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Vasseur, Loïc, Florence Morin, Corinne Pondarré, Florian Chevillon, Aude-Marie Fourmont, Regis Peffault De Latour, Nicolas Boissel, Hélène Moins-Teisserenc, Sophie Caillat-Zucman, and Nathalie Dhedin. "Early Immune Reconstitution after Hematopoietic Stem Cell Transplantation for Adolescents and Adults with Sickle Cell Disease." Blood 138, Supplement 1 (November 5, 2021): 3907. http://dx.doi.org/10.1182/blood-2021-147133.
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Abstract Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p < 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p < 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.
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Alcolea, Javier, Marcelino Agúndez, Valentín Bujarrabal, Arancha Castro Carrizo, Jean-François Desmurs, Carmen Sánchez-Contreras, and Miguel Santander-García. "M 1–92 revisited: the chemistry of a common envelope nebula?" Proceedings of the International Astronomical Union 14, S343 (August 2018): 343–44. http://dx.doi.org/10.1017/s1743921318005021.
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AbstractWe report on new molecular-line observations of the bipolar pre-planetary nebula M 1–92. The new IRAM 30 m MRT and NOEMA data shows the presence of shock induced chemistry in the nebula. From the derived [17O]/[18O] ratio, we suggest that the sudden mass loss event responsible for the formation of the nebula 1200 yr ago may also have resulted in the premature end of the AGB phase of the central star.
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Kostrub, O. O., Iu V. Poliachenko, M. A. Gerasimenko, V. V. Kotiuk, R. I. Blonskii, V. B. Mazevych, and N. S. Vadzyuk. "ANTEROLATERAL LIGAMENT AS ROTATION STABILISER OF KNEE- JOINT. THE ROLE OF MRT AND ULTRASONOGRAPHY IN UNDERSTANDING ITS ANATOMY AND IN SELECTING SURGICAL TREATMENT STRATEGY FOR ITS INJURIES." Novosti Khirurgii 29, no. 5 (October 11, 2021): 581–89. http://dx.doi.org/10.18484/2305-0047.2021.5.581.
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Objective. To assess the variability of the anterolateral ligament according to MRT and ultrasonography data and to coordinate it with surgical treatment strategy for its injuries. Methods. The anterolateral ligament was analyzed on 100 series of MRI images of knee joints without traumatic pathology on Philips Achieva 1.5 T tomograph using the standard research protocol in three mutually perpendicular planes and 150 series of MRT images of knee joints with injuries and without injuries of the anterolateral ligament obtained on different tomographs from 0.2 to 3 Tesla. The quality of visualization of anterolateral ligament separate portions, the number of layers, and the contact with the joint capsule were evaluated. Both knee joints were analyzed by ultrasonography in 30 patients with anterior cruciate ligament injuries of one of the knee-joint and in 30 patients with intact knee-joints. Results. During the studies in the identification of anterolateral ligament with magnetic resonance tomography (MRT 1.5T)it was revealed at least partially in 92% of cases (in 68% as a two-layer structure; in 24% as a single-layer structure; in 14% as a thickening of the capsule or in 10% as a separate extracapsular structure), ultrasound examination - in 100% (the structure was not determined, however, in 26.67% of patients without clinically pronounced pathology of the knee-joint and significant trauma in anamnesis ultrasound scan revealed a violation of the integrity of the cortical layer at the tibial attachment site), Conclusion. According to MRT and ultrasonography data, the anterolateral ligament is a constant structure of the knee-joint, but very variable in its anatomical parameters, which in some cases may be poorly visualized on MRT, may have a two-layer structure, may be located either extracapsular or as a thickening of the knee-joint capsule. The variability of its anatomical structure makes it impossible to make the theoretical substantiation of the advantages of one separate method of its restoration, but, on the contrary, justifies a differentiated approach to the selection of optimal surgical treatment. What this paper adds With the help of current research methods, the normal anatomical parameters and anatomical variants of the anterolateral ligament of the knee joint have been clarified and detailed. It is necessary to emphasize the importance of a differentiated approach to choosethe optimal methods of surgical treatment for its injuries.
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Bailey, Stephen J., Anni Vanhatalo, Matthew I. Black, Fred J. DiMenna, and Andrew M. Jones. "Effects of Priming and Pacing Strategy on Oxygen-Uptake Kinetics and Cycling Performance." International Journal of Sports Physiology and Performance 11, no. 4 (May 2016): 440–47. http://dx.doi.org/10.1123/ijspp.2015-0292.
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Purpose:To assess whether combining prior “priming” exercise with an all-out pacing strategy is more effective at improving oxygen-uptake (V̇O2) kinetics and cycling performance than either intervention administered independently.Methods:Nine men completed target-work cycling performance trials using a self-paced or all-out pacing strategy with or without prior severe-intensity (70%Δ) priming exercise. Breath-by-breath pulmonary V̇O2 and cycling power output were measured during all trials.Results:Compared with the self-paced unprimed control trial (22 ± 5 s), the V̇O2 mean response time (MRT) was shorter (V̇O2 kinetics were faster) with all-out pacing (17 ± 4 s) and priming (17 ± 3 s), with the lowest V̇O2 MRT observed when all-out pacing and priming were combined (15 ± 4 s) (P < .05). However, total O2 consumed and end-exercise V̇O2 were only higher than the control condition in the primed trials (P < .05). Similarly, cycling performance was improved compared with control (98 ± 11 s) in the self-paced primed (93 ± 8 s) and all-out primed (92 ± 8 s) trials (P < .05) but not the all-out unprimed trial (97 ± 5 s; P > .05).Conclusions:These findings suggest that combining an all-out start with severe-intensity priming exercise additively improves V̇O2 MRT but not total O2 consumption and cycling performance since these were improved by a similar magnitude in both primed trials relative to the self-paced unprimed control condition. Therefore, these results support the use of priming exercise as a precompetition intervention to improve oxidative metabolism and performance during short-duration high-intensity cycling exercise, independent of the pacing strategy adopted.
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Hoch, Lucile, Helene Faure, Hermine Roudaut, Angele Schoenfelder, Andre Mann, Nicolas Girard, Laure Bihannic, et al. "MRT‐92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor." FASEB Journal 29, no. 5 (January 30, 2015): 1817–29. http://dx.doi.org/10.1096/fj.14-267849.
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Umutlu, Lale, Felix Nensa, Aydin Demircioglu, Gerald Antoch, Ken Herrmann, Michael Forsting, and Johannes Stefan Grueneisen. "Radiomics Analysis of Multiparametric PET/MRI for N- and M-Staging in Patients with Primary Cervical Cancer." RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren 192, no. 08 (April 30, 2020): 754–63. http://dx.doi.org/10.1055/a-1100-0127.
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Zielsetzung Ziel dieser Studie war die Evaluierung des prädiktiven Potenzials der Radiomics-Analyse zur Bestimmung des N- und M-Stadiums des primären Zervixkarzinoms anhand multiparametrischer 18F-FDG-PET/MRT-Bildgebung. Material und Methoden 30 Patientinnen mit einem histologisch gesicherten, primären und therapienaiven Zervixkarzinom unterzogen sich einer multiparametrischen 18F-FDG-PET/MRT-Untersuchung unter Verwendung eines dedizierten Untersuchungsprotokolls des weiblichen Beckens. Nach Segmentierung der Primärtumoren wurden quantitative Bildparameter mittels der Radiomic-Image-Processing-Toolbox bestimmt. Insgesamt wurden 45 verschiedene quantitative Bildmerkmale jeweils anhand der T2-gewichteten TSE-Sequenzen, der nativen und kontrastmittelgestützten T1-gewichteten TSE-Sequenzen, der ADC-Map, verschiedenen Perfusionsparametern (Ktrans, Kep, Ve and iAUC) und den 18F-FDG-PET-Datensätzen für jeden Tumor extrahiert. Die statistische Analyse zur Bestimmung des N- und M-Stadiums erfolgte unter der Verwendung der Python 3.5 und Scikit-learn-Software-Bibliothek für maschinelles Lernen. Ergebnisse Insgesamt zeigte sich eine höhere Genauigkeit zur Prädiktion des korrekten M-Stadiums im Vergleich zum N-Stadium. Zur Prädiktion des korrekten M-Stadiums zeigten sich unter der Verwendung von SVM und SVM-RFE zur Feature-Auswahl die besten Ergebnisse mit einer Sensitivität von 91 %, einer Spezifität von 92 % und einer Fläche unter der Kurve (AUC) von 0,97. Die höchste Genauigkeit für die Bestimmung des N-Stadiums erfolgte unter der Verwendung von RBF-SVM und MIFS zur Feature-Auswahl mit einer Sensitivität von 83 %, einer Spezifität von 67 % und einer Fläche unter der Kurve (AUC) von 0,82. Schlussfolgerung Die Radiomics-Analyse von multiparametrischen PET/MR-Datensätzen ermöglicht eine präzise Prädiktion des M- und N-Stadiums von Patientinnen mit primärem Zervixkarzinom und könnte damit supportiv zur nichtinvasiven Tumor-Phänotypisierung und Patientenstratifizierung eingesetzt werden. Kernaussagen: Citation Format
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Goppold, Ramona, Corinna Trenker, Christoph F. Dietrich, Andreas Neubauer, and Christian Görg. "Der Stellenwert der Sonografie in der Hämatologie und Onkologie – Eine retrospektive Studie von Sonografie-Zuweisungen in einem universitären Ultraschallzentrum." TumorDiagnostik & Therapie 42, no. 10 (November 25, 2021): 725–31. http://dx.doi.org/10.1055/a-1282-8288.
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Zusammenfassung Hintergrund In den Leitlinien onkologischer Krankheitsbilder wird zur bildgebenden Diagnostik vorrangig ein PET-CT, CT und MRT gefordert. Der Stellenwert der Sonografie ist unklar. Fragestellung Ziel der Arbeit ist es, den Stellenwert des Ultraschalls in der Hämatologie und Onkologie in einem universitären interdisziplinären Ultraschallzentrum zu analysieren. Material und Methoden Von Januar bis April 2017 wurden 5019 Ultraschalluntersuchungen durchgeführt. In n = 1506 (30 %) Fällen lag eine hämatologische (H) oder onkologische (O) Problemstellung vor. Die retrospektive Auswertung der Ultraschallanforderungen und Ultraschallbefunde erfolgte hinsichtlich: 1. H/O-Fragestellung, 2. Zuweiser, 3. Untersuchungsmodalität, 4. Organuntersuchung, und 5. Klinischer Hintergrund. Ergebnisse H/O-Fragestellung betrafen: Screeninguntersuchungen (165; 11 %), Primärdiagnostik (508; 34 %), Ausbreitungsdiagnostik (92; 6 %), Therapieansprechen (264; 18 %), Nachsorge (100; 7 %) und akute Probleme (377; 25 %). Die untersuchten Fälle waren ambulant (675; 44,8 %) oder stationär (831; 55,2 %). Neben dem B-Bild Ultraschall (100 %) kamen kontrastmittelunterstützte Sonografie (162; 11 %) und Interventionen (79; 5 %) zum Einsatz. Ultraschalluntersuchungen des Abdomens wurden am häufigsten angefordert (1033; 69 %). Diskussion Diese unizentrische Studie zeigt, dass Ultraschalldiagnostik einen breiten Einsatz bei hämatologischen und onkologischen Patienten einnimmt. Die größte Bedeutung des Ultraschalls liegt in der primären Tumordiagnostik und bei akuten Therapie- und/oder erkrankungsassoziierten Komplikationen.
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Jannat, N., MS Rahman, E. Islam, NA Rumi, M. Giasuddin, M. Hasan, MR Islam, and MZ Hassan. "Seroprevalance And Molecular Detection Of Fmdv In Cattle At Savar In Bangladesh." SAARC Journal of Agriculture 17, no. 2 (February 3, 2020): 67–78. http://dx.doi.org/10.3329/sja.v17i2.45295.
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The study was conducted to observe the overall seroprevalence and molecular detection of circulating FMD virus from infected cattle and efficacy of antibacterial drugs against secondary bacterial infection at Savar, Dhaka from January- December 2018. A total of 92 serum samples were collected for indirect c-ELISA to detect antibodies against non-structural proteins of FMD virus, and overall seroprevalence was 94.02%. The seroprevalence of serotype O and A was higher (95.83% and 95.83%) in male cattle than female (93.18% and 90.91%) respectively. 6 Months to 3 years aged cattle showed, significantly (p<0.01) higher seroprevalence (100%) than above 4 years age groups for serotype O (82.14%) and A (78.57%). Local cattle were more seropositive 96.88% compared to crossbred cattle 93.33% for serotype O and 91.67% for serotype A and this variation was not statistically significant (p>0.05). Among 10 clinical samples of FMD from infected cattle, 8 samples were positive for different serotypes, among them 2 each were identified as serotype A and Asia-1. On the other hand,4 samples were identified as mixed infection (1 sample of serotype O+A, 3 samples of O+Asia-1) by mRT-PCR. In this study on therapeutic intervention with sulphadimidine significantly (p<0.05) reduced the clinical signs of FMD than Gentamycin and Ampicillin. The higher seroprevalence of the disease has substantial economic implications which signify the need for devising effective control measure. However, the detection of ‘O’, Asia-1and ‘A’ serotype emphasizes the critical need for use of atrivalent vaccine in the field.
SAARC J. Agri., 17(2): 67-78 (2019)
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Nanjundappa, Sathish, Suresh Narayanan Nair, Darsana Udayan, Sreelekha Kanapadinchareveetil, Mathew Jacob, Reghu Ravindran, and Sanis Juliet. "Disposition Kinetics of Amitraz in Lactating Does." Molecules 26, no. 16 (August 6, 2021): 4769. http://dx.doi.org/10.3390/molecules26164769.
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Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.
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Qodir, Abdul, Erni Setyowati, and Suryono Suryono. "ANALISIS PENGARUH BENTUK SERAMBI MASJID TERHADAP KENYAMANAN TERMAL ADAPTIF." Jurnal Arsitektur ARCADE 4, no. 3 (November 19, 2020): 261. http://dx.doi.org/10.31848/arcade.v4i3.522.
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This study examines the effect of the porch on the adaptive thermal comfort of mosques by taking 2 mosques that have different porch shapes with the specific purpose of obtaining data on the neutrality, acceptability and preferences of the mosque respondents' thermal conditions in the framework of developing adaptive thermal comfort standards for Indonesia. Measurement of physical environment variables is done by taking data on temperature, humidity, air velocity, and mean radiant temperature (MRT) at 2 mosques and at the same time the impression and thermal preference questionnaire data are taken, examination of clothing types and activities, and list of thermal environment controls to 40 respondents in each mosque. Data of thermal neutrality and thermal preferences were analyzed by regression analysis using SPSS 19 software, while thermal acceptance was analyzed based on the results of the questionnaire answers. The analysis showed that the neutrality value at Ulul Albab mosque was Tdb = 28.47 OC, ET * = 30.11 OC, SET * = 23.11 OC, TSENS = 1.17, DISC = -1.06, and PMV = -0.65, this data shows that the neutral condition desired by respondents is slightly below the average condition, while the neutrality in Nurul Ilmi mosque at Tdb = 30.27 OC, ET * = 31.65 OC, SET * = 29.05 OC, TSENS = 1.03, DISC = 1.68, and PMV = 1.22, this data also shows that the neutral conditions desired by respondents are slightly below average conditions. While the preference value at Ulul Albab mosque is Tdb = 22.25 OC, ET * = 28.62 OC, SET * = 24.24 OC, TSENS = 0.23, DISC = 0.23, and PMV = -0.60 and preference conditions at Nurul Ilmi mosque at Tdb = 29.11 OC, ET * = 31.17 OC, SET * = 28.50 OC, TSENS = 1.04, DISC = 1.45, and PMV = 1.03. As many as 92% of respondents in the Ulul Albab mosque can accept local thermal conditions in the temperature range of 27oC - 31oC. While 90% of respondents in the Nurul Ilmi mosque can accept local thermal conditions in the temperature range of 27oC-32oC. The results of the neutrality, acceptance and preference analysis show that the Ulul Albab mosque is better than the Nurul Ilmi mosque.
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Elsaidi, Hassan, Fatemeh Ahmadi, Leonard Wiebe, and Piyush Kumar. "Development of [131I]I-EOE-TPZ and [131I]I-EOE-TPZMO: Novel Tirapazamine (TPZ)-Based Radioiodinated Pharmaceuticals for Application in Theranostic Management of Hypoxia." Pharmaceuticals 12, no. 1 (January 1, 2019): 3. http://dx.doi.org/10.3390/ph12010003.
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Introduction: Benzotriazine-1,4-dioxides (BTDOs) such as tirapazamine (TPZ) and its derivatives act as radiosensitizers of hypoxic tissues. The benzotriazine-1-monoxide (BTMO) metabolite (SR 4317, TPZMO) of TPZ also has radiosensitizing properties, and via unknown mechanisms, is a potent enhancer of the radiosensitizing effects of TPZ. Unlike their 2-nitroimidazole radiosensitizer counterparts, radiolabeled benzotriazine oxides have not been used as radiopharmaceuticals for diagnostic imaging or molecular radiotherapy (MRT) of hypoxia. The radioiodination chemistry for preparing model radioiodinated BTDOs and BTMOs is now reported. Hypothesis: Radioiodinated 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ), a novel bioisosteric analogue of TPZ, and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide (I-EOE-TPZMO), its monoxide analogue, are candidates for in vivo and in vitro investigations of biochemical mechanisms in pathologies that develop hypoxic microenvironments. In theory, both radiotracers can be prepared from the same precursors. Methods: Radioiodination procedures were based on classical nucleophilic [131I]iodide substitution on Tos-EOE-TPZ (P1) and by [131I]iodide exchange on I-EOE-TPZ (P2). Reaction parameters, including temperature, reaction time, solvent and the influence of pivalic acid on products’ formation and the corresponding radiochemical yields (RCY) were investigated. Results: The [131I]iodide labeling reactions invariably led to the synthesis of both products, but with careful manipulation of conditions the preferred product could be recovered as the major product. Radioiodide exchange on P2 in ACN at 80 ± 5 °C for 30 min afforded the highest RCY, 89%, of [131I]I-EOE-TPZ, which upon solid phase purification on an alumina cartridge gave 60% yield of the product with over 97% of radiochemical purity. Similarly, radioiodide exchange on P2 in ACN at 50 ± 5 °C for 30 min with pivalic acid afforded the highest yield, 92%, of [131I]I-EOE-TPZMO exclusively with no trace of [131I]I-EOE-TPZ. In both cases, extended reaction times and/or elevated temperatures resulted in the formation of at least two additional radioactive reaction products. Conclusions: Radioiodination of P1 and P2 with [131I]iodide leads to the facile formation of [131I]I-EOE-TPZMO. At 80 °C and short reaction times, the facile reduction of the N-4-oxide moiety was minimized to afford acceptable radiochemical yields of [131I]I-EOE-TPZ from either precursor. Regeneration of [131I]I-EOE-TPZ from [131I]I-EOE-TPZMO is impractical after reaction work-up.
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Tefferi, Ayalew, Kebede Begna, William J. Hogan, Mark R. Litzow, Curtis A. Hanson, and Animesh Pardanani. "Long-Term Outcome of Treatment with Ruxolitinib in Myelofibrosis." Blood 118, no. 21 (November 18, 2011): 1752. http://dx.doi.org/10.1182/blood.v118.21.1752.1752.
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Abstract Abstract 1752 Background: Patients with primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis often harbor a JAK2 mutation and also display abnormally increased inflammatory cytokines (J Clin Oncol. 2011;29:1356). Therefore, JAK-STAT is an appealing drug target in such patients. Ruxolitinib (INCB018424) is a small molecule ATP mimetic that inhibits both JAK1 and JAK2 and has been evaluated for its therapeutic activity in MF, in the setting of phases 1, 2, and 3 clinical trials. Methods: The first phase-1/2 MF study using ruxolitinib was conducted at the MD Anderson Cancer Center and Mayo Clinic. A total of 153 patients were included in the study whose first line results were published in September, 2010 (NEJM 2010;363:1117). The current report constitutes a sponsor-independent analysis of long-term outcome in the 51 Mayo Clinic patients who participated in the particular clinical trial. Results I: Baseline characteristics: The 51 patients (37 males) from the Mayo Clinic were enrolled between October, 2007 and February 2009. The median time from treatment initiation is now 3.5 years. MF subtype distributions were PMF 60%, post-PV MF 32% and post-ET MF 10%. Median (range) values were age 61 years (39–79), hemoglobin 10.6 g/dL (7.4-15.3), leukocyte count 15.8 (2.0–136), and palpable spleen size 19 cm (0–32). The proportion of patients with red cell transfusion dependency was 24%, hemoglobin <10 g/dL 38%, unfavorable karyotype 18%, pruritus 24%, night sweats 26%, and JAK2V617F 84%. DIPSS-plus risk distributions were high 18%, intermediate-2 48%, intermediate-1 22% and low 14%. Results II: Response and treatment duration: According to the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria, spleen response rate was 29% and anemia response rate 21%. Responses were also seen in constitutional symptoms (63%) and pruritus (92%). To date, treatment has been discontinued in 47 (92%) patients. The treatment discontinuation rates at 1, 2 and 3 years were 51%, 72% and 89%, respectively. For the 47 patients who were taken off study, median duration of treatment was 9.2 months (range 1.3–42 months). Reasons for treatment discontinuation included loss or lack of response/disease progression (∼40%), toxicity with and without lack of response/disease progression (∼34%), patient/physician choice often associated with lack of response (13%), and death on study (∼4%). Results III: Toxicity: Grade ≥2 thrombocytopenia and anemia occurred in 26% and 33% of patients and persisted in the majority of afflicted patients after drug discontinuation. To date, 18 deaths (36%) and 5 (10%) leukemic transformations have been recorded. Serious adverse events occurred upon drug discontinuation in 6 cases (13%) and were characterized by immediate relapse of symptoms, rapid and painful enlargement of spleen sometimes associated to splenic infarct, and acute hemodynamic decompensation occasionally leading to a septic shock-like syndrome. Results IV: Survival: There was no significant difference in the survival of the 51 ruxolitinib-treated patients compared to that of a cohort of 410 cases of PMF seen at the Mayo Clinic in the most recent 10-year period: unadjusted (Figure 1; p=0.43) and adjusted for DIPSS-plus (Figure 2; p=0.58). Conclusions: Ruxolitinib is effective in alleviating constitutional symptoms in the majority of patients with MF. Its activity in reducing spleen size is modest and not always durable. It is imperative that patients be alerted about important drug adverse events including potentially irreversible thrombocytopenia, worsening of anemia, and potentially catastrophic withdrawal symptoms. Ruxolitinib therapy does not appear to affect survival in MF. Disclosures: No relevant conflicts of interest to declare.
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Jung, Chul Won, Lee-Yung Shih, Zhijian Xiao, Jie Jin, Hsin-An Hou, Xin Du, Ming-Chung Wang, et al. "A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)." Blood 122, no. 21 (November 15, 2013): 4086. http://dx.doi.org/10.1182/blood.v122.21.4086.4086.
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Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
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Kulesh, A. A., N. Kh Gorst, V. E. Drobakha, N. A. Kaileva, and V. V. Shestakov. "Cortical superficial siderosis is a new MRT-phenomenon in neurological practice: clinical observations and review of literature." Perm Medical Journal 35, no. 5 (December 15, 2018): 82–92. http://dx.doi.org/10.17816/pmj35582-92.
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Cerebral amyloid angiopathy (CAA) is a specific variant of cerebral small vessel disease, associated with high risk of spontaneous intracerebral bleedings, cognitive disorders and hemorrhagic complications of antithrombotic and thrombolytic therapy. One of key markers of CAA is a relatively rare neurovisual phenomenon – cortical superficial siderosis (CSS). Two clinical cases of CAA with CSS are described in the present paper. In the first case, typical CAA complication were observed: intracerebral bleeding and cognitive disorders. In the second case, CAA was symptom-free. Analysis of clinical cases and literature data shows phenotypic heterogeneity of CAA and confirms advisability of routine use of paramagnetic conditions of MRT to examine patients with cerebrovascular disease.
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Kimševaitė, Liudmila. "NEUROLOGINĖ PATOLOGIJA SERGANT 2 TIPO CUKRINIU DIABETU." Medicinos teorija ir praktika 22, no. 4 (January 10, 2017): 328–35. http://dx.doi.org/10.15591/mtp.2016.053.
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Reikšminiai žodžiai: cukrinis diabetas, neurologinė patologija, neurologinės komplikacijos. Darbo tikslas. Išanalizuoti 2 tipo cukriniu diabetu sergančių asmenų neurologinę patologiją. Tyrimo medžiaga ir metodai. Vilniaus miesto klinikinės ligoninės Vidaus ligų, Nefrologijos, I ir II angiochirurgijos, Urologijos skyriuose 2015 m. rugpjūtį – 2016 m. birželį tyrėme 102 2 tipo cukriniu diabetu sergančius ligonius (80 moterų ir 22 vyrus), kuriems buvo ar pasireiškė neurologinė patologija. Ligonių amžius 49–92 metai (vidurkis 73,2 ± 1,1 metų). Visiems ligoniams atliktas bendras kraujo tyrimas, nustatyta gliukozės koncentracija kraujo serume, glikozilintas hemoglobinas HbA1C, atlikta vidaus organų echoskopija, daliai ligonių – pilvo organų kompiuterinė tomografija (KT), esant indikacijoms – galvos (stuburo) KT, magnetinio rezonanso tomografija (MRT). Statistinių duomenų vidurkių skirtumai vertinti Stjudento patikimumo kriterijumi t. Skirtumai laikyti statistiškai patikimi esant p < 0,05. Rezultatai. Išanalizuota sergančiųjų 2 tipo cukriniu diabetu neurologinė patologija. Galvos smegenų kraujotakos sutrikimai buvo 23 (22,5 proc.) ligoniams, diabetinė encefalopatija – 4 (3,9 proc.), diabetinė koma – 1 (1 proc.), hipoglikeminė koma – 1 (1 proc.), lėtinė galvos smegenų išemija – 10 (9,8 proc.), epilepsiniai priepuoliai – 3 (2,9 proc.), Parkinsono liga – 3 (2,9 proc.), diabetinė chorėja – 1 (1 proc.), diabetinė mielopatija – 1 (1 proc.), diabetinė periferinė neuropatija – 46 (45,1 proc.), diabetinė autonominė neuropatija – 3(2,9 proc.), peties rezginio neuropatija (plexopathia brachialis) – 1 (1 proc.), veidinio nervo neuropatija – 2 (2 proc.), vidurinio nervo neuropatija – 1 (1 proc.), meralgia paraesthetica – 2 (2 proc.). Galvos smegenų infarkto atveju, palyginus su sergančiųjų lėtine galvos smegenų išemija grupe, nustatyta statistiškai patikimai didesnė hiperglikemija: ženkliai padidėjęs gliukozės (11,08 ± 1,3 mmol/l, p < 0,02), glikozilinto hemoglobino HbA1C (8,5 ± 1,2 proc., p < 0,05) kiekis kraujyje. Lėtine galvos smegenų išemija sergančiųjų grupėje gliukozės kiekis kraujyje buvo 7,26 ± 0,4 mmol/l, glikozilinto hemoglobino HbA1C – 6,03 ± 0,2 proc. Padidėjęs gliukozės, glikozilinto hemoglobino HbA1C kiekis kraujyje, palyginus su sergančiųjų lėtine galvos smegenų išemija grupe, nustatytas ir praeityje galvos smegenų infarktą patyrusiems ligoniams – atitinkamai 8,65 ± 0,7 mmol/l ir 7,26 ± 0,4 mmol/l (p > 0,05), 7,2 ± 0,4 proc. ir 6,03 ± 0,2 proc. (p < 0,01). Nustatyta sergančiųjų diabetine polineuropatija hiperglikemijos dydžio priklausomybė nuo cukrinio diabeto trukmės: sergančiųjų cukriniu diabetu daugiau kaip 10 metų, palyginus su sergančiųjų iki 5 metų grupe, gliukozės kiekis kraujyje buvo atitinkamai 9,93 ± 0,8 mmol/l ir 7,6 ± 0,7 mmol/l (p < 0,05), glikozilinto hemoglobino HbA1C – 8,2 ± 0,3 proc. ir 5,78 ± 0,1 proc. (p < 0,001). Sergančiųjų cukriniu diabetu nuo 5 iki 10 metų gliukozės kiekis kraujyje buvo 8,3 ± 1,0 mmol/l, (p > 0,05), glikozilinto hemoglobino HbA1C – 6,6 ± 0,4 proc. (p < 0,05), palyginus su sergančiųjų cukriniu diabetu iki 5 metų grupe. Pateikti klinikiniai atvejai. Apžvelgta naujausia mokslinė literatūra apie sergančiųjų 2 tipo cukriniu diabetu neurologinę patologiją. Atliktų tyrimų duomenys palyginti su literatūros duomenimis. Išvados. Diabetinė polineuropatija yra dažniausia cukrinio diabeto komplikacija. Ji pasireiškia beveik pusei sergančiųjų cukriniu diabetu. Nustatyta sergančiųjų diabetine polineuropatija hiperglikemijos dydžio priklausomybė nuo cukrinio diabeto trukmės. Vidurinio nervo neuropatija yra ankstyva cukrinio diabeto komplikacija. Meralgia paraesthetica – skausminė neuropatija, susijusi su cukriniu diabetu. Cukriniu diabetu sergantiems ligoniams dažniau įvyksta aterotrombozinis insultas. Galvos smegenų infarkto atveju, palyginus su sergančiųjų lėtine galvos smegenų išemija grupe, nustatyta statistiškai patikimai didesnė hiperglikemija. Diabetinė encefalopatija – naujai pripažinta cukrinio diabeto komplikacija. Jos klinikinis spektras platus – nuo nežymios kognityvinės disfunkcijos iki demencijos. Epilepsiniai priepuoliai yra hiperglikemijos manifestacija. Jie gali būti pirminė klinikinė cukrinio diabeto apraiška. Neramių kojų sindromas dažnesnis diabetikams. Polineuropatija yra pagrindinis neramių kojų sindromo rizikos veiksnys sergant cukriniu diabetu.
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Gowin, Krisstina, Prakash Thapaliya, J. Samuelson, C. N. Harrison, Deepti Radia, Bjorn Andreasson, John Mascarenhas, et al. "Pegylated Interferon Alpha – 2a in Patients with Myeloproliferative Neoplasms (MPN): International Experience in 115 Cases." Blood 118, no. 21 (November 18, 2011): 2818. http://dx.doi.org/10.1182/blood.v118.21.2818.2818.
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Abstract Abstract 2818 Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET) and polycythemia vera (PV), as well as treatment for early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in MPN patients treated outside the constraints of a clinical trial in the USA and EU. Methods: Clinical records of MPN patients treated at the participating centers, receiving Peg INF2a outside of the context of a clinical trial, were analyzed for response (ET and PV by ELN criteria; MF by EUNMET and IWG-MRT criteria), toxicity, and duration of response. Results: Patients: 115 patients were identified (54 PV (47%), 44 ET (38%), 17 MF (15%)) with a median age at diagnosis (48) and gender distribution (59% females) typical for the disorders. The patients had been diagnosed with the MPN a median of 44 months (0.0–312 months) prior to initiation of the Peg IFN2a and 64% harbored the JAK2-V617F mutation. The majority of patients (81%) had received at least one prior cytoreductive therapy for their disease (73 hydroxyurea, 39 anagrelide, 37 aspirin, 21 prior interferon (non pegylated), 3 phlebotomy alone). Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range: 22.5–180) with peak starting doses ranging from 30 to 300 micrograms/week. A total of 84 patients (73%) remain on Peg IFN2a with median duration of treatment of 17 months (range: 1.0–92). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity was Gr 3 or lower. There were 6 cases with anemia (5%), 10 with thrombocytopenia (9%) and 8 had leukopenia (7%). Most common non-hematologic toxicities were Gr 1–3 fatigue in 27 (23%), Gr 1 LFT elevation in 6 (5%), Gr 2–3 skin/allergic reaction in 6 (5%), Gr 1–2 nausea in 5 (4%), and Gr 2 mood disorder in 5 (4%) patients. Twenty patients (17%) discontinued therapy secondary to toxicity. Response: ET-PV: By ELN criteria, 30 PV patients achieved CR (55%), 17 achieved PR (31%), 4 achieved NR (7%), and 3 patients (5%) were lost to follow up or were too early to evaluate for response. In ET, the responses were CR in 27 (61%), PR in 7 (16%), NR in 4 (9%), and 6 patients (14%) were lost to follow up or were too early to evaluate for response. MF: The responses by IWG criteria were 1 CR (6%), 2 PR (12%), 2 CI (12%) and 9 SD (53%). By EUNMET, there were 2 CR (12%), 4 major responses (24%), 4 moderate responses (24%), 1 minor response (6%), 2 no response (12%), and 3 patients (17%) were lost to follow up or were too early to evaluate for response. Conclusions: Peg INF2a used at doses consistent with published clinical trials is active and well-tolerated when administered in a clinical setting outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg INF2a as first line therapy in high-risk MPNs. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.
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Passamonti, Francesco, Susanne Schnittger, François Girodon, Jean-Jacques Kiladjian, Mary Frances McMullin, Marco Ruggeri, Eric Lippert, et al. "Molecular and Clinical Features of the Myeloproliferative Neoplasm Associated with JAK2 Exon 12 Mutations: a European Multicenter Study." Blood 114, no. 22 (November 20, 2009): 3904. http://dx.doi.org/10.1182/blood.v114.22.3904.3904.
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Abstract Abstract 3904 Poster Board III-840 While about 95% of patients with polycythemia vera carry the unique V617F mutation in JAK2 exon 14, several mutations in exon 12 have been described in the minority of JAK2 (V617F)-negative subjects. The initial study [N Engl J Med 2007 Feb 1;356(5):459-68] led to the conclusion that JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis. Very recent studies suggest that the 'GGCC' haplotype of JAK2 confers susceptibility to the somatic acquisition of both JAK2 (V617F) and exon 12 mutations [Nat Genet 2009 Apr;41(4):450-4, Leukemia 2009 May 14, Epub ahead of print]. Indeed, we reported pedigrees with familial polycythemia vera in which there were both JAK2 (V617F)-positive and JAK2 exon 12 mutation-positive siblings [Blood 2008 Feb 1;111(3):1686-9]. The myeloproliferative neoplasm associated with JAK2 exon 12 mutations is a rare disorder, and only small groups of patients have been reported so far by various investigators. We therefore started a collaborative study in Europe with the aim of collecting about 100 patients with this condition in order to define the molecular and clinical features of this myeloproliferative neoplasm. An ad hoc database was developed for data collection and management. As of August 1, 2009, 77 patients with the required clinical and hematologic data at diagnosis have been recruited (median follow-up 3.2 years, range 0-27 years), while complete follow-up information was available for 57 of these patients. Various approaches were employed for the detection of JAK2 exon 12 mutations, including genomic DNA sequencing, allele-specific PCR assays, and high resolution melting. Overall, 16 different exon 12 mutations were identified. The most frequent mutation were N542-E543del (26 patients), K539L (12 patients), R541-E543delinsK (6 patients), and F537-K539delinsL (6 patients); the remaining mutations occurred less frequently. With respect to the clinical phenotype at presentation, the Kruskal-Wallis test did not reveal any significant difference between the above most frequent mutations. Median age at diagnosis was 53 years (range 15-92), and the male/female ratio was 43/34. Mean hemoglobin level was 19.3 ± 2.2 g/dL, mean WBC count 8.5 ± 3.2 × 109/L, and mean PLT count 334 ± 197 × 109/L. Overall, 48 out of 77 (62%) patients presented with isolated erythrocytosis, 12 (16%) with erythrocytosis and leukocytosis (WBC count > 10 × 109/L), 8 (10%) with erythrocytosis and thrombocytosis (PLT count > 400 × 109/L), and 8 (10%) displayed a full myeloproliferative pattern (erythrocytosis, leukocytosis and thrombocytosis). Serum erythropoietin level was below the lower normal limit in 46 out of 58 (79%) patients. Twenty-one of 25 (84%) patients had endogenous erythroid colonies. During follow-up, two patients had deep venous thrombosis, two progressed to post-polycythemia vera myelofibrosis (diagnosed according to the IWG-MRT criteria) and two developed a myelodysplastic syndrome. In conclusion, the available data indicate that the myeloproliferative neoplasm associated with JAK2 exon 12 mutations is mainly associated with isolated erythrocytosis at clinical onset, but also suggest that the subsequent clinical course may be similar to that of JAK2 (V617F)-positive polycythemia vera, at least in a portion of patients. Disclosures: No relevant conflicts of interest to declare.
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Pardanani, Animesh, Ramy A. Abdelrahman, Christy Finke, Terra L. Lasho, Kebede Begna, Aref Al-Kali, William J. Hogan, et al. "Genetic Determinants of Response and Survival in Momelotinib Treated Myelofibrosis Patients." Blood 124, no. 21 (December 6, 2014): 3162. http://dx.doi.org/10.1182/blood.v124.21.3162.3162.
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Abstract Background : Momelotinib is a JAK1 and JAK2 inhibitor that is currently being evaluated in phase-3 clinical trials for the treatment of myelofibrosis (MF) (NCT01969838, NCT02101268). In a phase-1/2 clinical trial of patients with MF, the drug was shown to improve anemia, reduce spleen size and alleviate symptoms (Leukemia 2013;27:1322). In the current study, we considered 100 consecutive patients from the Mayo Clinic who received momelotinib therapy, in order to identify molecular and cytogenetic predictors of treatment response and survival from the time of study entry. Methods : The study patients constituted part of a phase-1/2 clinical trial (NCT00935987) using momelotinib in MF. Details of the protocol, including inclusion and exclusion criteria were previously published (Leukemia 2013;27:1322). Response was determined by the 2006 response criteria published by the IWG-MRT. Data analysis and interpretation was carried out independent of any influence from the sponsor. Results : 100 patients with MF (median age 66 years; 58% males) were treated at the Mayo Clinic between 11/20/09 and 11/10/10. MF type was primary in 64% of the patients and post-polycythemia vera/essential thrombocythemia in 36%. DIPSS-plus risk distribution was 63% high, 36% intermediate-2 and 1% intermediate-1. Red cell transfusion dependency was documented in 49% and palpable spleen size of >5 cm (median 19 cm) in 92%. All patients were annotated for JAK2/CALR/MPL mutations with respective frequencies of 73%, 16% and 7%. Frequencies for other mutations included 42% for ASXL1 (84 evaluable) and 18% for SRSF2(78 evaluable). All patients were evaluable for karyotype, which was unfavorable in 17%. Previous treatment included other JAK inhibitors in 21 patients, thalidomide/lenalidomide/pomalidomide in 31 and hydroxyurea or other cytoreductive agents in 55. Momelotinib was initiated at 100 mg/day in 3 patients, 150 mg/day in 21, 150 mg twice-daily in 20, 200 mg/day in 3, 300 mg/day in 47 and 400 mg/day in 6. The maximum momelotinib dose was 150 mg/day in 6 patients, 150 mg twice-daily in 20, 300 mg/day in 68 and 400 mg/day in 6. Treatment duration was <6 months in 12 patients, 6-12 months in 22, 12-24 months in 19 and >24 months in 47. Genetic correlates of response to momelotinib : Overall response rate was 57% and included no complete remissions (0%), one (1%) partial remission and 57 (57%) clinical improvements (CI). Response rates for spleen/liver and anemia were 43% (91 evaluable) and 44% (68 evaluable), respectively. Transfusion independency was achieved in 25 (51%) of 49 evaluable cases. Spleen/liver response rate was significantly affected by JAK2/CALR/MPL mutational status (34% vs 73% vs 60%, respectively, and 50% in triple-negative; p=0.04), CALR mutated vs unmutated status (73% vs 37%; p=0.009), and unmutated vs mutated ASXL1 (53% vs 29%; p=0.035). Furthermore, all 8 (100%) patients who were CALR+/ASXL1- responded vs 6 (25%) of 24 CALR-/ASXL1+ vs 3 (50%) of 6 CALR+/ASXL1+ vs 16 (43%) of 37 CALR-/ASXL1- patients (p=0.003). Spleen/liver response rates were not affected by SRSF2 mutations (p=0.93) or karyotype (p=0.41). Anemia response rate was not affected by JAK2/CALR/MPL (p=0.81), ASXL1 (p=0.16), SRSF2 (p=0.12) or CALR/ASXL1 (p=0.42) mutational status or karyotype (p=0.65). The number of informative cases for EZH2, IDH, SF3B1 and U2AF1mutations were not adequate enough to warrant similar analysis. Genetic correlates of survival from time of protocol entry : Median follow-up after the institution of protocol drug therapy was 35 months (range 1-49). During this period, 57 (57%) deaths and 12 (12%) leukemic transformations were documented. On multivariable analysis, shortened survival was predicted by the presence of ASXL1 (p=0.01; HR 2.1, 95% CI 1.2-3.8) or SRSF2 (0.01; HR 2.4, 95% CI 1.2-4.8) mutations and the absence of CALR mutations (p=0.03; HR 3.2, 95% CI 1.1-8.9). Karyotype was significant on univariate (p=0.01) but not in multivariable (p=0.6) analysis that included the aforementioned mutations. The prognostic relevance of each specific mutation was DIPSS-plus independent. Conclusions : We demonstrate significant associations between CALR and ASXL1 mutational status and spleen response to momelotinib therapy in MF. We also show that momelotinib therapy did not overcome the inferior survival associated with the presence of ASXL1 or SRSF2 mutations or the absence of CALR mutations. Disclosures No relevant conflicts of interest to declare.
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Rotunno, Giada, Annalisa Pacilli, Giada Brogi, Valentina Artusi, Elisa Rumi, Federica Delaini, Carmela Mannarelli, et al. "Impact of Mutation Status of ASXL1, EZH2, SRSF2, IDH1/2 on Clinical Phenotype and Prognosis in Patients with Post-Polycythemia and Post-Essential Thrombocythemia Myelofibrosis: An AGIMM Study." Blood 124, no. 21 (December 6, 2014): 1867. http://dx.doi.org/10.1182/blood.v124.21.1867.1867.
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Abstract Background: We reported that mutations in ASXL1, EZH2, IDH1/2 and SRSF2 are negative prognostic variables for survival in primary myelofibrosis (PMF). Patients harboring any one of these mutations comprise IPSS and DIPSS-plus independent high molecular risk (HMR) category. Conversely, prognostic variables in secondary myelofibrosis (sMF), including post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF are not defined. Aims: The aim was to evaluate the correlations of HMR mutational status with hematologic characteristics and clinical presentation, and the role for outcome predition, in PPV- and PET-MF. Methods: PPV- and PET-MF were diagnosed by IWG-MRT criteria; all pts provided informed consent. Previously published methods were used to screen mutations involving JAK2,MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. The prognostic value of the molecular variables with regard to OS was estimated by the Kaplan-Meier method and Cox regression. Results: A series of 200 sMF pts from 3 Italian centres was collected: 108 were PPV-MF (54%), 92 PET-MF (46%). PPV-MF cohort: Median age was 65y. Median follow up from PPV-MF diagnosis 4.7y (0.2-25.9y) and median time from PV to PPV-MF 10y (1.08-30.7y). Death occurred in 34 pts (31.8%), 7 pts (6.5%) developed leukemia. Median OS from PPV-MF diagnosis was 9.5y (7.1-11.9y). Frequency of mutations was: JAK2V617F 100% (median allele burden 77%, range 23-100), ASXL1 17.8%, EZH2 3.7%, IDH 5.6%, SRSF2 1%; 29 patients (26.9%) were classified as HMR cases. Hematologic characteristics: median leucocytes 13.0x109/L, hemoglobin 13.3g/dL, platelets 328x109/L, blasts ≥1% 23.4%. Constitutional symptoms in 45.8%, splenomegaly 94.1% (43.3% >10cm from LCM), pruritus 49%; median percentage of BM cellularity was 90% (25-100%) and grade 3 fibrosis in 16.8%. Overall 73 patients were evaluable for karyotype and abnormalities were detected in 42.5%. We did not find significant correlations between individual mutations or HMR category and hematologic and clinical characteristics. PET-MF cohort: Median age was 63.6y. Median follow up from the PET diagnosis 3.3y (0.2-14.5y), median time from ET to PET-MF 11.8y (0.9-30.6y). Death occurred in 30 pts (32.6%), 11 pts (12.0%) developed leukemia. Median OS from PET-MF diagnosis was 9.2y (4.9-13.6y). Frequency of mutations was: JAK2V617F 48.9% (median allele burden 49%, range 0-100), CALR 40.2%, MPL 4.3% and triple negativity (TN) 6.5%; ASXL1 29.3%, EZH2 6.5%, IDH 1.1%, SRSF2 3.3%; 33 pts (35.9%) were HMR. Hematologic characteristics: median leucokytes 8.0x109/L, hemoglobin 10.9 g/dL, platelets 375x109/L, blasts ≥1% 26.4%. Constitutional symptoms 35.4% of pts, splenomegaly 82% (18.2% >10cm from LCM), pruritus i31%; median percentage of BM cellularity was 70% (15-90%) and grade 3 fibrosis was found in 31.7%. Overall 56 patients were evaluable for karyotype and abnormalities were detected in 25.0%. By correlating hematologic and clinical characteristics with unique mutations and HMR category, we found that HMR mutated pts presented greater leukocytosis (P=0.04) and higher JAK2V617F allele burden (P=0.017) than pts in the low-molecular risk –LMR- category (ie, wild-type for ASXL1, EZH2, SRSF2, IDH1/2). Comparison of PPV-MF and PET-MF: a comparison of hematologic and clinical characteristics according to the diagnosis sMF disclosed that PPV-MF pts presented more frequently splenomegaly (P=0.008; for >10cm from LCM P<0.001), pruritus (P=0.009), abnormal karyotype (P=0.009), increased leukocytes (P<0.001), higher hemoglobin (P<0.001) and BM cellularity (P<0.001) compared with PET-MF. Conversely, PET-MF pts presented higher incidence of grade 3 of BM fibrosis (P=0.04). The median JAK2 allele burden (P<0.001) was higher in PPV-MF pts, while PET-MF pts showed more frequent mutations of ASXL1 (29.3% vs 17.8%; P=0.03). Univariate analysis disclosed significant correlations between shortened survival and mutated ASXL1 (P=0.02, HR 2.2 95% CI, 1.02-4.8) or EZH2 (P=0.05, HR 5.0 95% CI, 1.0-40.7) in PPV-MF. A HMR category was associated with reduced survival in PPV-MF: median survival 6.1y versus 9.5yr LMR (HR 1.07, 95%CI 1.0-4.4; P=0.04). In PET-MF survival was 4.8y in HMR versus 10.9y in LMR (HR1.6, 95%CI 0.8-3.4; P=0.2). Conclusion: We conclude that a HMR status is associated with shorter survival in sMF, but the overal impact is narrower than in primary MF, even though the rate of mutations is similar (Table1). Disclosures No relevant conflicts of interest to declare.
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Abu-Zeinah, Ghaith, Silvana Di Giandomenico, Tatiana Cruz, Daniel Choi, Elwood Taylor, Ellen Ritchie, Richard T. Silver, and Joseph Scandura. "Hematopoietic Stem and Progenitor Cell Fitness As a Novel Prognostic and Monitoring Biomarker for JAK2 V617F Myeloproliferative Neoplasms (MPNs)." Blood 138, Supplement 1 (November 5, 2021): 627. http://dx.doi.org/10.1182/blood-2021-153003.
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Abstract Introduction: MPNs are chronic malignancies associated with significant morbidity and mortality due to cardiovascular events (CVE) and progression to more aggressive myeloid neoplasms (progression). CVE, progression, and survival are not feasible clinical trial endpoints due to the long follow-up required for analysis, leading to use of short-term measures. A reliable biomarker linking MPN biology with these important outcomes would facilitate development of new agents that can meaningfully reduce these risks and improve survival. Ultimately, MPNs result from hematopoietic stem cell (HSC) acquisition of highly recurrent driver mutations, most commonly JAK2 V617F. Here, we study MPN fitness - the competitive advantage of mutated hematopoietic stem and progenitor cells (HSPC) over their normal counterparts- as a prognostic and monitoring biomarker in MPNs, and compare it to whole blood (WB) mutation allele frequency (MAF). Methods: We measured fitness by sorting peripheral blood (PB) specimens from MPN patients (pts) at Weill Cornell Medicine (WCM) into 11 well-defined and strictly validated immunophenotypic HSPC and mature cell compartments and measured MAF in each and in WB (Fig 1A). The study was approved by WCM institutional review board. Pt age, sex, diagnosis (Dx), duration of disease (Dur), symptoms, blood counts, mutations, spleen size, treatment, follow-up, and events (CVE, progression, death) were tabulated. Principal component (PC) analysis was used for unsupervised hierarchical clustering of 11-population MAFs to identify predominant patterns of fitness. Event-free survival (EFS) was assessed using Kaplan-Meier (KM) methods and log-rank test. Cox multivariable analysis (MVA) of EFS was used to assess the independent prognostic value of baseline MPN fitness, compared to WB MAF. A Cox model was used to translate change in fitness (PCs 1-3, Fig 1E) from serial samples into a relative risk of events. A Fisher's test was used to determine if changes in fitness were associated with events and/or IWG-MRT/ELN response (Barosi et al. & Tefferi et al. Blood 2013). Results: A total of 212 PB samples from 93 JAK2 V617F MPN pts with essential thrombocythemia (ET, n = 20, 22%), polycythemia vera (PV, n = 39, 42%), myelofibrosis (MF, n = 32, 34%) or unclassified MPN (MPNU, n = 2, 2%) were prospectively collected between 7/2017-7/2021 and analyzed. Median age was 68 years (yr) (range 28-90) and median Dur was 6 yr (0-45). The majority were females (n=58, 62%). Unsupervised PC clustering at baseline revealed 4 major fitness levels (FLs): F1, F2, F3, and F4 (Fig 1B). The pattern of JAK2 V617F propagation from HSPC to mature lineages differed across FLs (Fig 1C). EFS was strongly (KM, p<0.001, Fig 1D) and independently (Cox MVA) associated with FL when covariates of age, sex, Dx, Dur, and WB MAF were considered (F2, 3, 4, versus F1: HR of 7 [p=0.15], 31 [p=0.009], and 92 [p=0.009], respectively). In contrast, EFS was not statistically linked to WB MAF quartiles in KM analysis (p=0.06) and was not associated with WB MAF in MVA (HR 0.97, p=0.06). We developed a Cox model to predict relative risk of events from serial fitness measures and tested the model in 25 pts. Pts with increased fitness were more likely to experience an adverse event (33% vs 0%, p=0.047) and were less likely to achieve clinical response (13% versus 75%, p=0.007) than pts with decreased fitness. Change in WB MAF did not correlate with change in fitness (r 2=0.0116) and did not predict events (p=1) nor clinical response (p=0.23). Discussion: Reliable biomarkers are needed to efficiently identify disease-modifying treatments mitigating the risk of progression and other adverse events. Our study offers a feasible approach to monitor risk by tracking MPN fitness in clinically accessible PB specimens. In this large study, MPN fitness outperformed WB MAF as a biomarker and was highly prognostic of EFS. Fitness dynamics were strongly predictive of events and clinical response whereas changes in WB MAF were unreliable. Methods to simplify routine measurement of MPN fitness are being developed to support clinical trials. Updated validation of MPN fitness as a biomarker in clinical trials will be presented. Conclusion: MPN fitness may serve as both a prognostic biomarker identifying MPN pts at high risk of disease-related events and a monitoring biomarker for use as a short-term surrogate of long-term outcomes in clinical trials. Figure 1 Figure 1. Disclosures Abu-Zeinah: PharmaEssentia: Consultancy. Ritchie: ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Protaganist: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Scandura: MPN-RF (Foundation): Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees .
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Pietrobono, Silvia, Eugenio Gaudio, Sinforosa Gagliardi, Mariapaola Zitani, Laura Carrassa, Francesca Migliorini, Elena Petricci, et al. "Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma." Oncogene, May 6, 2021. http://dx.doi.org/10.1038/s41388-021-01783-9.
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AbstractDespite the development of new targeted and immune therapies, the prognosis of metastatic melanoma remains bleak. Therefore, it is critical to better understand the mechanisms controlling advanced melanoma to develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting the central pathway transducer Smoothened (SMO) have shown to be clinical efficacious in skin cancer; however, several mechanisms of non-canonical HH/GLI pathway activation limit their efficacy. Here, we identify a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the HH/GLI pathway, providing a novel mechanism of non-canonical SMO-independent activation of HH/GLI signaling in melanoma. Consistently, we find a positive correlation between the expression of GLI1 and SOX2 in human melanoma samples and cell lines. Further, we show that combined targeting of canonical HH/GLI pathway with the SMO inhibitor MRT-92 and of the SOX2-BRD4 complex using a potent Proteolysis Targeted Chimeras (PROTACs)-derived BRD4 degrader (MZ1), yields a synergistic anti-proliferative effect in melanoma cells independently of their BRAF, NRAS, and NF1 mutational status, with complete abrogation of GLI1 expression. Combination of MRT-92 and MZ1 strongly potentiates the antitumor effect of either drug as single agents in an orthotopic melanoma model. Together, our data provide evidence of a novel mechanism of non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex, and describe the efficacy of a new combinatorial treatment for a subset of melanomas with an active SOX2-BRD4-GLI1 axis.
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Anichini, Giulia, Chiara Raggi, Mirella Pastore, Laura Carrassa, Luisa Maresca, Enrica Crivaro, Tiziano Lottini, et al. "Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma." Molecular Cancer Therapeutics, February 20, 2023, OF1—OF14. http://dx.doi.org/10.1158/1535-7163.mct-22-0379.
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Abstract Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2–M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.
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Ueberreiter, Charlotte Sophie, Klaus Ueberreiter, Chris Mohrmann, Juliane Herm, and Christian Herold. "Langzeitevaluation nach autologer Fetttransplantation zur Brustvergrößerung." Handchirurgie · Mikrochirurgie · Plastische Chirurgie, August 10, 2020. http://dx.doi.org/10.1055/a-1183-4338.
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Zusammenfassung Hintergrund Die Transplantation autologen Fettgewebes ist eine vermehrt angewandte, jedoch nicht standardisierte Prozedur in der plastischen und rekonstruktiven Chirurgie. Bisher gab es lediglich Untersuchungen zu kurzfristigen Ergebnissen über den Volumenerhalt nach einer Fettgewebstransplantation. In dieser Arbeit werden die Ergebnisse einer Langzeitstudie über Fettgewebstransplantationen zur Brustvergrößerung vorgestellt. Patienten/Material und Methoden Bei 14 Patientinnen wurde präoperativ sowie 5–9 Jahre (Median 6 Jahre) nach der Transplantation autologen Fettgewebes in die Brust nach dem BEAULI-Protokoll ein MRT angefertigt. Die Volumendifferenz wurde mit der Software OsiriX miteinander verglichen. Da zusätzlich die Auswirkung von Gewichtsschwankungen ermittelt werden sollten, wurden die Patientinnen in zwei Gruppen eingeteilt. In Gruppe 1 wurden Patientinnen mit einer Gewichtszunahme von < 1 kg/m2, in Gruppe 2 Patientinnen mit einer Gewichtszunahme von > 1 kg/m2 eingeschlossen. Die mediane BMI-Zunahme lag bei 1,6 kg/m2 (Minimal 0 – maximal 3,9). Eine der Patientinnen hatte nach vorübergehender Gewichtszunahme während der Transplantationen wieder ihr Ausgangsgewicht erreicht. Ergebnisse Die Patientinnen erhielten je nach gewünschtem Endergebnis zwischen einem und 4 Eingriffe, in welchen ein mittleres Volumen von 176 ml Fettgewebe pro Brust pro Eingriff transplantiert wurde. In der ersten Gruppe konnte ein medianer Volumenerhalt des transplantierten Fettgewebes von 74 % (IQA 58 % – 92 %) errechnet werden. In der zweiten Gruppe wurde sogar eine Volumenzunahme von im Median 135 % (IQA 105 % – 318 %) beobachtet. Schlussfolgerung In der vorliegenden Studie zeigen sich stabile Langzeitergebnisse bei der Einheilungsrate vom transplantierten Fettgewebe. Es konnte eine signifikante Korrelation zwischen Gewichtszunahme und Volumenerhalt des transplantierten Gewebes gezeigt werden. Damit ist auch die teilweise überproportional hohe Volumenzunahme bei einigen Patientinnen zu erklären. Die Transplantation autologen Fettgewebes ergibt die Möglichkeit einer sicheren und effizienten Methode zur Brustvergrößerung. Für eine genauere Aussage sind jedoch weiterführende Studien mit größeren Fallzahlen notwendig.
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"Signal relationship from parathyroid adenomas on mrt-comparative contrast to the thyroid and fat." Clinical Imaging 16, no. 4 (October 1992): 285. http://dx.doi.org/10.1016/0899-7071(92)90031-4.
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