scholarly journals Polycythemia Vera Presenting as Tinnitus and Hearing Loss: A Case Report

2020 ◽  
Vol 8 (C) ◽  
pp. 125-128
Author(s):  
How Kit Thong ◽  
Kim Yen Goh ◽  
Aminuddin Bin Saim
Keyword(s):  
Hearing Loss ◽  
Polycythemia Vera ◽  
Hematological Parameters ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Sudden Onset ◽  
Hearing Impairments ◽  
Main Complaint ◽  
Hearing Assessment ◽  
High Index Of Suspicion

BACKGROUND: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by erythrocytosis and commonly associated with the JAK2 V617F mutation. PV is a relatively rare disease with a prevalence rate of 22 per 100,000. Historically, hearing impairments were first described as a complication of PV in 1963, and it was stated that symptoms recovered after a phlebotomy. Occlusion and thrombosis of the feeding labyrinthine artery causing cochlear ischemia were thought to be the cause of such symptoms and complaints. CASE PRESENTATION: We are reporting a case of PV that was presented in our ENT outpatient clinic. The patient presented with a main complaint of sudden-onset bilateral tinnitus with one-sided hearing loss. The patient was treated medically with hydroxyurea, aspirin, and phlebotomy. On improvement of the hematological parameters, the patient noted an improvement in his hearing and it was confirmed with the finding on the repeated hearing assessment. CONCLUSION: This case emphasizes the importance of otolaryngologists remaining vigilant and maintaining a high index of suspicion as PV can present with audiological symptoms. The early diagnosis and initiation of treatment can improve patients’ hearing and reduce the morbidity of such patients.

scholarly journals Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F

2015 ◽  
Vol 33 (33) ◽  
pp. 3953-3960 ◽  
Author(s):  
Brady L. Stein ◽  
Stephen T. Oh ◽  
Dmitriy Berenzon ◽  
Gabriela S. Hobbs ◽  
Marina Kremyanskaya ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Treatment Options ◽  
Myeloproliferative Neoplasm ◽  
Symptom Burden ◽  
Jak2 V617f ◽  
Clinical Aspects ◽  
Therapeutic Modalities ◽  
Secondary Acute Myeloid Leukemia ◽  
Activating Mutation ◽  
New Treatment

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis. We summarize recent studies delineating the genetic basis of PV, including their implications for evolution to myelofibrosis and secondary acute myeloid leukemia. We assess the quality of evidence to support the use of currently available therapies, including aspirin, phlebotomy, hydroxyurea, and interferon. We analyze recent studies evaluating the safety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of other available therapies for PV. This review provides a framework for practicing hematologists and oncologists to make rational treatment decisions for patients with PV.

scholarly journals Ruxolitinib for Patients (Pts) with Polycythemia Vera: Responders Vs Non-Responders As Defined in the Response Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2947-2947
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Monika Wroclawska ◽  
Tuochuan Dong ◽  
Alessandro M. Vannucchi
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematological Parameters ◽  
Jak2 V617f ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Allele Burden ◽  
To Receive ◽  
Response Trial

Introduction: The RESPONSE trial (NCT01243944) compared ruxolitinib (Rux) and best available therapy (BAT) in pts with polycythemia vera (PV) who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNET criteria. In the primary analysis, at week (Wk) 32, 60% of (pts) randomized to Rux achieved HCT control (HCT <45%). The present analysis evaluated the effect of baseline characteristics on HCT response at Wk 32, and aimed to determine the long-term clinical efficacy of Rux in pts who did and did not achieve the protocol-defined HCT control (i.e., HCT control responders and non-responders at Wk 32) in RESPONSE at Wk 256. Methods: Adult pts with phlebotomy-dependent PV with splenomegaly, and resistant to or intolerant of HU were enrolled. Pts were randomized to receive Rux (at a starting dose of 10 mg BID) or single-agent BAT (1:1). HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (HCT > 45% and ≥ 3 percentage points higher than baseline or > 48%, whichever was lower; regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In this analysis, a logistic regression model was fitted to identify the significant baseline factors to predict HCT control response at Wk 32. Time to phlebotomy eligibility in the HCT control responders and time from the first phlebotomy eligibility to the second phlebotomy eligibility in the HCT control non-responders were plotted, and the changes in hematological parameters (HCT, WBC and platelet count), spleen volume and allele burden over time, up to Wk 256, were studied in HCT control responders and non-responders who were randomized to Rux treatment arm in RESPONSE. Results: A total of 222 pts were randomized to receive either Rux (n = 110) or BAT (n = 112). Baseline WBC (P=0.0198) and baseline JAK2 V617F allele burden (P=0.0159), were found to be predictors of the HCT response within Rux treated pt group (n = 110). In the HCT responder subgroup of the Rux arm, 23% (15/66) pts needed their first phlebotomy by Wk 256. In the HCT non-responder subgroup of the Rux arm, out of 28 patients who experienced their first phlebotomy between Wk 8 and Wk 32, 64% (18/28) of pts required subsequent phlebotomy by Wk 256, with a median duration of 28.4 Wks (12.7, NA). Pts receiving Rux demonstrated controlled hematologic parameters (HCT, WBC, and platelets) over the course of study, regardless of whether they were HCT control responders and HCT control non-responders at Wk 32. From Wk 48 to Wk 80, 97% HCT control responder pts and 84% HCT control non-responder pts of the Rux treatment arm required no phlebotomies. From Wk 80 to Wk 256, 91% and 68% of the evaluable pts in the Rux treatment arm remained phlebotomy-free for HCT control responders and non-responders, respectively. By Wk 256, spleen volume on an average was reduced from baseline by approximately 35% and 50% for HCT control responders and non-responders, respectively. In pts with available assessments, allele burden on an average was reduced approximately from 80% at baseline to 55% at Wk 256 in the HCT control responders, and approximately from 70% at baseline to 40% at Wk 256 in the HCT control non-responders. Conclusions: The results from present analysis demonstrated that the benefits of the Rux treatment were not limited to pts who achieved HCT control at Wk 32. Patients treated with Rux were able to maintain hematological parameters, spleen volume reduction, and JAK2 V617F allele burden reduction for a longer duration (up to 5 years), regardless of whether they were HCT control responders or non-responders at Wk 32. Disclosures Verstovsek: Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Wroclawska:Novartis Pharma AG: Employment. Dong:Novartis: Employment. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2813-2816 ◽  
Author(s):  
Francesco Passamonti ◽  
Chiara Elena ◽  
Susanne Schnittger ◽  
Radek C. Skoda ◽  
Anthony R. Green ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Clinical Features ◽  
Collaborative Study ◽  
Multivariable Analysis ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Hemoglobin Level ◽  
Leukocyte Counts ◽  
European Collaborative Study ◽  
V617f Mutation

Abstract Although approximately 95% of patients with polycythemia vera (PV) harbor the V617F mutation in JAK2 exon 14, several mutations in exon 12 have been described in the remaining patients. We conducted a European collaborative study to define the molecular and clinical features of patients harboring these mutations. Overall, 106 PVs were recruited and 17 different mutations identified. Irrespective of the mutation, two-thirds of patients had isolated erythrocytosis, whereas the remaining subjects had erythrocytosis plus leukocytosis and/or thrombocytosis. Compared with JAK2 (V617F)-positive PV patients, those with exon 12 mutations had significantly higher hemoglobin level and lower platelet and leukocyte counts at diagnosis but similar incidences of thrombosis, myelofibrosis, leukemia, and death. In a multivariable analysis, age more than 60 years and prior thrombosis predicted thrombosis. These findings suggest that, despite the phenotypical difference, the outcome of JAK2 exon 12 mutations-positive PV is similar to that of JAK2 (V617F)-positive PV.

Molecular and Clinical Features of the Myeloproliferative Neoplasm Associated with JAK2 Exon 12 Mutations: a European Multicenter Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3904-3904 ◽  
Author(s):  
Francesco Passamonti ◽  
Susanne Schnittger ◽  
François Girodon ◽  
Jean-Jacques Kiladjian ◽  
Mary Frances McMullin ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Clinical Features ◽  
Conflicts Of Interest ◽  
Collaborative Study ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Female Ratio ◽  
Significant Difference ◽  
Wbc Count

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.

Evaluation Of The JAK2-V617F Gene Mutation In Egyptian Patients With Essential Thrombocythemia and Polycythemia Vera

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5254-5254
Author(s):  
Maha Ibrahim El Zaafarany ◽  
A. Hasan Abdel-Ghaffar ◽  
Tawfik R. Elkhodary ◽  
Dalia A. Salem ◽  
Eman A. Soliman ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Hematological Parameters ◽  
Mutation Screening ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Egyptian Patients ◽  
V617f Mutation

Abstract An activating mutation of Janus kinase 2 (JAK2-V617F) was previously described in chronic myeloproliferative disorders (MPD). In previously published studies, the frequency of the JAK2-V617F mutation was determined to be 80–90 % for patients with polycythemia vera (PV) and 40–70 % for essential thrombocythemia (ET). In this study, we analyzed the relationship between the JAK2-V617F mutation and clinical-hematological parameters in Egyptian patients with MPD and compared these findings with published studies from other geographic regions and previous studies in EGYPT. A total of 56 patients were studied; of which, 32 were diagnosed with PV and 24 with ET. The mutation status of JAK2 was determined using allele-specific oligonucleotide (ASO) PCR assay. We found that 53% of the PV group and 79% of the ET group were positive for the JAK2-V617F mutation. When all patients were analyzed; patient age, levels of WBCs, levels of hemoglobin, levels of platelets and splenomegaly were significantly different in patients with the JAK2-V617F mutation (p < 0.05). The JAK2-V617F mutation is frequently detected in the Egyptian patients with MPD, and especially in patients with ET. Hence, it would be useful to include JAK2 mutation screening in the initial evaluation of patients suspected to have MPD especially ET. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evaluating several methods of JAK2 V617F mutation-genotyping to predict the risk of getting polycythemia vera and other myeloproliferative neoplasm diseases

2021 ◽  
Vol 19 (3) ◽  
pp. 433-440
Author(s):  
Nguyen Thy Ngoc ◽  
Bui Bich Hau ◽  
Pham Hoang Nam ◽  
Tran Tuan Anh ◽  
Do Thi Trang ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
In Silico ◽  
Sanger Sequencing ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Arms Pcr ◽  
Pcr Rflp ◽  
V617f Mutation

Polycythemia vera, essential thrombocythemia and primary myelofibrosis are members of the Philadelphia negative chronic subgroup of Myeloproliferative neoplasm. Published studies showed that the mutation JAK2 V617F is mostly responsible for the diseases; therefore, an accurate, low-cost and rapid molecular method to identify this mutation is important in screening and early diagnostic of these diseases. Different methods for genotyping of JAK2 V617F have been proposed. In this study, we evaluated the quality and cost-effectiveness of three genotyping methods, i.e., PCR-ARMS, PCR-RFLP, Sanger sequencing, to determine the appropriate genotyping for JAK2 V617F and predicted in silico the effect of this mutation on the structure and function of Janus kinase 2 protein. Results showed that the Sanger sequencing and PCR-RFLP genotyping methods were more accurate than PCR-ARMS. PCR-RFLP was also more rapid and economical than the other methods. In silico studies also demonstrated that the JAK2 V617F mutation had a large effect on the activity of corresponding protein. These results provided the initial data for further studies on genetic screening and prediction of myeloproliferative neoplasm and other related diseases in the Vietnamese population.

scholarly journals Comparative assessment of the effectiveness of hearing assessment protocols in identifying SNHL in elderly and senile people

2022 ◽  
pp. 44-50
Author(s):  
N. A. Daikhes ◽  
T. Yu. Vladimirova ◽  
S. V. Bulgakova ◽  
A. B. Martynova
Keyword(s):  
Health Care ◽  
Hearing Loss ◽  
Primary Health Care ◽  
Web Application ◽  
Sensitivity Index ◽  
Hearing Impairments ◽  
Primary Health ◽  
Hearing Assessment ◽  
The Right ◽  
The Web

Introduction. The article discusses methods of screening for hearing impairments in patients of the older age group in the frame-work of primary health care.Aim of the study. Conduct a comparative analysis of the effectiveness of different hearing assessment protocols in primary health care.Materials and methods. Сlinical and demographic data were collected in 585 elderly and senile patients (mean age 76.43 ± 9.83), tonal threshold audiometry was performed in the frequency range from 250 Hz to 12000 Hz, hearing was studied using the web application “Automated primary hearing assessment” (patent No. 2019664671) and analyzed the self-assessment of hearing with the HHIE questionnaire.Results. Most of the patients were elderly people (57.44%) with a high percentage of concomitant diseases (up to 89.23%). When interviewing a geriatrician about a complaint of hearing loss, a sensitivity of 91.5% and a specificity of 82.2% for detecting mild hearing loss, a sensitivity of 95.5% and a specificity of 71.8% for screening for moderate to severe hearing loss were obtained. When assessing the total score of the HHIE questionnaire (>17 points) and moderate hearing loss, the sensitivity was 84.7% and the specificity was 88.7%. The sensitivity index of the web application «Automated primary hearing assessment» for detecting moderate hearing impairment was 90.6% for the left ear and 88.5% for the right ear, and specificity – 88.5% for the left ear and 97.5% for the right ear.Discussion. Raising awareness of hearing problems through the introduction of feasible methods of assessing hearing function should lead to an increase in the number of older adults receiving adequate hearing rehabilitation.Conclusions. The authors conclude that it is important to take preliminary account of data on the sensitivity and specificity of assessment protocols for detecting hearing impairments of varying severity at the stage of examination of an older patient by a geriatrician and an otorhinolaryngologist.

scholarly journals PEAR1 Genetic Variants in Essential Thrombocythemia: A New Study of The Prevalence and Association of PEAR1 Variants with Hematological Parameters and ET Mutations

2021 ◽  
Author(s):  
Mohsen Maleknia ◽  
Mohammad Taha Jalali ◽  
Gholam Abbas Kaydani ◽  
Ahmad Ahmadzadeh ◽  
Najmaldin Saki
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Significant Relationship ◽  
Hematological Parameters ◽  
Myeloproliferative Neoplasm ◽  
Pcr Amplification ◽  
Jak2 V617f ◽  
P Value ◽  
Arms Pcr ◽  
Calr Mutation

Abstract Objective: Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the expansion of the megakaryocytic/platelet line. Given the undeniable role of genetic variations in the pathogenesis of ET, as well as the proven effects of PEAR1 SNPs on platelet function, the innovative purpose of this study is to investigate the prevalence of PEAR1 variants (rs12041331 and rs12566888) and their relationship to hematological parameters and ET-related mutations.Materials and Methods: We studied 105 ET patients and analyzed ET patients' mutational profiles, including JAK2 V617F mutation (detected by Allele-specific PCR), CALR, and MPL mutations (both through PCR amplification). Two SNPs of the PEAR1 gene were assessed through ARMS-PCR, and the Sanger method was used for the validation of ARMS-PCR amplification.Results: The prevalence of rs12041331 and rs12566888 in ET patients were 43.9% and 38.5%, respectively, and rs12041331 was significantly associated with increased platelet counts (P-Value: 0.02). A significant relationship was also found between the rs12041331 and CALR mutation (P-Value: 0.03). Platelet count was higher in CALR+ patients (934.45 ×10 9/L ± 265.35 SD) than in JAK2 + patients (790.11 ×10 9/L ± 265.35 SD). Conversely, other hematological parameters and thrombosis were higher in JAK2 + patients than the CALR + patients.Conclusions: Our findings reinforce the idea that rs12041331 and rs12566888 may be associated with ET, and rs12041331 is significantly associated with increased platelet count. Besides, the prevalence of ET-related mutations in patients with rs12041331 and rs12566888 was almost similar; however, only CALR mutation had a significant relationship with rs12041331.

scholarly journals Young Versus Old Age at Diagnosis Confers Distinct Genomic Profiles in Patients with Polycythemia Vera

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4322-4322
Author(s):  
Jared S Fowles ◽  
Chi-Joan How ◽  
Stephen T Oh
Keyword(s):  
Polycythemia Vera ◽  
Research Funding ◽  
Somatic Mutations ◽  
Plasma Concentrations ◽  
Myeloproliferative Neoplasm ◽  
Young Patients ◽  
Jak2 V617f ◽  
Driver Mutations ◽  
Exome Capture ◽  
Old Patients

Abstract Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by overproduction of mature erythrocytes and a propensity for transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). The defining genetic feature of PV is the JAK2 V617F mutation, present in 95-97% of patients, resulting in overactive JAK-STAT signaling. Secondary mutations have been identified which may modulate PV disease phenotype. Although typically diagnosed in older individuals, PV occurs in young patients (≤ 45 years old) as well. Compared with old patients (≥ 65 years old), a significant association with young PV and female gender, lower white blood cell count, lower JAK2 V617F allele burden, palpable splenomegaly, and splanchnic vein thrombosis has been reported. In the same study, the frequency of transformation to MF or AML was found to be similar, although the median time to transformation was shorter in old PV. The reasons for these age-related associations are not clearly understood. Since somatic mutations have been shown to accumulate with age, we hypothesized that the mutational profile of young PV patients may differ from that of old PV, which could contribute to the differences in clinical phenotypes observed. Methods: DNA from tumor (bulk peripheral blood mononuclear cells or granulocytes) and matched normal tissue (skin or sorted CD3+ T cells) was isolated from samples from 10 young (≤ 45 years old) and 11 old (≥ 65 years old) PV patients. Enhanced exome sequencing utilizing the standard IDT exome capture panel plus additional probes for genes known to be recurrently mutated in MPN and/or AML was performed. To determine order of mutation acquisition (and to rule out the possibility of biclonal disease) qPCR-based genotyping was performed on single cell-derived colonies from patients with ≥ 1 secondary mutation (in addition to JAK2 V617F). Plasma concentrations of 10 cytokines were assayed in 15 young and 23 old PV patient samples compared with age-matched healthy controls. Results: Comparative analysis of 7 young and 10 old patients (four samples were removed due to sample contamination/artifact issues) identified a total of 133 somatic mutations. A significantly higher overall mutational load was observed in the old group (mean 10.9 vs 3.4; p = 0.0025). A trend toward higher JAK2 V617F variant allele frequency (VAF) was observed in old versus young PV in the sequenced patients, and in a separate clinical cohort the JAK2 V617F VAF was significantly higher in old PV patients (p = 0.0067). Notably, putative secondary driver mutations were identified in 9/10 old PV patients (including ASXL1, TET2, and DNMT3A), whereas JAK2 appeared to be the only driver mutation present in each of the young PV patients. Secondary mutations were validated as being acquired before, after, or coincident with JAK2 V617F, with no specific predominant pattern observed. MPN-predisposing germline JAK2 46/1 haplotype occurrence did not differ with age, and additional germline mutations in MPN genes were not enriched in either cohort. Supranormal levels of multiple cytokines (e.g. IFNγ, IL-2Rα, IP-10, MIP-1α) were observed in both young and old PV, with a slight enhancement observed with increased age. Conclusions: These data indicate a striking age-based distinction in the near uniform absence (young) or presence (old) of secondary non-JAK2 mutations in PV patients. The finding that putative secondary driver mutations were acquired before JAK2 V617F in only a minority of old PV suggests that the overall increase of secondary mutations in this cohort may not merely be a function of aging, implying that these mutations do in fact contribute to PV development and/or progression. As transformation can be induced by accrual of disease-modifying mutations, the presence of secondary mutations in old PV patients is consistent with the reported shorter time to transformation in this age group, since young PV patients would likely need additional time to acquire secondary mutations. Abnormal inflammatory cytokine production was common to both young and old PV, suggesting this is not the predominant factor distinguishing these two cohorts. The contribution of additional non-genomic factors (e.g. epigenetic, hormonal) will be the subject of future study. Disclosures Oh: Janssen: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Takeda: Research Funding.

Sensorineural hearing loss associated with psoriatic arthritis

2004 ◽  
Vol 118 (11) ◽  
pp. 909-911 ◽  
Author(s):  
S. Srikumar ◽  
M.K. Deepak ◽  
S. Basu ◽  
B.N. Kumar
Keyword(s):  
Hearing Loss ◽  
Psoriatic Arthritis ◽  
Sensorineural Hearing Loss ◽  
Immunosuppressive Agents ◽  
Sudden Onset ◽  
Sensorineural Hearing ◽  
Presumptive Diagnosis ◽  
Inner Ear Disease ◽  
High Index Of Suspicion ◽  
Autoimmune Inner Ear Disease

Autoimmune inner ear disease is a well described entity. We report a case of sudden-onset sensorineural hearing loss in association with psoriatic arthritis, which has not been reported in the literature. The case satisfies the criteria for the presumptive diagnosis of autoimmune hearing loss. A high index of suspicion, with early diagnosis and aggressive treatment with steroids and/or immunosuppressive agents, is essential to prevent irreversible hearing loss. The condition of psoriatic arthritis must be added to the pantheon of autoimmune diseases that can lead to sensorineural hearing loss.

Sign in / Sign up

Export Citation Format

Share Document