Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies.

PURPOSE: Hypereosinophilia represents a heterogenous group of severe medical conditions characterized by elevated numbers of eosinophil granulocytes in peripheral blood, bone marrow or tissue. Treatment options for hypereosinophilia remain limited despite recent approaches including IL-5-targeted monoclonal antibodies and tyrosine kinase inhibitors. METHODS: To understand aberrant survival patterns and options for pharmacologic intervention, we characterized BCL-2-regulated apoptosis signaling by testing for BCL-2 family expression levels as well as pharmacologic inhibition using primary patient samples from diverse subtypes of hypereosinophilia (hypereosinophilic syndrome n = 18, chronic eosinophilic leukemia not otherwise specified n = 9, lymphocyte-variant hypereosinophilia n = 2, myeloproliferative neoplasm with eosinophilia n = 2, eosinophilic granulomatosis with polyangiitis n = 11, reactive eosinophilia n = 3). RESULTS: Contrary to published literature, we found no difference in the levels of the lncRNA Morrbid and its target BIM. Yet, we identified a near complete loss of expression of pro-apoptotic PUMA as well as a reduction in anti-apoptotic BCL-2. Accordingly, BCL-2 inhibition using venetoclax failed to achieve cell death induction in eosinophil granulocytes and bone marrow mononuclear cells from patients with hypereosinophilia. In contrast, MCL1 inhibition using S63845 specifically decreased the viability of bone marrow progenitor cells in patients with hypereosinophilia. In patients diagnosed with Chronic Eosinophilic Leukemia (CEL-NOS) or Myeloid and Lymphatic Neoplasia with hypereosinophilia (MLN-Eo) repression of survival was specifically powerful. CONCLUSION: Our study shows that MCL1 inhibition might be a promising therapeutic option for hypereosinophilia patients specifically for CEL-NOS and MLN-Eo.

Significance of eosinophilia in granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe disease presentation and long-term outcome of granulomatosis with polyangiitis (GPA) patients according to blood eosinophils count (Eos) at vasculitis diagnosis. METHODS: Data from newly diagnosed GPA patients registered in the French Vasculitis Study Group database with available eosinophil count at diagnosis were reviewed. Disease characteristics, rate and type of relapses, and overall survival were analysed according to Eos, categorized as normal (<500/mm3), mild-to-moderate hypereosinophilia (HE) (between 500 and 1500/mm3) and severe HE (>1500/mm3). RESULTS: Three hundred and fifty-four patients were included. At diagnosis, 90 (25.4%) patients had HE ≥500/mm3; they were more likely male (73% vs 56%, P = 0.006) and had more frequent cutaneous manifestations (49% vs 33%, P = 0.01), peripheral neuropathy (32% vs 17%, P = 0.004) and higher BVAS (21 vs 18, P = 0.01), compared with those with Eos <500/mm3. Patients with severe HE (n = 28; median Eos 2355, range 1500-9114) had more frequent renal function worsening at presentation (P = 0.008). After a median follow-up of 3.95 (interquartile range 1.95-6.76) years, no difference was found in overall relapse rates according to baseline Eos, but those with HE experienced more neurological (P = 0.013) and skin (P = 0.024) relapses and had more frequently peripheral neuropathy as damage at last follow-up (P = 0.02). Overall survival was not significantly different in patients with normal Eos or HE at diagnosis. (P = 0.08). CONCLUSIONS: Blood HE at diagnosis, observed in about one-quarter of GPA patients, identifies a subgroup of patients with a more severe disease and higher rate of skin and neurological involvement both at presentation and during follow-up.

Clinical Characteristics and Outcomes of Eosinophilic Colitis in Patients With Cancer.

BACKGROUND: Eosinophilic colitis (EoC) is a rare form of eosinophilic gastrointestinal disease characterized by diffuse eosinophilic infiltration in the deep lamina propria of colonic mucosa. The pathophysiology is unclear, but EoC has been associated with multiple known risk factors. AIM: The aim of this study was to characterize the clinical characteristics and disease course of patients with EoC at a major cancer center. MATERIAL AND METHODS: We retrospectively reviewed colonic samples obtained between January 2000 and December 2018 from our institutional database and included cases with significant colonic eosinophilia. Baseline clinical data and EoC-related clinical course and outcomes were documented. RESULTS: Forty-one patients were included. One fourth had coexisting autoimmune conditions. Seventy-eight percent had a cancer diagnosis. Half the patients received chemotherapy, with a median duration of 180 days between chemotherapy and EoC onset. Symptoms were present in 76% of patients. Diarrhea was more prevalent in patients who received chemotherapy (85% vs. 42%). Median duration of EoC symptoms was 30 days in patients with cancer and 240 days in those without cancer (P=0.03). Most patients (88%) had normal colonoscopy findings. Fifteen percent of patients required hospitalization. All-cause mortality was 37%, mostly related to underlying malignancy and organ failure. CONCLUSIONS: EoC in cancer patients appears to have more diarrhea-predominant symptoms, particularly in patients receiving chemotherapy, but a shorter disease duration compared with patients without cancer. Hospitalization can be required for serious cases. Treatment may be reserved for patients requiring symptom management, as most patients with EoC have good clinical outcomes regardless of treatment.

Myocarditis Presenting as Sudden Death in Infants and Children: A Single Centre Analysis by ESGFOR Study Group.

BACKGROUND: Acute myocarditis is an inflammatory disease of the heart mostly diagnosed in young people, which can present as sudden death. The etiology includes infectious agents (mostly viruses), systemic diseases and toxins. We aim to characterize infants and children with myocarditis at post-mortem presenting as sudden deaths. METHODS: Retrospective evaluation of 813 post-mortems in infants and children dying suddenly and unexpectedly between 2009-2019. Data retrieved included histological features, microbiology and clinical history. RESULTS: 23 of 813 post-mortems reviewed corresponded to acute myocarditis and 1 to dilated cardiomyopathy related to remote Parvovirus infection. PCR identified enterovirus (7), parvovirus (7 cases, 2 also with HHV6 and 1 case with EVB), Influenza A (1), Parainfluenza type 3 (1). Two cases corresponded to hypersensitivity myocarditis, 1 was Group A Streptococcus and 5 idiopathic myocarditis. Enterovirus was frequent in infants (7/10), and in newborns was associated with meningoencephalitis or congenital myocarditis. More than 50% were less than 2 years of age and all remained clinically unsuspected. CONCLUSION: Myocarditis represents almost 3% of all sudden pediatric deaths. Enterovirus and parvovirus were the most common viruses. This retrospective analysis showed that patients experienced viral symptoms but remained unsuspected, highlighting the need for more clinical awareness of myocarditis.

Potentially life­threatening severe cutaneous adverse reactions associated with tyrosine kinase inhibitors (Review).

Tyrosine kinase inhibitors (TKIs) have emerged as a new frontier of cancer therapy. These agents include inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), BRAF, mitogen­activated protein kinase kinase (also referred to as MEK), bcr­abl, c­KIT, platelet­derived growth factor (PDGFR), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK) and vascular endothelial growth factor (VEGF). Along with the evolving applications of TKIs, there has been an increased recognition of the breadth of potential cutaneous toxicities to these agents. In this review, we provide an overview of potentially life­threatening severe cutaneous adverse reactions (SCARs) that may occur during therapy with TKIs. These toxicities include Stevens­Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

The relationship between asthma, eosinophilia, and outcomes in coronavirus disease 2019 infection.

BACKGROUND: The impact of asthma diagnosis and asthma endotype on outcomes from coronavirus disease 2019 (COVID-19) infection remains unclear. OBJECTIVE: To describe the association between asthma diagnosis and endotype and clinical outcomes among patients diagnosed as having COVID-19 infection. METHODS: Retrospective multicenter cohort study of outpatients and inpatients presenting to 6 hospitals in the Mount Sinai Health System New York metropolitan region between March 7, 2020, and June 7, 2020, with COVID-19 infection, with and without a history of asthma. The primary outcome evaluated was in-hospital mortality. Secondary outcomes included hospitalization, intensive care unit admission, mechanical ventilation, and hospital length of stay. The outcomes were compared in patients with or without asthma using a multivariate Cox regression model. The outcomes stratified by blood eosinophilia count were also evaluated. RESULTS: Of 10,523 patients diagnosed as having COVID-19 infection, 4902 were hospitalized and 468 had a diagnosis of asthma (4.4%). When adjusted for COVID-19 disease severity, comorbidities, and concurrent therapies, patients with asthma had a lower mortality (adjusted odds ratio [OR], 0.64 (0.53-0.77); P < .001) and a lower rate of hospitalization and intensive care unit admission (OR, 0.43 (0.28-0.64); P < .001 and OR, 0.51 (0.41-0.64); P < .001, respectively). Those with blood eosinophils greater than or equal to 200 cells/µL, both with and without asthma, had lower mortality. CONCLUSION: Patients with asthma may be at a reduced risk of poor outcomes from COVID-19 infection. Eosinophilia, both in those with and without asthma, may be associated with reduced mortality risk.

Higher Eosinophils Predict Death-Censored Technique Failure in Peritoneal Dialysis Patients.

INTRODUCTION: Eosinophilia (eosinophil fraction of leukocytes >5%), an indicative parameter for bioincompatibility in various circumstances, is well established in hemodialysis. However, change in eosinophil count (EOC) and its association with death-censored technique failure among peritoneal dialysis (PD) patients remain unclear. METHODS: We compared eosinophils before and after PD initiation among 1,432 eligible continuous ambulatory PD patients regularly followed up in our PD center during 2007-2018. Risk factors of early-stage eosinophilia were examined by the logistic regression test. The relationship of early-stage eosinophilia and EOC with death-censored technique failure was examined using the Cox proportional hazards model for overall patients and for men and women separately. RESULTS: After PD initiation, the EOC and percentage of patients with eosinophilia were significantly increased compared with baseline. Being male (odds ratio [OR]: 2.26; 95% confidence interval [CI]: 1.55-3.31; p < 0.001) and higher EOC at baseline (100 cells/µL increase, OR: 1.62; 95% CI: 1.45-1.82; p < 0.001) were risk factors of early-stage eosinophilia after PD initiation. During follow-up, 204 death-censored technique failures were recorded. In fully adjusted models, each with 100 cells/µL increase in EOC, the adjusted hazard ratios (HRs) of technique failure were 1.11 (95% CI: 1.03-1.20; p = 0.009) in the whole cohort, 1.29 (95% CI: 1.10-1.51; p = 0.002) in women, and 1.07 (95% CI: 0.97-1.17; p = 0.196) in men. Eosinophilia was significantly associated with the risk of technique failure for women (HR: 2.24; 95% CI: 1.07-4.70; p = 0.033), which was especially significant for women aged <55 years (HR: 7.61; 95% CI: 1.88-30.90; p = 0.005). CONCLUSION: EOC was increased significantly after PD initiation, and increased numbers of eosinophils were associated with higher death-censored technique failure in PD patients, especially women.

Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.

Fatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c).

Background: Cardiac damage is frequently referred to in patients with SARS-CoV-2, is usually diagnosed by enzyme elevations, and is generally thought to be due to underlying coronary artery disease. There are references to cardiomyopathies accompanying coronavirus, but there has been no histologic confirmation.Case report: A previously healthy 17 year male old presented in full cardiac arrest to the emergency department after a 2 day history of headache, dizziness, nausea and vomiting. Autopsy demonstrated an enlarged flabby heart with eosinophilic myocarditis. There was no interstitial pneumonia or diffuse alveolar damage. Postmortem nasopharyngeal swabs detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) known to cause coronavirus disease 2019 (COVID-19). No other cause for the eosinophilic myocarditis was elucidated.Conclusion: Like other viruses, SARS-CoV-2 may be associated with fulminant myocarditis.

Eosinophil count and mortality risk in incident hemodialysis patients.

BACKGROUND: Eosinophils are traditionally known as moderators of allergic reactions; however, they have now emerged as one of the principal immune-regulating cells as well as predictors of vascular disease and mortality in the general population. Although eosinophilia has been demonstrated in hemodialysis (HD) patients, associations of eosinophil count (EOC) and its changes with mortality in HD patients are still unknown. METHODS: In 107 506 incident HD patients treated by a large dialysis organization during 2007-11, we examined the relationships of baseline and time-varying EOC and its changes (ΔEOC) over the first 3 months with all-cause mortality using Cox proportional hazards models with three levels of hierarchical adjustment. RESULTS: Baseline median EOC was 231 (interquartile range 155-339) cells/µL and eosinophilia (>350 cells/µL) was observed in 23.4% of patients. There was a gradual increase in EOC over time after HD initiation with a median ΔEOC of 5.1 (IQR -53-199) cells/µL, which did not parallel the changes in white blood cell count. In fully adjusted models, mortality risk was highest in subjects with lower baseline and time-varying EOC (<100 cells/µL) and was also slightly higher in patients with higher levels (≥550 cells/µL), resulting in a reverse J-shaped relationship. The relationship of ΔEOC with all-cause mortality risk was also a reverse J-shape where both an increase and decrease exhibited a higher mortality risk. CONCLUSIONS: Both lower and higher EOCs and changes in EOC over the first 3 months after HD initiation were associated with higher all-cause mortality in incident HD patients.

Heart disease in a mutant mouse model of spontaneous eosinophilic myocarditis maps to three loci.

BACKGROUND: Heart disease (HD) is the major cause of morbidity and mortality in patients with hypereosinophilic diseases. Due to a lack of adequate animal models, our understanding of the pathophysiology of eosinophil-mediated diseases with heart complications is limited. We have discovered a mouse mutant, now maintained on an A/J inbred background, that spontaneously develops hypereosinophilia in multiple organs. Cellular infiltration into the heart causes an eosinophilic myocarditis, with affected mice of the mutant line (i.e., A/JHD) demonstrating extensive myocardial damage and remodeling that leads to HD and premature death, usually by 15-weeks old. RESULTS: Maintaining the A/JHD line for many generations established that the HD trait was heritable and implied the mode of inheritance was not too complex. Backcross and intercross populations generated from mating A/JHD males with females from four different inbred strains produced recombinant populations with highly variable rates of affected offspring, ranging from none in C57BL/6 J intercrosses, to a few mice with HD using 129S1/SvImJ intercrosses and C57BL/6 J backcrosses, but nearly 8% of intercrosses and > 17% of backcrosses from SJL/J related populations developed HD. Linkage analyses of these SJL/J derived recombinants identified three highly significant loci: a recessive locus mapping to distal chromosome 5 (LOD = 4.88; named Emhd1 for eosinophilic myocarditis to heart disease-1); and two dominant variants mapping to chromosome 17, one (Emhd2; LOD = 7.51) proximal to the major histocompatibility complex, and a second (Emhd3; LOD = 6.89) that includes the major histocompatibility region. Haplotype analysis identified the specific crossovers that defined the Emhd1 (2.65 Mb), Emhd2 (8.46 Mb) and Emhd3 (14.59 Mb) intervals. CONCLUSIONS: These results indicate the HD trait in this mutant mouse model of eosinophilic myocarditis is oligogenic with variable penetrance, due to multiple segregating variants and possibly additional genetic or nongenetic factors. The A/JHD mouse model represents a unique and valuable resource to understand the interplay of causal factors that underlie the pathology of this newly discovered eosinophil-associated disease with cardiac complications.

Comparison of early warning scores in patients with COPD exacerbation: DECAF and NEWS score.

BACKGROUND: The National Early Warning Score 2 (NEWS2) includes two oxygen saturation scales; the second adjusts target saturations to 88%-92% for those with hypercapnic respiratory failure. Using this second scale in all patients with COPD exacerbation ('NEWS2All COPD') would simplify practice, but the impact on alert frequency and prognostic performance is unknown. Admission NEWS2 score has not been compared with DECAF (dyspnoea, eosinopenia, consolidation, acidaemia, atrial fibrillation) for inpatient mortality prediction. METHODS: NEWS, NEWS2 and NEWS2All COPD and DECAF were calculated at admission in 2645 patients with COPD exacerbation attending consecutively to one of six UK hospitals, all of whom met spirometry criteria for COPD. Alert frequency and appropriateness were assessed for all NEWS iterations. Prognostic performance was compared using the area under the receiver operating characteristic (AUROC) curve. Missing data were imputed using multiple imputation. FINDINGS: Compared with NEWS, NEWS2 reclassified 3.1% patients as not requiring review by a senior clinician (score≥5). NEWS2All COPD reduced alerts by 12.6%, or 16.1% if scoring for injudicious use of oxygen was exempted. Mortality was low in reclassified patients, with no patients dying the same day as being identified as low risk. NEWS2All COPD was a better prognostic score than NEWS (AUROC 0.72 vs 0.65, p<0.001), with similar performance to NEWS2 (AUROC 0.72 vs 0.70, p=0.090). DECAF was superior to all scores (validation cohort AUROC 0.82) and offered a more clinically useful range of risk stratification (DECAF=1.2%-25.5%; NEWS2=3.5%-15.4%). CONCLUSION: NEWS2All COPD safely reduces the alert frequency compared with NEWS2. DECAF offers superior prognostic performance to guide clinical decision-making on admission, but does not replace repeated measures of NEWS2 during hospitalisation to detect the deteriorating patient.

Could hypereosinophilia at diagnosis estimate the current activity or predict relapse in systemic immunosuppressive drug-naïve patients with eosinophilic granulomatosis with polyangiitis?

In this study, we investigated whether hypereosinophilia (peripheral eosinophil ≥ 1500/mm3) at diagnosis could estimate the increased current activity and predict the poor prognosis during follow-up in patients with eosinophilic granulomatosis with polyangiitis (EGPA). We retrospectively reviewed the medical records of 42 patients with EGPA and finally included 30 systemic immunosuppressive drug-naïve patients. We obtained clinical and laboratory data including clinical manifestations, Birmingham vasculitis activity score (BVAS), five-factor score (FFS) (2009), and routine laboratory results. Hypereosinophilia was defined as peripheral eosinophil ≥ 1500/mm3. We divided EGPA patients based on hypereosinophilia and compared variables between the two groups. The cumulative relapse-free survival rates were compared by the Kaplan-Meier survival analysis. Patients with hypereosinophilia more commonly exhibited cutaneous manifestation than those without (50.0% vs. 14.3%, P = 0.038), but there were no significant differences in BVAS and FFS (2009) at diagnosis. Patients with hypereosinophilia showed the higher median WBC (14,200.0/mm3 vs. 7940.0/mm3) and CRP (17.6 mg/L vs. 2.0 mg/L) at diagnosis than those without. During follow-up, patients with hypereosinophilia at diagnosis exhibited the similar cumulative relapse-free survival rate to those without (P = 0.393). Whereas, patients with FFS (2009) at diagnosis ≥ 2, which was a well-known predictor of the poor prognosis of EGPA, exhibited the lower cumulative relapse-free survival rate than those with FFS (2009) < 2 (P = 0.030). Hypereosinophilia at diagnosis could neither estimate the current activity nor predict relapse in systemic immunosuppressive drug-naïve patients with EGPA unlike theoretical assumption.

Clinical burden of illness among patients with severe eosinophilic COPD.

Background: There are currently limited real-world data on the clinical burden of illness in patients with COPD who continue to exacerbate despite receiving triple therapy. The aim of this study was to compare the burden of COPD in patients with and without a phenotype characterized by a high blood eosinophil count and high risk of exacerbations while receiving triple therapy. Methods: This retrospective cohort study (GSK ID: 207323/PRJ2647) used UK Clinical Practice Research Datalink records linked with Hospital Episode Statistics. Eligible patients had a COPD medical diagnosis code recorded between January 1, 2004 and December 31, 2014, and a blood eosinophil count recorded on/after that date. Patients were followed from index date (first qualifying blood eosinophil count) until December 31, 2015. The study phenotype was defined as ≥2 moderate/≥1 severe acute exacerbation of COPD (AECOPD) in the year prior to the index date, current use of multiple-inhaler triple therapy (MITT), and blood eosinophil count ≥150 cells/µL on the index date. Outcomes measured during follow-up included moderate/severe AECOPDs, severe AECOPDs, all-cause mortality, primary care (GP) clinical consultations, and non-AECOPD-related unscheduled hospitalizations. Results: Of 46,814 patients eligible for inclusion, 2512 (5.4%) met the definition of the study phenotype. Adjusted rate ratios (95% CI) of moderate/severe AECOPDs and all-cause mortality in patients with the study phenotype versus those without were 2.32 (2.22, 2.43) and 1.26 (1.16, 1.37), respectively. For GP visits and non-AECOPD-related unscheduled hospitalizations, adjusted rate ratios (95% CI), in patients with the study phenotype versus those without, were 1.09 (1.05, 1.12) and 1.31 (1.18, 1.46), respectively. Conclusion: Patients with COPD and raised blood eosinophil counts who continue to exacerbate despite MITT represent a distinct subgroup who experience substantial clinical burden and account for high healthcare expenditure. There is a need for more effective management and therapeutic options for these patients.

The Impact of Peritumoral Retraction Clefting & Intratumoral Eosinophils on Overall Survival in Oral Squamous Carcinoma Patients.

This retrospective study aimed to investigate the impact of peritumoral retraction clefts (RC) and tumor-associated tissue eosinophilia (TATE) as predictors of overall survival (OS) in oral squamous cell carcinoma (OSCC) patients. Their relationships with tumor-factors were also examined. Eighty-seven OSCC cases (pTNM: I + II/III + IV; 32/55), post-curative surgery, comprised the study cohort. Three observers independently estimated the percent RC semi-quantitatively in the selected tumor sections. Additionally, stromal eosinophils were counted in ten consecutive high-power fields of intratumoral and peritumoral regions to evaluate the corresponding TATE. The percent RC ranged between 0% -90% (Mean ± SD: 16 ± 24%; Median: 5%). The stromal eosinophils were greater in peritumoral as compared to intratumoral region. The events of death and tumor recurrence were reached in 16 (18.4%) and 36 (41%) cases respectively. The 3-years OS was 69% [Median OS: 1880 days; Mean follow up: 471(Range; 36-1880) days]. Increased percent RC exhibited relationship with pathologic stage (pTNM III&IV), primary tumor (pT III&IV), tumor depth > 4 mm and categorical tumor recurrence. Additionally, peritumoral eosinophilic infiltrates increased with increasing tumor depths and muscle invasion. Kaplan-Meier curves revealed significantly reduced OS in OSCC cases exhibiting: increased percent RC (>2.5%), mild -moderate/absent intratumoral TATE (versus intense TATE) or categorical tumor recurrence. In subsequent multivariate tests, all the three variables retained significance. Additionally, intraclass correlation coefficient demonstrated acceptable internal consistency for the observers who estimated percent RC. In conclusion, RC and intratumoral TATE proved to be independent predictors of OS in our OSCC cohort. Additionally, increased percent RC pointed towards aggressive tumor behaviour.

Clinical Implications of Tumor-Associated Tissue Eosinophilia in Tongue Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: The role of tumor-associated tissue eosinophilia (TATE) in oral cavity cancer remains quite controversial. This study investigated the potential role of TATE in tongue squamous cell carcinoma (TSCC). STUDY DESIGN: Retrospective case series. METHODS: This study retrospectively enrolled 259 consecutive TSCC patients who underwent surgery between July 2004 and December 2015. Histopathological examinations for TATE in TSCC tumors were reviewed, and the association of TATE with different clinicopathological factors was evaluated. A nomogram was generated based on several major clinicopathological factors and TATE to improve the accuracy of prognostic prediction. RESULTS: Higher levels of TATE were significantly associated with male sex, alcohol consumption, cigarette smoking, higher pT classification, advanced disease stage, and tumor depth (P = .006, .003, .024, .041, .013 and .006, respectively). Our results indicated that extranodal extension, cell differentiation, and TATE were independent predictors of overall survival (P < .001, .004, and .032, respectively) and disease-free survival (P < .001, .012, and .013, respectively). TATE levels significantly correlated with circulating eosinophils (r = 0.139, P = .040), and the c-index of our nomogram foroverall survival was 0.786, which demonstrates better accuracy in prognosis prediction than the TNM stage only (c-index = 0.738). CONCLUSIONS: Higher levels of TATE were associated with several clinicopathological factors and poorer survival rates, and a nomogram incorporating TATE levels may strengthen the prediction accuracy of prognosis in TSCC patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1123-1129, 2019.

World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes which includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2," and the "MPN subtype, chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., < 1500/mm3 ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils remains an active area of investigation.

Repercussions of eosinophils in a renal allograft - Predictor of early graft loss!

We present 5-year experience of renal transplantation (RT) with tissue eosinophilia (TE) in renal allograft biopsy (RAB) and its repercussions on the outcome. In total, 1217 recipients underwent RT from 2011 to 2015, and they were evaluated for the presence of ≥4% TE. Group 1 consisted of RT with RAB showing TE, Group 2 consisted of RT with RAB with rejections without TE, and Group 3 consisted of RT without rejections. Group 1 had 27 recipients, Group 2 had 395, and Group 3 had 795 recipients. The outcome in terms of graft function, patient and graft survival were evaluated and compared between three groups. All recipients received standard triple immunosuppression. One-year patient and death-censored graft survival were 80.7% and 82.7% in Group 1, 87.2% and 95.1% in Group 2, and 92.6% and 99.6%, respectively in Group 3 and corresponding mean serum creatinine (SCr, mg/dL) was 1.60 ± 0.45 in Group 1, 1.63 ± 0.58 in Group 2, and 1.19 ± 0.39 Group three, respectively. Five-year patient and death-censored graft survival were 72.9 % and 71.1% for Group 2 and 87% and 98.2% for Group 3 with SCr of 1.63 ± 0.38 and 1.25 ± 0.4, respectively. Group 1 recipients did not appear at five years. At four years posttransplant, patient and death-censored graft survival were 71.7% and 59.5% in Group 1 with SCr of 1.55 ± 0.65 mg/dL. In conclusion, the presence of eosino-phils in a renal allograft is an impending sign of graft damage and eventual graft loss.

Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase.

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,

Clinical and prognostic significance of eosinophilia and inv(16)/t(16;16) in pediatric acute myelomonocytic leukemia (AML-M4).

BACKGROUND: The cytogenetic aberrations inv(16)(p13.1q22)/t(16;16)(p13.1;q22), frequently detected in acute myelomonocytic leukemia with eosinophilia (FAB type M4eo), are generally considered a prognostically favorable subgroup. M4eo comprises a distinct morphology compared to M4 without eosinophilia (M4eo-) and therefore may be indicative for a different pathogenesis. PROCEDURES: Morphology and cytogenetic/molecular analyses of a Dutch cohort of pediatric acute myelomonocytic leukemia (AML-M4) patients were performed and studied in order to analyze the association between the presence of eosinophilia morphology (M4eo+), inv(16)/t(16;16) (inv(16)+), clinical features, and outcome. RESULTS: Of the 119 included patients with available combined morphological and cytogenetic results, 60% had M4eo- without inv(16) (inv(16)-), 10% had M4eo-/inv(16)+, 13% had M4eo+/inv(16)-, and 17% had M4eo+/inv(16)+. M4eo+ was significantly associated with the presence of inv(16)/t(16;16) (P < 0.001). Patients with M4eo+ had no significantly superior outcome compared with patients with M4eo-, whereas patients with inv(16)+ had significantly superior probabilities of event-free survival and probabilities of overall survival compared with patients without inv(16)-. Patients with M4eo+/inv(16)+ had no significantly better outcome than those with M4eo-/inv(16)+. CONCLUSION: The prognostically favorable impact of distinct morphology with eosinophilia probably relies on its association with inv(16)/t(16;16). Simultaneous presence of both eosinophilia and inv(16) was not associated with superior outcome in our study. These results may be relevant for risk-group classification and risk-group adapted treatment and underline the importance of accurate cytogenetic analysis.