Use of cystic fibrosis inhaled medication before and after elexacaftor/tezacaftor/ivacaftor initiation.

Elexacator/tezacaftor/ivacaftor (ETI) has improved cystic fibrosis (CF) outcomes. A reduction in use of maintenance medication after its initiation has been reported. Seventy-one adult people with CF (PwCF) who are followed in three CF centers and completed one year of treatment with ETI were included in this study. Their use of inhaled dornase-α, colistin, tobramycin, aztreonam and levofloxacin during this period was compared with the corresponding use during one year without ETI, using the Medication Possession Ratio (MPR). MPR was significantly decreased after ETI initiation for dornase-α (67±35% vs 48±40%, p<0.001) and for all four inhaled antibiotics together (62±33% vs 41±37%, p<0.001). The findings of this multi-center, retrospective, study suggest that the initiation of ETI significantly leads to decrease in use of standard inhaled medication in PwCF. The significance of this finding in the course of the disease is yet to be investigated by larger prospective clinical trials.

Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c-Met to up-regulate angiogenesis and lung adenocarcinoma growth.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A165 (VEGFA165 ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1-/- and Ptprz1+/+ mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1-/- lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1+/+ LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1-/- compared with Ptprz1+/+ mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (ß3 ) integrin is decreased in Ptprz1-/- LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1-/- mice. A selective PTPRZ1 TP inhibitor, VEGFA165 and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN.

Adherence to inhaled therapies over 4 years in people with cystic fibrosis.

BACKGROUND: This study examined the drug-specific and overall adherence of teenagers and adults with cystic fibrosis (CF) to inhaled therapies, to assess the degree of adherence, stability over a period of 4 years, and its association with health outcomes. METHODS: Fifty-five participants (30 women and 25 men) aged 14 years or older from two CF centers were enrolled in a retrospective review of inhaled medication adherence over 4 years. Adherence was assessed by the number of doses that were obtained by each participant based on the "e-prescription.gr" platform and the calculation of the medication possession ratio (MPR). RESULTS: The mean composite MPR (cMPR) for the entire research period was 0.75 ± 0.19. A total of 43.4% of participants showed a variance of adherence <25%. Participants with stable adherence had a significantly higher mean cMPR compared with those with variable adherence (0.86 ± 0.16 vs. 0.66 ± 0.17, p < 0.001). A statistically significant difference between groups of patients with different degrees of mean cMPR and mean weight was observed (p = 0.011). Patients with a mean cMPR ≥0.80 weighed significantly more than those with moderate and low adherence. In addition, mean weight correlated significantly with the mean cMPR (Β [95% confidence interval] = 14.845 [0.191-29.498], r = 0.269, p = 0.047). CONCLUSIONS: In our setting, the cMPR was easy to assess and showed that adherence was probably better than expected. The association of cMPR with weight should be further investigated. Stable adherence seemed to be related to high adherence. This observation could enhance our understanding of people with CF and their approach to treatment.

Multiple Sites of Arterial Thrombosis in A 35-Year Old Patient after ChAdOx1 (AstraZeneca) Vaccination, Requiring Emergent Femoral and Carotid Surgical Thrombectomy.

BACKGROUND: Vaccine Induced Thrombotic Thrombocytopenia (VITT) is a rare complication following ChAdOx1 (AstraZeneca) vaccination. Venous thrombosis in unusual sites such as splachnic or intracranial thrombosis, is the commonest manifestation. CASE REPORT: We report a 35-year-old male patient who presented with acute left leg ischemia and thrombocytopenia 11-days after vaccination requiring emergent thrombectomy. During work-up, a localized thrombus was detected in the left carotid bifurcation mandating carotid thrombectomy. Localized right iliac thrombus causing a non-limiting flow stenosis was treated conservatively. The platelet aggregating capacity of patient's plasma was confirmed in a functional assay, thereby establishing VITT. CONCLUSION: To the best of our knowledge this is the first case presenting multiple arterial thromboses requiring surgical treatment after ChAdOx1 vaccination.

Stem cell factor is implicated in microenvironmental interactions and cellular dynamics of chronic lymphocytic leukemia.

The inflammatory cytokine stem cell factor (SCF, ligand of c-kit receptor) has been implicated as a pro-oncogenic driver and an adverse prognosticator in several human cancers. Increased SCF levels have recently been reported in a small series of patients with chronic lymphocytic leukemia (CLL), however its precise role in CLL pathophysiology remains elusive. In this study, CLL cells were found to express predominantly the membrane isoform of SCF, which is known to elicit a more robust activation of the c-kit receptor. SCF was significantly overexpressed in CLL cells compared to healthy tonsillar B cells and it correlated with adverse prognostic biomarkers, shorter time-to-first treatment and shorter overall survival. Activation of immune receptors and long-term cell-cell interactions with the mesenchymal stroma led to an elevation of SCF primarily in CLL cases with an adverse prognosis. Contrariwise, suppression of oxidative stress and the BTK inhibitor ibrutinib lowered SCF levels. Interestingly, SCF significantly correlated with mitochondrial dynamics and hypoxia-inducible factor-1a which have previously been linked with clinical aggressiveness in CLL. SCF was able to elicit direct biological effects in CLL cells, affecting redox homeostasis and cell proliferation. Overall, the aberrantly expressed SCF in CLL cells emerges as a key response regulator to microenvironmental stimuli while correlating with poor prognosis. On these grounds, specific targeting of this inflammatory molecule could serve as a novel therapeutic approach in CLL.

Correction to: Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

The original version of this article contained a mistake. The name of Eirini Katroditou should have been Eirini Katodritou. The original article has been corrected.

Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

Chronic obstructive pulmonary disease in patients with lung cancer: prevalence, impact and management challenges.

Chronic obstructive pulmonary disease (COPD) and lung cancer share a common etiological factor (cigarette smoking) and usually coexist in everyday clinical practice. The prevalence of COPD among newly diagnosed patients with lung cancer sometimes exceeds 50%. COPD is an independent risk factor (2-4 times higher than non-COPD subjects) for lung cancer development. The presence of emphysema in addition to other factors (e.g., smoking history, age) could be incorporated into risk scores in order to define the most appropriate target group for lung cancer screening using low-dose computed tomography. Clinical management of patients with coexistence of COPD and lung cancer requires a multidisciplinary oncology board that includes a pulmonologist. Detailed evaluation (lung function tests, cardiopulmonary exercise test) and management (inhaled drugs, smoking cessation, pulmonary rehabilitation) of COPD should be taken into account for lung cancer treatment (surgical approach, radiotherapy).

Miliary tuberculosis in a patient with tuberculous mycotic aneurysm of the abdominal aorta: Case report and review of the literature.

The combination of miliary tuberculosis and tuberculous mycotic aneurysm has been described in the literature. We present the case of an 84-year-old man who was diagnosed with a mycotic aneurysm of the abdominal aorta and an adjacent soft tissue mass, after a 3- month history of fever. The patient underwent endovascular restoration of the aneurysm and was treated with broad-spectrum antibiotics. One and a half months later the fever relapsed and the chest CT scan revealed findings consistent with miliary tuberculosis and opacities of both upper lobes not present before, while the abdominal CT scan revealed an increase in the size of the para-aortic mass. Tuberculosis was documented by positive culture for M. tuberculosis of bronchial washing and by the CT-guided para-aortic mass biopsy. The patient received anti-TB treatment for 9 months leading to a spectacular improvement of his clinical condition and imaging findings. A review of the literature since 2008 revealed 28 more cases of tuberculous mycotic aneurysm. The treatment and outcome of all cases are described. Mycotic aneurysm of tuberculous etiology remains a reality and has a relatively good prognosis. Although miliary tuberculosis affects mortality even elderly patients may benefit from "aggressive" management and treatment.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) immobilized on laser-fabricated 3D scaffolds enhance osteogenesis.

The regeneration of bone via a tissue engineering approach involves components from the macroscopic to the nanoscopic level, including appropriate 3D scaffolds, cells and growth factors. In this study, hexagonal scaffolds of different diagonals were fabricated by Direct Laser Writing using a photopolymerizable hybrid material. The proliferation of bone marrow (BM) mesenchymal stem cells (MSCs) cultured on structures with various diagonals, 50, 100, 150 and 200µm increased significantly after 10days in culture, however without significant differences among them. Next, recombinant human bone morphogenetic protein 2 (rhBMP-2) was immobilized onto the hybrid material both via covalent binding and physical adsorption. Both immobilization types exhibited similar high releaseate bioactivity profiles and a sustained delivery of rhBMP-2. The collagen and calcium levels produced in the extracellular matrix (ECM) were significantly elevated for the samples functionalized with BMP-2 compared to those in the osteogenic medium. Furthermore, significant upregulation of gene expression in both types of BMP-2 immobilized scaffolds was observed for alkaline phosphatase (ALPL) and osteocalcin (BGLAP) at days 7, 14, and 21, for RUNX2 at day 21, and for osteonectin (SPARC) at days 7 and 14. The results suggest that the release of bioactive rhBMP-2 from the hybrid scaffolds enhance the control over the osteogenic differentiation during cell culture.

Apparent Diffusion Coefficient Quantification in Determining the Histological Diagnosis of Malignant Liver Lesions.

PURPOSE: Diffusion Weighted Imaging is an established diagnostic tool for accurate differential diagnosis between benign and malignant liver lesions. The aim of our study was to evaluate the role of Histogram Analysis of ADC quantification in determining the histological diagnosis as well as the grade of malignant liver tumours. To our knowledge, there is no study evaluating the role of Histogram Analysis of ADC quantification in determining the histological diagnosis as well as the grade of malignant liver tumours. METHODS: During five years, 115 patients with known liver lesions underwent Diffusion Weighted Imaging in 3Tesla MR scanner prior to core needle biopsy. Histogram analyses of ADC in regions of interest were drawn and were correlated with biopsy histological diagnosis and grading. RESULTS: Histogram analysis of ADC values shows that 5th and 30th percentile parameters have statistically significant potency of discrimination between primary and secondary lesions groups (p values 0.0036 and 0.0125 respectively). Skewness of the histogram can help discriminate between good and poor differentiated (p value 0.17). Discrimination between primary malignancy site in metastases failed for the present number of patients in each subgroup. CONCLUSION: Statistical parameters reflecting the shape of the left side of the ADC histogram can be useful for discriminating between primary and secondary lesions and also between well differentiated versus moderate or poor. For the secondary malignancies, they failed to predict the original site of tumour.

Drug Eluting Stents for Malignant Airway Obstruction: A Critical Review of the Literature.

Lung cancer being the most prevalent malignancy in men and the 3(rd) most frequent in women is still associated with dismal prognosis due to advanced disease at the time of diagnosis. Novel targeted therapies are already on the market and several others are under investigation. However non-specific cytotoxic agents still remain the cornerstone of treatment for many patients. Central airways stenosis or obstruction may often complicate and decrease quality of life and survival of these patients. Interventional pulmonology modalities (mainly debulking and stent placement) can alleviate symptoms related to airways stenosis and improve the quality of life of patients. Mitomycin C and sirolimus have been observed to assist a successful stent placement by reducing granuloma tissue formation. Additionally, these drugs enhance the normal tissue ability against cancer cell infiltration. In this mini review we will concentrate on mitomycin C and sirolimus and their use in stent placement.

Immunohistochemical profile of NF-κB/p50, NF-κB/p65, MMP-9, MMP-2, and u-PA in experimental cervical spondylotic myelopathy.

STUDY DESIGN: The immunohistochemical profile of nuclear factor-κ B (NF-κB)/p50, NF-κB/p65, matrix metalloproteinase (MMP)-9, MMP-2, and urokinase-type plasminogen activator (u-PA) proteins was examined in spinal cord tissues coming from rabbits, which underwent chronic cervical spinal cord compression. OBJECTIVE: To study the potential role of NF-κB and extracellular matrix proteins under the chronic mechanical compression of the cervical spinal cord. SUMMARY OF BACKGROUND DATA: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction among adults older than 55 years. Neuronal loss, myelin destruction, axonal degeneration, and glial scar formation are the principal neuropathological features of CSM. However, the biologic pathways that lead to these features remain unclear. METHODS: In this study, we used a new animal experimental model of CSM developed in our laboratory. Briefly, after posterior cervical laminectomy, gradual and progressive compression (during 20 weeks) was achieved by introducing a piece of aromatic polyether (0.07 mm thick) under the C6 lamina in 15 New Zealand rabbits. In control animals (n = 15), the aromatic polyether was implanted and then removed after 60 seconds (sham operation). The immunoreactivity of p50 and p65 subunits of NF-kB, as well as that of MMP-2, MMP-9, and u-PA, was evaluated in paraffin-embedded spinal cord sections coming from both groups. The evaluation was performed using immunohistochemistry technique and the results were analyzed using SPSS for Windows, release 12.0 (SPSS Inc., Chicago, IL). RESULTS: Increased immunoreactivity of both NF-κB subunits, p50 and p65, as well as MMP-2, MMP-9, and u-PA was demonstrated in animals with CSM in comparison with controls. Statistical analysis of the results revealed strong positive correlation between NF-κB subunits immunoreactivity and that of MMP-9, MMP-2, and u-PA. CONCLUSION: There is a strong correlation between the immunoexpression of NF-κB/p50, NF-κB/p65, MMP-2, MMP-9, u-PA, and CSM.

Mutation analysis of IgVH genes in splenic marginal zone lymphomas: correlation with clinical characteristics and outcome.

BACKGROUND: To determine the immunoglobulin variable heavy chain (IgVH) gene usage and somatic mutation patterns in a series of SMZL patients and to correlate these findings with the clinical features and outcome. PATIENTS AND METHODS: IgVH genes were amplified and sequenced from 22 SMZL cases. Clinical and laboratory data of these patients were recorded. RESULTS: A biased usage of IgVH gene was found with overrepresentation of VH3 in 16/22 cases. A total of 13/22 (59%) of cases were found to have mutated IgVH genes, whereas 9/22 (41%) were unmutated. Positive antigen selection process was identified in two cases. Treatment was different between the cases with mutation and those without. No differences in clinical and laboratory characteristics, or survival were found between the mutated and unmutated cases. CONCLUSION: SMZL are characterized by marked molecular heterogeneity. A biased usage of certain sequences suggests antigen selection. Prognostic significance of mutational status was not confirmed in this study. However further studies are needed in order to confirm these results.

Non-gastric extra-nodal marginal zone lymphomas--a single centre experience on 76 patients.

In the present study, we assessed the clinical and pathological data of 76 patients with the diagnosis of non-gastric extranodal marginal zone B-cell lymphoma. The most commonly affected sites were salivary glands, skin, ocular adnexa, lung, intestine and Waldeyer's ring. Ann Arbor stage I disease was present in 39 patients (51%), stage II in 10 (13%) and stage IV in 27 (36%). In 17 cases (21%), the lymphoma presented at multiple mucosal sites. Lymph node and bone marrow involvement were present in 21% and 16%, respectively. Most cases were in the low or low-intermediate risk group. Treatment was heterogeneous and included chlorambucil in 59% either alone or in combination with other agents. Complete and partial remission was achieved in 79% and 7%, respectively, with an overall response rate of 86%. The 5- and 10-year overall survival and cause-specific survival rates were 94%, 82% and 95%, 91%, respectively. The 5- and 10-year progression free survival was 56% and 41%, respectively. The only feature associated with inferior outcome was disease localisation to the lung.

Primary nasal non-Hodgkin lymphomas presented initially as benign disease.

BACKGROUND: Primary non-Hodgkin lymphomas (NHLs) of the sinonasal tract comprise a rare entity that constitutes 1.5% of all NHLs and 2.2% of extranodal lymphomas in the whites. Clinical diagnosis may be very challenging because of the variety and low specificity of the presenting symptoms and signs. METHODS-RESULTS: We present three cases of NHLs, initially diagnosed as benign diseases. All three cases have been eventually correctly diagnosed and treated in our hospital between January 2000 and December 2003. The patients have been under close follow-up from 11 to 36 months after the initial treatment. One of them remains without clinical or radiological evidence of recurrence, whereas the two others died 11 and 16 months after the initial diagnosis. CONCLUSION: It is important to underline that atypical or persistent symptoms of rhinosinusitis may represent the initial expression of a more serious condition such as deep fungal infection, vasculitis, lymphoma, or other malignancy.