Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.

Eur Respir J. 2018 Mar 15;:

Authors: Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, Taggart CC, Herth F, Schultz C, Mall MA

Abstract
Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We, therefore, determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and 8 healthy controls using novel lipidated Foerster resonance energy transfer (FRET) reporters and correlated with free NE activity, neutrophil counts, IL-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with FEV1% predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with FRCpleth% predicted (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

PMID: 29545279 [PubMed - as supplied by publisher]

Comparison of ex vivo and in vitro intestinal cystic fibrosis models to measure CFTR-dependent ion channel activity.

J Cyst Fibros. 2018 Mar 13;:

Authors: Zomer-van Ommen DD, de Poel E, Kruisselbrink E, Oppelaar H, Vonk AM, Janssens HM, van der Ent CK, Hagemeijer MC, Beekman JM

Abstract
BACKGROUND: New functional assays using primary human intestinal adult stem cell cultures can be valuable tools to study epithelial defects in human diseases such as cystic fibrosis.
METHODS: CFTR-mediated ion transport was measured in rectal organoid-derived monolayers grown from subjects with various CFTR mutations and compared to donor-matched intestinal current measurements (ICM) in rectal biopsies and forskolin-induced swelling of rectal organoids.
RESULTS: Rectal organoid-derived monolayers were generated within four days. Ion transport measurements of CFTR function using these monolayers correlated with ICM and organoid swelling (r = 0.73 and 0.79 respectively). Culturing the monolayers under differentiation conditions enhanced the detection of mucus-secreting cells and was accompanied by reduced CFTR function.
CONCLUSIONS: CFTR-dependent intestinal epithelial ion transport properties can be measured in rectal organoid-derived monolayers of subjects and correlate with donor-matched ICM and rectal organoid swelling.

PMID: 29544685 [PubMed - as supplied by publisher]

Ileoileal Intussusceptions Caused by Eosinophilic Enteropathy.

J Pediatr Gastroenterol Nutr. 2016 06;62(6):e60

Authors: Bramuzzo M, Martelossi S, Villanacci V, Maschio M, Costa S, Ventura A

PMID: 25000350 [PubMed - indexed for MEDLINE]

Atypical pyridoxine dependent epilepsy resulting from a new homozygous missense mutation, in ALDH7A1.

Seizure. 2018 Mar 10;57:32-33

Authors: Haidar Z, Jalkh N, Corbani S, Fawaz A, Chouery E, Mégarbané A

Abstract
Pyridoxine dependent epilepsy (PDE) is a rare autosomal recessive neurometabolic disorder. In the classical form, seizures are observed within the first month of life, while in the atypical form seizures appear later in life, sometimes as late as at the age of 3 years of life. Both types are unresponsive to conventional anticonvulsant therapy, but can be controlled with pyridoxine monotherapy. Mutations in the ALDH7A1 gene, encoding α-aminoadipic semialdehyde dehydrogenase have been reported to cause this disease in most patients. Here, we report on a boy with developmental delay, dysmorphic facial features, and uncontrolled episodes of seizures that appeared at the age of 18 months. By whole exome sequencing (WES) a homozygous missense mutation in ALDH7A1 (NM_001182: c.239T > G, p.V80G) was found. We discuss the importance of WES in such atypical cases.

PMID: 29547829 [PubMed - as supplied by publisher]

Mutations in EEA1 are associated with allergic bronchopulmonary aspergillosis and affect phagocytosis of Aspergillus fumigatus by human macrophages.

PLoS One. 2018;13(3):e0185706

Authors: Overton NLD, Brakhage AA, Thywißen A, Denning DW, Bowyer P

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) in asthma is a severe, life-affecting disease that potentially affects over 4.8 million people globally. In the UK, ABPA is predominantly caused by the fungus Aspergillus fumigatus. Phagocytosis is important in clearance of this fungus, and Early Endosome Antigen 1 (EEA1) has been demonstrated to be involved in phagocytosis of fungi. We sought to investigate the role of EEA1 mutations and phagocytosis in ABPA. We used exome sequencing to identify variants in EEA1 associated with ABPA. We then cultured monocyte-derived macrophages (MDMs) from 17 ABPA subjects with A. fumigatus conidia, and analyzed phagocytosis and phagolysosome acidification in relation to the presence of these variants. We found that variants in EEA1 were associated with ABPA and with the rate of phagocytosis of A. fumigatus conidia and the acidification of phagolysosomes. MDMs from ABPA subjects carrying the disease associated genotype showed increased acidification and phagocytosis compared to those from ABPA subjects carrying the non-associated genotypes or healthy controls.The identification of ABPA-associated variants in EEA that have functional effects on MDM phagocytosis and phagolysosome acidification of A. fumigatus conidia revolutionizes our understanding of susceptibility to this disease, which may in future benefit patients by earlier identification or improved treatments. We suggest that the increased phagocytosis and acidification observed demonstrates an over-active MDM profile in these patients, resulting in an exaggerated cellular response to the presence of A. fumigatus in the airways.

PMID: 29547649 [PubMed - in process]

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation is a Novel Defect in Thyroid Dyshormonogenesis.

J Clin Endocrinol Metab. 2018 Mar 12;:

Authors: Zou M, Alzahrani AS, Al-Odaib A, Alqahtani MA, Babiker O, Al-Rijjal RA, BinEssa HA, Kattan WE, Al-Enezi AF, Al Qarni A, Al-Faham MSA, Baitei EY, Alsagheir A, Meyer BF, Shi Y

Abstract
Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000-4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied.
Objective: To identify mutation spectrum of CH-causing genes.
Methods: Fifty-five patients from 47 families were studied by next-generation-exome sequencing.
Results: Mutations were identified in 52.7% of patients (29/55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them co-existing with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in 6 patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel including three TG, two TSHR, and one in each of DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively.
Conclusions: TG and TSHR mutations are the most common genetic defects in Saudi CH patients. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

PMID: 29546359 [PubMed - as supplied by publisher]

Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma.

Blood. 2018 Mar 15;:

Authors: Ren W, Ye X, Su H, Li W, Liu D, Pirmoradian M, Wang X, Zhang B, Zhang Q, Chen L, Nie M, Liu Y, Meng B, Huang H, Jiang W, Zeng Y, Li W, Wu K, Hou Y, Wiman KG, Li Z, Zhang H, Peng R, Zhu S, Pan-Hammarström Q

Abstract
Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive, HBsAg+) are characterized by a younger age, a more advanced disease stage at diagnosis and a reduced overall survival. Furthermore, by whole genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted-sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation induced cytidine deaminase (AID). By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1 and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favoured in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The targetable genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

PMID: 29545328 [PubMed - as supplied by publisher]

Unique autosomal recessive variant of palmoplantar keratoderma associated with hearing loss not caused by known mutations.

An Bras Dermatol. 2017;92(5 Suppl 1):154-158

Authors: Hegazi MA, Manou S, Sakr H, Camp GV

Abstract
Inherited Palmoplantar Keratodermas are rare disorders of genodermatosis that are conventionally regarded as autosomal dominant in inheritance with extensive clinical and genetic heterogeneity. This is the first report of a unique autosomal recessive Inherited Palmoplantar keratoderma -sensorineural hearing loss syndrome which has not been reported before in 3 siblings of a large consanguineous family. The patients presented unique clinical features that were different from other known Inherited Palmoplantar Keratodermas -hearing loss syndromes. Mutations in GJB2 or GJB6 and the mitochondrial A7445G mutation, known to be the major causes of diverse Inherited Palmoplantar Keratodermas -hearing loss syndromes were not detected by Sanger sequencing. Moreover, the pathogenic mutation could not be identified using whole exome sequencing. Other known Inherited Palmoplantar keratoderma syndromes were excluded based on both clinical criteria and genetic analysis.

PMID: 29267478 [PubMed - indexed for MEDLINE]

Efficacy and safety of apatinib in patients with previously treated metastatic colorectal cancer: a real-world retrospective study.

Sci Rep. 2018 Mar 15;8(1):4602

Authors: Gou M, Si H, Zhang Y, Qian N, Wang Z, Shi W, Dai G

Abstract
No definitive treatment strategy has been established for patients with metastatic colorectal cancer (mCRC) who experienced progression after three or more lines of chemotherapy. A total of 36 mCRC patients were enrolled in this retrospective study who received apatinib therapy under non-clinical trial setting after progression in People's liberation army general Hospital from March 2015 and August 2017. Progression free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR) and treatment-related adverse events (AEs) were reviewed and evaluated. Five patients achieved partial response (PR), and 25 achieved stable disease (SD), and 6 achieved progression disease (PD), illustrating a DCR of 83.3% and an ORR of 13.9%. Median PFS was 3.82 m and median OS was not reached. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 adverse event incidence of 27.8%. The most common grade 3/4 adverse events were hypertension (n = 4, 11.1%), liver function damage (n = 3, 8.3%) and hand-foot syndrome (n = 2, 5.6%). No drug-related death occurred. Apatinib therapy provides a reasonable option with an acceptable safety profile for Chinese mCRC patients failed to prior chemotherapy.

PMID: 29545575 [PubMed - in process]

Prevalence and Management of Symptoms Associated With Statin Therapy in Community Practice: Insights From the PALM (Patient and Provider Assessment of Lipid Management) Registry.

Circ Cardiovasc Qual Outcomes. 2018 Mar;11(3):e004249

Authors: Navar AM, Peterson ED, Li S, Robinson JG, Roger VL, Goldberg AC, Virani S, Wilson PWF, Nanna MG, Lee LV, Elassal J, Wang TY

PMID: 29545393 [PubMed - in process]

Sequence symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies.

Eur J Epidemiol. 2017 Jul;32(7):567-582

Authors: Lai EC, Pratt N, Hsieh CY, Lin SJ, Pottegård A, Roughead EE, Kao Yang YH, Hallas J

Abstract
Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice. SSA is based on analyzing the sequences of medications; if one medication (drug B) is more often initiated after another medication (drug A) than before, it may be an indication of an adverse effect of drug A. The main advantage of the method is that it requires a minimal dataset and is computationally efficient. By design, SSA controls time-constant confounders. However, the validity of SSA may be affected by time-varying confounders, as well as by time trends in the occurrence of exposure or outcome events. Trend effects may be adjusted by modeling the expected sequence ratio in the absence of a true association. There is a potential for false positive or negative results and careful consideration should be given to potential sources of bias when interpreting the results of SSA studies.

PMID: 28698923 [PubMed - indexed for MEDLINE]

Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301.

Oncologist. 2017 Jun;22(6):640-e59

Authors: Miyauchi E, Inoue A, Usui K, Sugawara S, Maemondo M, Saito H, Fujita Y, Kato T, Suzuki T, Harada T, Watanabe H, Nakagawa T, Ichinose M

Abstract
LESSONS LEARNED: Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity.This modified regimen offers potential for the treatment of elderly patients.
BACKGROUND: The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC.
METHODS: Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS: Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33-67) and 94% (95% CI: 85-100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8-8.0) and 17.5 months (95% CI: 11.9-23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed.
CONCLUSION: Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC.

PMID: 28526722 [PubMed - indexed for MEDLINE]

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis.

Oncologist. 2017 Jun;22(6):709-718

Authors: Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, Suijkerbuijk KPM, Azevedo S, Li H, Reshef D, Avila A, Reardon DA

Abstract
BACKGROUND: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.
METHODS: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.
RESULTS: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal.
CONCLUSION: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.
IMPLICATIONS FOR PRACTICE: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

PMID: 28495807 [PubMed - indexed for MEDLINE]

Phase I Dose-Escalation Study of Ramucirumab in Chinese Patients with Advanced Solid Tumors.

Oncologist. 2017 Jun;22(6):638-e56

Authors: Cao J, Ji D, Chen Z, Shen W, Wang J, Li B, Chi H, Long A, Gao L, Li J

Abstract
LESSONS LEARNED: Ramucirumab was well tolerated in Chinese patients with advanced solid tumors, and adverse events were manageable in this study.Pharmacokinetics characteristics in Chinese patients were similar to those in other populations. Immunogenicity was not detected.No efficacy conclusion could be drawn, and further randomized studies are warranted.
BACKGROUND: This single-arm, nonrandomized, open-label, dose-escalation, phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of ramucirumab in Chinese patients with advanced solid tumors that were resistant to standard therapy or no standard therapy was available.
METHODS: Dose escalation was a 3 + 3 design, with expansion in Cohorts 2 and 3 for PK. Ramucirumab was given intravenously at three different dosages: 6 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 8 mg/kg every 2 weeks. Safety analyses included all patients. PK, immunogenicity, and antitumor activity were also assessed.
RESULTS: Among 28 patients treated, 2 experienced dose-limiting toxicity, possibly related to ramucirumab. No maximum tolerated dose was determined. All patients experienced at least one treatment-emergent adverse event. Grade ≥3 adverse event was reported for 53.6% (n = 15) of patients. PK analyses indicated that ramucirumab had low clearance, small volume of distribution, and long half-life in Chinese patients, as in other populations. Immunogenicity was not detected. No patient had complete/partial response, and 64.3% (n = 18) had stable disease with a median duration of 5.55 months (95% confidence interval: 3.38-7.13 months).
CONCLUSION: Ramucirumab appeared to be well tolerated in Chinese patients with advanced solid tumors. PK characteristics in Chinese patients were similar to those in other populations.

PMID: 28465370 [PubMed - indexed for MEDLINE]

Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting.

Oncologist. 2017 Jun;22(6):648-654

Authors: Generali D, Montemurro F, Bordonaro R, Mafodda A, Romito S, Michelotti A, Piovano P, Ionta MT, Bighin C, Sartori D, Frassoldati A, Cazzaniga ME, Riccardi F, Testore F, Vici P, Barone CA, Schirone A, Piacentini F, Nolè F, Molino A, Latini L, Simoncini EL, Roila F, Cognetti F, Nuzzo F, Foglietta J, Minisini AM, Goffredo F, Portera G, Ascione G, Mariani G

Abstract
BACKGROUND: The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%).
PATIENTS AND METHODS: One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%).
RESULTS: One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting.
CONCLUSION: Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane.
IMPLICATIONS FOR PRACTICE: With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis.

PMID: 28432226 [PubMed - indexed for MEDLINE]

Safety issues of compounds acting on adenosinergic signalling.

J Pharm Pharmacol. 2017 Jul;69(7):790-806

Authors: Schmidt J, Ferk P

Abstract
OBJECTIVES: Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting.
KEY FINDINGS: Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic.
SUMMARY: Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

PMID: 28397249 [PubMed - indexed for MEDLINE]

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Clin Cancer Res. 2017 Jun 01;23(11):2730-2741

Authors: Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, Terwisscha van Scheltinga AGT, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WPTM, Van der Wall E, van Diest PJ, de Vries EGE, Ntziachristos V, van Dam GM

Abstract
Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.

PMID: 28119364 [PubMed - indexed for MEDLINE]

[Global intervention in the polymedicated patient].

Gac Sanit. 2016 Sep-Oct;30(5):402

Authors: Rodríguez Del Río E, Martínez Agüero M, Arias Fernández L, Martín-Sánchez FJ

PMID: 27342617 [PubMed - indexed for MEDLINE]

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