead to fibrotic stage. This subgroup, with the exception of two women, who received corticosteroids additionally, presented stable disease. One of those had to be sent to surgery because of endangered optical nerve. Clinical ophthalmological control showed promising results in patients receiving somatostatin analogues at early stage when positive on octreo-scan. PMID:11593900

  10. Plasmid Dynamics in KPC-Positive Klebsiella pneumoniae during Long-Term Patient Colonization

    PubMed Central

    Park, Morgan; Deming, Clayton; Thomas, Pamela J.; Young, Alice C.; Coleman, Holly; Sison, Christina; Weingarten, Rebecca A.; Lau, Anna F.; Dekker, John P.; Palmore, Tara N.; Frank, Karen M.

    2016-01-01

    ABSTRACT Carbapenem-resistant Klebsiella pneumoniae strains are formidable hospital pathogens that pose a serious threat to patients around the globe due to a rising incidence in health care facilities, high mortality rates associated with infection, and potential to spread antibiotic resistance to other bacterial species, such as Escherichia coli. Over 6 months in 2011, 17 patients at the National Institutes of Health (NIH) Clinical Center became colonized with a highly virulent, transmissible carbapenem-resistant strain of K. pneumoniae. Our real-time genomic sequencing tracked patient-to-patient routes of transmission and informed epidemiologists’ actions to monitor and control this outbreak. Two of these patients remained colonized with carbapenemase-producing organisms for at least 2 to 4 years, providing the opportunity to undertake a focused genomic study of long-term colonization with antibiotic-resistant bacteria. Whole-genome sequencing studies shed light on the underlying complex microbial colonization, including mixed or evolving bacterial populations and gain or loss of plasmids. Isolates from NIH patient 15 showed complex plasmid rearrangements, leaving the chromosome and the blaKPC-carrying plasmid intact but rearranging the two other plasmids of this outbreak strain. NIH patient 16 has shown continuous colonization with blaKPC-positive organisms across multiple time points spanning 2011 to 2015. Genomic studies defined a complex pattern of succession and plasmid transmission across two different K. pneumoniae sequence types and an E. coli isolate. These findings demonstrate the utility of genomic methods for understanding strain succession, genome plasticity, and long-term carriage of antibiotic-resistant organisms. PMID:27353756

  11. [Follow-up of extensive burns in an HIV positive patient. Case report].

    PubMed

    de Roche, R; Lüscher, N J; Zimmerli, W

    1990-02-01

    The case of a 33-year-old HIV-positive patient who suffered from second- and third-degree burn injuries involving 30% of the body surface is reported. She was treated by early tangential excision of the burnt skin and split-thickness mesh grafting. The burn wounds healed without complications within the usual time, with excellent cosmetic and functional results. In spite of the successful treatment, she suffered from fever and various infections for several months. With the appearance of these constitutional symptoms, we recognized the AIDS-related complex. Her general condition deteriorated continuously and 10 months after the accident she had to be admitted to a hospital again. The skin had nevertheless healed perfectly and in spite of not having compression treatment for the grafts or physiotherapy, she did not show any signs of hypertrophic scars. Some important conclusions drawn from this case are discussed. The fact that healing occurred without complications is in contrast to the results reported in the literature concerning impaired wound healing in AIDS patients with anorectal surgery. We therefore believe that the reluctant and perhaps even anxious attitude of the medical and nursing staff towards performing technical and expensive procedures in HIV-positive burn patients is not justified. PMID:2315721

  12. Robot assisted radical prostatectomy: how I do it. Part I: Patient preparation and positioning.

    PubMed

    Valdivieso, Roger F; Hueber, Pierre-Alain; Zorn, Kevin C

    2013-10-01

    Radical prostatectomy remains the standard treatment for long term cure of clinically localized prostate cancer, offering excellent oncologic outcomes, with cancer-specific survival approaching 95% at 15 years after surgery. The introduction of the "da Vinci Robotic Surgical System" (Intuitive Surgical, Sunnyvale, CA, USA) has been another important step toward a minimally invasive approach to radical prostatectomy. Technologic peculiarities, such as three-dimensional vision, wristed instrumentation with seven degrees of freedom of motion, lack of tremor, a 10x-magnification and a comfortable seated position for the surgeon has added value to the surgeon and patient. In this first part of a two article series, we describe preoperative patient preparation and positioning protocols for robot assisted radical prostatectomy (RARP) that are currently used in our institution (University of Montreal Hospital Center (CHUM)-Hopital St-Luc). We use the four-arm da Vinci Si Surgical System. Our experience with RARP is now over 250 cases with the senior surgeon having performed over 1200 RARPs and we have continually refined our technique to improve patient outcomes. PMID:24128839

  13. Cytodiagnosis of cutaneous histoplasmosis in HIV positive patient initially presenting with multiple umbilicated disseminated skin nodules.

    PubMed

    Arghya, Bandyopadhyay; Kaushik, Majumdar; Mimi, Gangopadhyay; Subrata, Chakraborty

    2013-05-01

    Histoplasmosis is usually an opportunistic fungal infection in patients with defective cell mediated immunity, and has been considered as one of the acquired immunodeficiency syndrome (AIDS) defining illness. However, cutaneous involvement in human immunodeficiency virus (HIV) positive patients is less common, and very rarely can be the initial presenting symptom for the diagnosis of AIDS. We present here an unusual case of multiple diffuse cutaneous nodular lesions predominantly in face, trunk, and upper extremities diagnosed initially on aspiration cytology as histoplasmosis. Subsequent serological test revealed positivity for HIV 1 and 2, along with a low CD4 count and low CD4:CD3 ratio. The cytomorphological features were further corroborated by histology and histochemical stains. Hence, cutaneous histoplasmosis can cause multiple wide spread nodular or umbilicated lesions in AIDS patients as the initial presentation. Fine needle aspiration cytology (FNAC) is a rapid, cost effective tool for diagnosis of the fungi from such lesions and initiating work up for immunocompromised states including AIDS. PMID:21987498

  14. An Abdominal CT may be Safe in Selected Hypotensive Trauma Patients with Positive FAST Exam

    PubMed Central

    Cook, Mackenzie R.; Holcomb, John B.; Rahbar, Mohammad H.; Alarcon, Louis H.; Bulger, Eileen M.; Brasel, Karen J.; Schreiber, Martin A.

    2016-01-01

    Background Positive Focused Assessment with Sonography in Trauma (FAST) and hypotension often indicates urgent surgery. An abdomen/pelvis CT (apCT) may allow less invasive management but the delay may be associated with adverse outcomes. Methods Patients in the Prospective Observational Multicenter Major Trauma Transfusion study with hypotension and a positive FAST (HF+) who underwent a CT (apCT+) were compared to those who did not. Results Of the 92 HF+ identified, 32(35%) underwent apCT during initial evaluation and apCT was associated with decreased odds of an emergency operation, OR 0.11 95% CI (0.001–0.116) and increased odds of angiographic intervention, OR 14.3 95% CI (1.5–135). There was no significant difference in 30 day mortality or need for dialysis. Conclusion An apCt in HF+ patients is associated with reduced odds of emergency surgery, but not mortality. Select HF+ patients can safely undergo apCT to obtain clinically useful information. PMID:25805456

  15. An unusual presentation of diffuse granuloma annulare in an HIV-positive patient - immunohistochemical evidence of predominant CD8 lymphocytes.

    PubMed

    Morris, S D; Cerio, R; Paige, D G

    2002-05-01

    Over the past decade there have been several reports in the literature of atypical forms of granuloma annulare (GA) occurring in HIV positive patients. We now report a case of diffuse granuloma annulare in an HIV positive patient with unusual clinical and immunohistological features. Our patient presented with a persistent extensive macular erythematous eruption on his face and upper trunk with bizarre sparing around the nipples and axillae. The histology showed an interstitial pattern of GA, with a predominance of CD8 positive cells, in contrast to the usual CD4 positive infiltrate typically seen in GA. PMID:12072009

  16. The Reverse Thomas Position for Thoracolumbar Fracture Height Restoration: Relative Contribution of Patient Positioning in Percutaneous Balloon Kyphoplasty for Acute Vertebral Compressions

    PubMed Central

    Cawley, Derek T.; Beecher, Suzanne M.; Baker, Joseph F.; McCabe, John P.

    2016-01-01

    Background Standard positioning for percutaneous balloon kyphoplasty requires placing a patient prone with supports under the iliac crests and upper thorax. The authors believe that hip hyperextension maximises pelvic anteversion creating anterior longitudinal ligamentotaxis, thus facilitating restoration of vertebral height. Methods Radiographic imaging including pre-operative, post-positioning, post balloon tamp inflation and post-operative lateral radiographs were analysed for anterior and posterior column height, wedge angle of the affected vertebra and 3-level Cobb angle in patients with recent fractures of T11-L1. Fracture dimensions of the index vertebra were expressed as percentage of the analogous dimension of the referent vertebra. Results From a total of 149 patients, a full imaging sequence was available on 21 cases of vertebral compression fractures. The described positioning technique created a mean anterior column height increase from 68.3% to 75.3% with positioning (p = 0.15), increasing to 82.3% post balloon inflation. Average Cobb and wedge angle improvement of 4.7° (p = 0.004)and 3.6° (p = 0.002) from positioning along were also recorded. Conclusion The Reverse Thomas Position is a safe and effective technique for augmenting thoracolumbar fracture height restoration in percutaneous balloon kyphoplasty. PMID:27441179

  17. Digital tomosynthesis (DTS) for verification of target position in early stage lung cancer patients

    SciTech Connect

    Sörnsen de Koste, John R. van; Dahele, Max; Senan, Suresh; Weide, Lineke van der; Slotman, Ben J.; Verbakel, Wilko F. A. R.; Mostafavi, Hassan

    2013-09-15

    Purpose: The ability to verify intrafraction tumor position is clinically useful for hypofractionated treatments. Short arc kV digital tomosynthesis (DTS) could facilitate more frequent target verification. The authors used DTS combined with triangulation to determine the mean temporal position of small-volume lung tumor targets treated with stereotactic radiotherapy. DTS registration results were benchmarked against online clinical localization using registration between free-breathing cone-beam computed tomography (CBCT) and the average intensity projection (AvIP) of the planning 4DCT.Methods: In this retrospective study, 76 sets of kV-projection images from online CBCT scans of 13 patients were used to generate DTS image slices (CB-DTS) with nonclinical research software (DTS Toolkit, Varian Medical Systems). Three-dimensional tumor motion was 1.3–4 mm in six patients and 6.1–25.4 mm in seven patients on 4DCT (significant difference in the mean of the groups, P < 0.01). The 4DCT AvIP was used to digitally reconstruct the Reference-DTS. DTS registration and DTS registration combined with triangulation were investigated. Progressive shortening of total DTS arc lengths from 95° to 35° around 0° gantry position was evaluated for different scenarios: DTS registration using the entire arc; DTS registration plus triangulation using two nonoverlapping arcs; and for 55° and 45° total gantry rotation, DTS registration plus triangulation using two overlapping arcs. Finally, DTS registration plus triangulation performed at eight gantry angles, each separated by 45° was evaluated using full fan kV projection data for one patient with an immobile tumor and five patients with mobile tumors.Results: For DTS registration alone, shortening arc length did not influence accuracy in X- and Y-directions, but in Z-direction, mean deviations from online CBCT localization systematically increased for shorter arc length (P < 0.05). For example, using a 95° arc mean DTS

  18. Positive Deviance: A New Tool for Infection Prevention and Patient Safety.

    PubMed

    Marra, Alexandre R; Pavão Dos Santos, Oscar Fernando; Cendoroglo Neto, Miguel; Edmond, Michael B

    2013-09-28

    Positive deviance (PD) may have an important role in infection prevention and patient safety in the hospital. There are many descriptions of successful stories of PD in different sectors from public health to education to business. PD has been applied in the healthcare setting to improve hand hygiene compliance, reduce methicillin-resistant Staphylococcus aureus, and reduce bloodstream infections in an outpatient hemodialysis center. PD promotes dialogue among leaders, managers and healthcare workers, which is a key factor in establishing a safety culture. It also enables cultural changes aimed at empowering frontline workers (the positive deviants) to innovate and improve compliance with infection prevention measures. The structure and the process of PD, and its ability to offer a space for experience discussions, changing ideas and making plans that emerge from team participation will also be discussed. PMID:24078405

  19. AA-negative and Kappa-positive Amyloidosis in a Patient with Rheumatoid Arthritis.

    PubMed

    Ueno, Toshiharu; Sumida, Keiichi; Hoshino, Junichi; Suwabe, Tatsuya; Mise, Koki; Hazue, Ryo; Hayami, Noriko; Hiramatsu, Rikako; Kawada, Masahiro; Imafuku, Aya; Hasegawa, Eiko; Sawa, Naoki; Takaichi, Kenmei; Kinowaki, Keiichi; Ohashi, Kenichi; Fujii, Takeshi; Nishida, Aya; Ubara, Yoshifumi

    2016-01-01

    A 57-year-old Japanese woman with a 5-year history of rheumatoid arthritis (RA) was admitted to our hospital for an evaluation of nephrotic range proteinuria (4.8 g/day). A renal biopsy led to the diagnosis of amyloidosis according to strong positivity for Congo red staining and the detection of microfibrillar structures on electron microscopy that were negative for AA and positive for kappa light chain. Combination therapy with high-dose melphalan and autologous stem cell transplantation was performed according to the regimen for AL amyloidosis. Her proteinuria and RA subsided, but relapsed after 3 years. This is the first report regarding kappa light chain amyloidosis in an RA patient. PMID:27580556

  20. Beam-centric algorithm for pretreatment patient position correction in external beam radiation therapy

    SciTech Connect

    Bose, Supratik; Shukla, Himanshu; Maltz, Jonathan

    2010-05-15

    Purpose: In current image guided pretreatment patient position adjustment methods, image registration is used to determine alignment parameters. Since most positioning hardware lacks the full six degrees of freedom (DOF), accuracy is compromised. The authors show that such compromises are often unnecessary when one models the planned treatment beams as part of the adjustment calculation process. The authors present a flexible algorithm for determining optimal realizable adjustments for both step-and-shoot and arc delivery methods. Methods: The beam shape model is based on the polygonal intersection of each beam segment with the plane in pretreatment image volume that passes through machine isocenter perpendicular to the central axis of the beam. Under a virtual six-DOF correction, ideal positions of these polygon vertices are computed. The proposed method determines the couch, gantry, and collimator adjustments that minimize the total mismatch of all vertices over all segments with respect to their ideal positions. Using this geometric error metric as a function of the number of available DOF, the user may select the most desirable correction regime. Results: For a simulated treatment plan consisting of three equally weighted coplanar fixed beams, the authors achieve a 7% residual geometric error (with respect to the ideal correction, considered 0% error) by applying gantry rotation as well as translation and isocentric rotation of the couch. For a clinical head-and-neck intensity modulated radiotherapy plan with seven beams and five segments per beam, the corresponding error is 6%. Correction involving only couch translation (typical clinical practice) leads to a much larger 18% mismatch. Clinically significant consequences of more accurate adjustment are apparent in the dose volume histograms of target and critical structures. Conclusions: The algorithm achieves improvements in delivery accuracy using standard delivery hardware without significantly increasing

  1. Fertility desires and intentions of HIV-positive patients at a suburban specialist center.

    PubMed Central

    Oladapo, Olufemi T.; Daniel, Olusoji J.; Odusoga, Okanlawon L.; Ayoola-Sotubo, Oluwafayokemi

    2005-01-01

    OBJECTIVES: To determine the extent of fertility desires and intentions of HIV-positive patients receiving care at a suburban specialist clinic and assess how these may vary by their sociodemographic and health-related factors. METHODS: Questionnaire-based interview of a consecutive sample of HIV-positive men (18-55 years) and HIV-positive women (18-45 years) who presented at the HIV clinic of the Center for Special Studies, Sagamu, Nigeria, between November and December 2004. RESULTS: 63.3% of the 147 studied participants expressed the desire for childbearing, even though 50.4% of them already had > or = 2 children. Respectively, 71.5% and 93.8% of men and women who desired children intended to have > or = 2 in the near future. Only 4.3% of those who desired children did not intend to have any. All 30 individuals who had no children intended to bear children in the future, and they constituted 32.3% of those who expressed the desire for childbearing. Multivariate logistic regression analyses of associated factors indicated that decreasing age, shorter time since diagnosis of HIV infection and nondisclosure of serostatus to current partner significantly increase the odds of desire for childbearing, while having no children and a poor most-recent CD4 count significantly increase the odds of intention to have > or = 3 children instead of 1-2. CONCLUSION: The extent of the fertility desires and intentions of these patients poses a threat to the preventive strategies against vertical and heterosexual transmission of HIV in this region. In view of their compelling desire for parenthood, it may be wise for caregivers to desist from the conventional systematic advice against pregnancy but, in addition to laying emphasis on the risks, provide adequate information on practicable reproductive options for HIV-positive individuals. PMID:16396059

  2. Crisis Management of Accidental Extubation in a Prone-Positioned Patient with Klippel-Feil Syndrome.

    PubMed

    Spond, Matthew; Burns, Tyler; Rosenbaum, Thea; Lienhart, Kristen

    2016-06-15

    We present the case of an accidental extubation in a prone-positioned patient with a challenging airway because of Klippel-Feil syndrome and previous cervical spine fusions. The surgical procedure was well underway when this occurred, which added substantially to the difficulties produced by this event. We herein highlight the corrective steps we took in our case. We also recommend the need for a comprehensive preoperative briefing with all operating room personnel together with an action plan for how to prevent this particular scenario. PMID:27301052

  3. [Unexpected Diseases in Two Patients with False-Positive Dengue Immunoglobulin M Antibody Test Results].

    PubMed

    Matono, Takashi; Kutsuna, Satoshi; Kato, Yasuyuki; Takeshita, Nozomi; Hayakawa, Kayoko; Kanagawa, Shuzo; Ohmagari, Norio

    2016-03-01

    In 2014, an outbreak of 162 domestic dengue fever infections occurred in Tokyo, Japan; the first outbreak of its kind in 70 years. Nineteen of these cases were confirmed in our center. Advancements in diagnostic methods have enabled an earlier diagnosis of dengue fever; however, unfamiliarity with the clinical course and characteristics of diagnostic tests for dengue fever can lead to misdiagnosis. We herein describe 2 cases of Japanese patients with false-positive dengue immunoglobulin M antibody test results, who were finally diagnosed as having dermatomyositis and acute hepatitis A infection, respectively. PMID:27197439

  4. Characterization of the Microenvironment in Positive and Negative Sentinel Lymph Nodes from Melanoma Patients

    PubMed Central

    Messaoudene, Meriem; Périer, Aurélie; Fregni, Giulia; Neves, Emmanuelle; Zitvogel, Laurence; Cremer, Isabelle; Chanal, Johan; Sastre-Garau, Xavier; Deschamps, Lydia; Marinho, Eduardo; Larousserie, Frederique; Maubec, Eve; Avril, Marie-Françoise; Caignard, Anne

    2015-01-01

    Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells. PMID:26218530

  5. Noninvasive positive pressure ventilation as treatment for acute respiratory failure in critically ill patients

    PubMed Central

    Antonelli, Massimo; Conti, Giorgio

    2000-01-01

    Our current state of knowledge on noninvasive positive pressure ventilation (NPPV) and technical aspects are discussed in the present review. In patients with chronic obstructive pulmonary disease, NPPV can be considered a valid therapeutic option to prevent endotracheal intubation. Evidence suggests that, before eventual endotracheal intubation, NPPV should be considered as first-line intervention in the early phases of acute exacerbation of chronic obstructive pulmonary disease. Small randomized and non-randomized studies on the application of NPPV in patients with acute hypoxaemic respiratory failure showed promising results, with reduction in complications such as sinusitis and ventilator-associated pneumonia, and in the duration of intensive care unit stay. The conventional use of NPPV in hypoxaemic acute respiratory failure still remains controversial, however. Large randomized studies are still needed before extensive clinical application in this condition. PMID:11094492

  6. Individualized positive end-expiratory pressure application in patients with acute respiratory distress syndrome.

    PubMed

    Pintado, M C; de Pablo, R

    2014-11-01

    Current treatment of acute respiratory distress syndrome is based on ventilatory support with a lung protective strategy, avoiding the development of iatrogenic injury, including ventilator-induced lung injury. One of the mechanisms underlying such injury is atelectrauma, and positive end-expiratory pressure (PEEP) is advocated in order to avoid it. The indicated PEEP level has not been defined, and in many cases is based on the patient oxygen requirements for maintaining adequate oxygenation. However, this strategy does not consider the mechanics of the respiratory system, which varies in each patient and depends on many factors-including particularly the duration of acute respiratory distress syndrome. A review is therefore made of the different methods for adjusting PEEP, focusing on the benefits of individualized application. PMID:24485531

  7. Multifocal Buruli Ulcer Associated with Secondary Infection in HIV Positive Patient

    PubMed Central

    Komenan, Kassi; Elidjé, Ecra J.; Ildevert, Gbery P.; Yao, Kouassi I.; Kanga, Kouame; Kouamé, Kouassi A.; Abdoulaye, Sangaré; Hamdam, Kourouma S.; Yao, Yoboué P.; Jean-Marie, Kanga

    2013-01-01

    Buruli ulcer is a chronic and infectious skin disease, caused by Mycobacterium ulcerans. It leads to large skin ulceration and sometimes bone infection which is responsible for deformities. Here, we report a case of multifocal form of Buruli ulcer associated with secondary infection in a 46-year-old human immunodeficiency virus (HIV) positive woman. The antimycobacterial drugs combined to surgery allowed curing this multifocal case and rose up two relevant issues: the susceptibility of immune reconstitution inflammatory syndrome (IRIS) occurrence and Mycobacterium dissemination. The deep immune depression, the underline biological, and clinical disorders of the patient might contribute to IRIS occurrence and Buruli ulcer dissemination. Future investigations have to be conducted on the mechanism of IRIS on set and on Mycobacterium ulcerans dissemination after ARV drugs initiation and the patient related underline clinical or biological disorders. PMID:24454398

  8. Single lung transplantation in a patient with retrospective positive cross-match

    PubMed Central

    Piotrowska, Maria; Dec, Paweł; Wasilewski, Piotr; Kubisa, Anna; Pieróg, Jarosław; Wójcik, Norbert; Czarnecka, Michalina; Kubisa, Bartosz; Grodzki, Tomasz

    2015-01-01

    Lung transplantation is a method useful in such non-malignant end-stage parenchymal and vascular diseases as: chronic obstructive pulmonary disease (COPD), idiopathic interstitial pulmonary fibrosis, cystic fibrosis, or primary pulmonary hypertension. The main aim of this procedure is to extend the patient's lifespan and quality of life. However, the availability of the operation is limited by organ access. In this paper we present the case of a 58-year-old female in the fourth stage of COPD, who was classified to have a single lung transplantation. Because of some technical problems it was decided to transplant a left donor lung in the right recipient lung locus. Positive cross match was demonstrated retrospectively, and we applied five courses of plasmapheresis. Human immunoglobulin and rituximab treatment were performed to decrease the impact of lymphocytotoxic antibodies. The patient survived 498 days after transplantation, 271 in the hospital. PMID:26855654

  9. Building a global consensus approach to chordoma: a position paper from the medical and patient community.

    PubMed

    Stacchiotti, Silvia; Sommer, Josh

    2015-02-01

    Chordomas are very rare bone malignant tumours that have had a shortage of effective treatments for a long time. New treatments are now available for both the local and the metastatic phase of the disease, but the degree of uncertainty in selecting the most appropriate treatment remains high and their adoption remains inconsistent across the world, resulting in suboptimum outcomes for many patients. In December, 2013, the European Society for Medical Oncology (ESMO) convened a consensus meeting to update its clinical practice guidelines on sarcomas. ESMO also hosted a parallel consensus meeting on chordoma that included more than 40 chordoma experts from several disciplines and from both sides of the Atlantic, with the contribution and sponsorship of the Chordoma Foundation, a global patient advocacy group. The consensus reached at that meeting is shown in this position paper. PMID:25638683

  10. Endovascular management of ruptured common iliac mycotic aneurysm in an HIV-positive patient.

    PubMed

    Aziz, Aamir; Mooka, Busi; Clarke Moloney, Mary; Kavanagh, Eamon

    2013-01-01

    Isolated iliac artery aneurysms are a rare entity. The majority of cases are asymptomatic and often escape detection. Mortality rates after sudden rupture and emergent surgery for iliac artery aneurysm are very high. We report a case of a 56-year-old man who presented with right hip pain masquerading as septic arthritis or psoas abscess. CT showed ruptured right common iliac artery aneurysm with extensive active extravasation into psoas with a retroperitoneal haematoma. Aneurysm was repaired using an endovascular technique. Postoperative recovery was eventful with the patient experiencing severe back pain radiating down the leg accompanied with fever. CT showed persistent, right iliopsoas haematoma and pelvic haematoma with secondary hydronephrosis. Viral screen for hepatitis B, C and HIV returned positive. The patient was started on intravenous meropenem. Fever and pain settled. Repeated CT scan showed decrease in retroperitoneal pelvic haematoma. PMID:23917370

  11. Cholelithiasis and Nephrolithiasis in HIV-Positive Patients in the Era of Combination Antiretroviral Therapy

    PubMed Central

    Lin, Kuan-Yin; Liao, Sih-Han; Liu, Wen-Chun; Cheng, Aristine; Lin, Shu-Wen; Chang, Sui-Yuan; Tsai, Mao-Song; Kuo, Ching-Hua; Wu, Mon-Ro; Wang, Hsiu-Po; Hung, Chien-Ching; Chang, Shan-Chwen

    2015-01-01

    Objectives This study aimed to describe the epidemiology and risk factors of cholelithiasis and nephrolithiasis among HIV-positive patients in the era of combination antiretroviral therapy. Methods We retrospectively reviewed the medical records of HIV-positive patients who underwent routine abdominal sonography for chronic viral hepatitis, fatty liver, or elevated aminotransferases between January 2004 and January 2015. Therapeutic drug monitoring of plasma concentrations of atazanavir was performed and genetic polymorphisms, including UDP-glucuronosyltransferase (UGT) 1A1*28 and multidrug resistance gene 1 (MDR1) G2677T/A, were determined in a subgroup of patients who received ritonavir-boosted or unboosted atazanavir-containing combination antiretroviral therapy. Information on demographics, clinical characteristics, and laboratory testing were collected and analyzed. Results During the 11-year study period, 910 patients who underwent routine abdominal sonography were included for analysis. The patients were mostly male (96.9%) with a mean age of 42.2 years and mean body-mass index of 22.9 kg/m2 and 85.8% being on antiretroviral therapy. The anchor antiretroviral agents included non-nucleoside reverse-transcriptase inhibitors (49.3%), unboosted atazanavir (34.4%), ritonavir-boosted lopinavir (20.4%), and ritonavir-boosted atazanavir (5.5%). The overall prevalence of cholelithiasis and nephrolithiasis was 12.5% and 8.2%, respectively. Among 680 antiretroviral-experienced patients with both baseline and follow-up sonography, the crude incidence of cholelithiasis and nephrolithiasis was 4.3% and 3.7%, respectively. In multivariate analysis, the independent factors associated with incident cholelithiasis were exposure to ritonavir-boosted atazanavir for >2 years (adjusted odds ratio [AOR], 6.29; 95% confidence interval [CI], 1.12–35.16) and older age (AOR, 1.04; 95% CI, 1.00–1.09). The positive association betw