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Background In patients receiving single lung transplantation for idiopathic pulmonary fibrosis, worsening of fibrosis of the native lung is usually progressive over time, with no significant effects on gas exchange. Case presentation Here, we describe the cases of two Caucasian male recipients of single lung transplants for idiopathic pulmonary fibrosis, 65 and 62 years of age, who exhibited acute worsening of lung fibrosis after an episode of serious viral infection (cytomegalovirus primo-infection in one case and COVID-19 in the other). In both cases, along with opacification of the native lung over several days, the patients presented acute respiratory failure that required the use of high-flow nasal oxygen therapy. Eventually, hypoxemic respiratory failure resolved, but with rapid progression of fibrosis of the native lung. Conclusion We conclude that acute worsening of fibrosis on the native lung secondary to a severe viral infection should be added to the list of potential complications developing on the native lung after single lung transplantation for idiopathic pulmonary fibrosis.

Background and Purpose: In the settings of thrombectomy, the first-pass effect (FPE), defined by a complete recanalization after one pass with no rescue therapy, has been shown to be associated with an improved outcome. As this phenomenon has been predominantly described in anterior circulation strokes, we aimed to study the prevalence, outcomes, and predictors of FPE in patients with a basilar artery occlusion. Methods: From a prospective multicentric registry, we collected the data of all consecutive basilar artery occlusion patients who underwent thrombectomy and compared the outcomes of patients who achieved FPE and those who did not. We also compared FPE patients with those who achieved a complete recanalization with >1 pass. Finally, a multivariate analysis was performed to determine the predictors of FPE. Results: Data from 280 patients were analyzed in our study, including 84 of 280 patients (30%) with an atheromatous etiology. An FPE was achieved in 93 patients (33.2%), with a significantly higher proportion of good outcomes (modified Rankin Scale score 0-2 at 3 months) and lower mortality than non-FPE patients. An FPE was also associated with improved outcomes compared with patients who went on to have full recanalization with >1 pass. Contact aspiration as first-line strategy was a strong predictor of FPE, whereas baseline antiplatelets and atheromatous etiology were negative predictors. Conclusions: In our study, an FPE was achieved in approximately one-third of patients with a basilar artery occlusion and was associated with improved outcomes. More research is needed to improve devices and techniques to increase the incidence of FPE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03776877.

MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this study, we evaluated the relative frequency of MYC rearrangement in 522 cases of FL and studied their clinicopathologic, cytogenetic, and molecular characteristics. Fluorescence in situ hybridization studies for MYC (break-apart probe), MYC/IGH, IGH/BCL2, and BCL6 rearrangements were performed on tissue microarrays. Immunohistochemical stains for CD10, BCL2, BCL6, and MYC were performed and scored on MYC-rearranged cases. On 4 FL cases, a custom targeted panel of 356 genes was used for mutation analysis. Ten cases (1.9%) were positive for MYC rearrangement. Histologically, 6 of 10 cases were grade 1-2, and 4 cases were grade 3A. By immunohistochemistry, 9 of 9 tested cases were CD10+, all cases were BCL6+, and 9/10 cases were BCL2+. MYC protein staining was low in all cases tested. IGH/BCL2 rearrangement was detected in 5 of 9 cases, whereas BCL6 rearrangement was detected in 3 of 7 tested cases and 4 of 10 cases showed MYC/IGH rearrangement. The most commonly detected mutations in the MYC-positive cases included HLA-B, TNFRSF14, and KMT2D. MYC and/or B2M abnormalities were detected in 2 cases. In conclusion, MYC rearrangement is uncommon in FL and these cases do not appear to have specific histologic characteristics. Molecular analysis showed abnormalities in genes associated with transformation, namely MYC and B2M. Larger studies are needed to evaluate if MYC-rearrangement in FL has prognostic significance.

Anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK– ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK– ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

Insecticide use has been linked to increased risk of non‐Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self‐reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B‐cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype‐specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20‐2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17‐2.16: FL, SLL) and DDT (OR = 1.36, 1.06‐1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (P trend = 1.7 × 10−4), chlordane (P trend = 1.0 × 10−3) and DDT (P trend = 4.2 × 10−3), however, the exposure‐response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45‐9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75‐16.53; P trend = 3.6 × 10−3). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure., What's new? Insecticides are persistent environmental pollutants that have been linked to increased risk of non‐Hodgkin lymphoma (NHL). Although NHL encompasses a heterogeneous group of malignancies, few studies have examined subtype‐specific associations for insecticide exposure. Analyzing data from population‐based case‐control studies of lymphatic cancers, the authors of this study show that lindane, chlordane, and DDT are associated with increased risk of multiple NHL subtypes. Analyses further uncovered a novel link between increased follicular lymphoma risk and pyrethrum use. None of the insecticides investigated, however, were associated with all NHL subtypes, suggesting a role for etiologic heterogeneity in pesticide exposure and NHL risk.

To evaluate outcomes of thrombectomy in patients with a basilar artery occlusion (BAO) and mild symptoms, defined by an initial National Institutes of Health Stroke Scale (NIHSS) score ≤6.We performed a retrospective analysis of a multicenter prospective cohort of consecutive patients with acute ischemic stroke with BAO who underwent thrombectomy. We compared baseline and procedural characteristics, as well as outcomes between patients with BAO with an NIHSS score ≤6 and6. Multivariate analyses were performed to determine baseline and procedural predictors of good outcome (modified Rankin Scale score 0-2) among patients with an NIHSS score ≤6.A total of 269 patients were included: 50 (19%) had an initial NIHSS score ≤6 and 219 (81%) had an NIHSS score6. Patients with mild strokes (NIHSS score ≤6) had better outcomes (68% of modified Rankin Scale score 0-2 vs. 27% for NIHSS score6; P0.0001), lower mortality (14% vs. 48; P0.0001) and fewer parenchymal hematomas at day 1 (0% vs. 10%; P = 0.016). A multivariate analysis identified the following predictors for good outcome among patients with BAO with an NIHSS score ≤6: younger age, fewer passes, a cardioembolic cause, and the absence of need for angioplasty/stenting.Thrombectomy seems to be safer and more effective for mild BAO strokes with NIHSS score ≤6 than for more severe patients. Even although thrombectomy showed high rates of recanalization, a substantial proportion (32%) nevertheless had a poor long-term clinical outcome. The number of passes, patient's age, and stroke cause seem to be predictors of clinical outcome.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

OBJECTIVES: Some epidemiological studies have suggested positive associations between glyphosate use and non-Hodgkin lymphoma (NHL), but evidence is inconsistent and few studies could evaluate histological sub-types. Here, associations between glyphosate use and NHL incidence overall and by histological sub-type were evaluated in a pooled analysis of case–control studies. METHODS: The analysis included 1690 NHL cases [647 diffuse large B-cell lymphoma (DLBCL), 468 follicular lymphoma (FL), 171 small lymphocytic lymphoma (SLL), and 404 other sub-types] and 5131 controls. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for NHL overall and sub-types with self-reported ever/never, duration, frequency, and lifetime-days of glyphosate use. RESULTS: Subjects who ever used glyphosate had an excess of NHL overall (OR 1.43, 95% CI 1.11–1.83). After adjustment for other pesticides, the OR for NHL overall with "ever use" was 1.13 (95% CI 0.84–1.51), with a statistically significant association for handling glyphosate >2 days/year (OR 1.73, 95% CI 1.02–2.94, P-trend=0.2). In pesticide-adjusted sub-type analyses, the ordinal measure of lifetime-days was statistically significant (P=0.03) for SLL, and associations were elevated, but not statistically significant, for ever years or days/year of use. Handling glyphosate >2 days/year had an excess of DLBCL (OR 2.14, 95% CI 1.07–4.28; P-trend=0.2). However, as with the other sub-types, consistent patterns of association across different metrics were not observed. CONCLUSIONS: There was some limited evidence of an association between glyphosate use and NHL in this pooled analysis. Suggestive associations, especially for SLL, deserve additional attention.

Background Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown. Patients and Methods We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control). Results No statistical significance was detected in patient’s overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model. Conclusion Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.

Several studies have implicated HLA in non-Hodgkin lymphoma (NHL) subtype etiology. However, NHL patients indicated for stem cell transplants are underrepresented in these reports. We therefore evaluated the association between HLA and NHL subtypes among a transplant-indicated population. One thousand three hundred and sixty-six NHL patients HLA-typed and indicated for transplant at the City of Hope National Medical Center (Duarte, CA) were compared to 10,271 prospective donors. Odds ratios and 95% confidence intervals were calculated for HLA haplotype and alleles, adjusted for sex and age. The HLA-A*0201∼C*0602∼B*1302∼DRB1*0701∼DQB1*0201 haplotype was significantly associated with follicular lymphoma (FL) risk among Caucasians. Several haplotypes were associated with diffuse large B-cell lymphoma (DLBCL) risk among Caucasians, including the previously implicated DLBCL risk loci, HLA-B*0801. The HLA-A*0101 allele was also observed to be associated with mantle cell lymphoma (MCL) risk. Our results support the association between previously reported susceptibility loci and FL and suggest potentially new DLBCL and MCL risk loci.

The prognosis of diffuse large B-cell lymphoma (DLBCL) has been associated with clinical parameters, cell of origin, and various genetic aberrations. Recently, a NanoString gene expression assay (DLBCL90) was developed, which identifies DLBCL cases with an outcome similar to those with double- or triple-hit DLBCL with both MYC and BCL2 rearrangements. This study validates the predictive ability of the DLBCL90 assay in an independent cohort of patients with the germinal center B-cell subtype DLBCL. A customized targeted sequencing panel was used to analyze the mutational profile in these patients. Cases with a double or triple hit by conventional fluorescence in situ hybridization cytogenetic analysis are known to have a poor prognosis, and the DLBCL90 gene expression signature identified these cases, as well as additional cases that would have otherwise been missed by fluorescence in situ hybridization analysis. Our findings validate use of the DLBCL90 assay for identifying high-risk patients for new and innovative therapies.

International audience; Background and purpose: Asymptomatic intracranial hemorrhage (aICH) is a common occurrence after endovascular treatment (EVT) for acute ischemic stroke (AIS). The aims of this study were to address its impact on 3-month functional outcome and to identify risk factors for aICH after EVT. Methods: Patients with AIS attributable to anterior circulation large vessel occlusion who underwent EVT were enrolled in a multicenter prospective registry. Based on imaging performed 22–36 h post-EVT, we included patients with no intracranial hemorrhage (ICH) or aICH. Poor outcome defined as a 3-month modified Rankin Scale (mRS) score 4–6 and overall 3-month mRS score distribution were compared according to presence/absence of aICH, and aICH subtype using logistic regression. We assessed the risk factors of aICH using a multivariate logistic regression model. Results: Of the 1526 patients included in the study, 653 (42.7%) had aICH. Patients with aICH had a higher rate of poor outcome: odds ratio (OR) 1.88 (95% confidence interval [CI] 1.44–2.44). Shift analysis of mRS score found a fully adjusted OR of 1.79 (95% CI 1.47–2.18). Hemorrhagic infarction (OR 1.63 [95% CI 1.22–2.18]) and parenchymal hematoma (OR 2.99 [95% CI 1.77–5.02]) were associated with higher risk of poor outcome. Male sex, diabetes, coronary artery disease, baseline National Institutes of Health Stroke Scale score and Alberta Stroke Program Early Computed Tomography Score, number of passes and onset to groin puncture time were independently associated with aICH. Conclusions: Patients with aICH, irrespective of the radiological pattern, have a worse functional outcome at 3 months compared with those without ICH after EVT for AIS. The number of EVT passes and the time from onset to groin puncture are factors that could be modified to reduce deleterious ICH.

Carriers of germline telomerase-related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range [IQR] 46-59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow-up of 26 months (IQR 15-46), 38 patients received LT. The overall post-LT median survival was 3.75 years (IQR 1.8-NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 [95% CI 1.5-11.5]) or short telomere (HR 2.2 [1.0-5.0]) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT.

ObjectiveTo better understand the functional state of circulating neutrophils in patients with ischemic stroke (IS) for planning future clinical trials.MethodsWe analyzed by flow cytometry activation state of circulating neutrophils and the distribution of neutrophil peripheral subsets in 41 patients with acute IS less than 6 hours before admission and compared them with 22 age-matched healthy controls.ResultsOur results demonstrated continuous basal hyperactivation of circulating neutrophils during acute IS, characterized by lower l-selectin expression and higher CD11b expression at the cell surface, increased ROS production by neutrophils, and greater circulating levels of neutrophil elastase. Neutrophil hyperactivation was associated with deregulation of the equilibrium between apoptotic and necrotic. Patients also had higher percentages than controls of the overactive senescent (CXCR4bright/CD62Ldim) neutrophil subset and increased percentage of neutrophils with a reverse transendothelial migration (CD54highCXCR1low) phenotype. Importantly, neutrophil alterations were associated with the clinical severity of the stroke, evaluated by its NIH Stroke Scale score.ConclusionAltogether, our results indicate that during acute IS, the inflammatory properties of circulating neutrophils rise, associated with the expansion of harmful neutrophil subsets. These changes in neutrophil homeostasis, associated with disease severity, may play an instrumental role by contributing to systemic inflammation and to the blood-brain barrier breakdown. Our findings highlight new potential therapeutic approaches of stroke by rebalancing the ratio of senescent to immunosuppressive neutrophils or decreasing reverse neutrophil transmigration or both.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies with approximately one-third of cases designated as PTCL-not otherwise specified (PTCL-NOS). Using gene expression profiling (GEP), we have previously defined two major molecular subtypes of PTCL-NOS; PTCL-GATA3 and PTCL-TBX21 that have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the two subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the two subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (p=0.03). The IHC algorithm classification showed high inter-observer reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n=124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (p=0.003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (p= 0.0015). Additionally, the two IHC-defined subtypes were significantly associated with distinct morphological features (p

Acute ischemic stroke (AIS) secondary to a basilar artery occlusion (BAO) carries a poor prognosis, especially in cases of severe symptoms, such as coma at presentation. Despite a lack of evidence, mechanical thrombectomy (MT) is often performed as the procedural risks are felt to be minimal compared to the natural history. We sought to evaluate MT efficacy and safety in comatose BAO patients.We performed a retrospective analysis of a multicenter prospective cohort of consecutive AIS patients with BAO who underwent MT. We compared baseline characteristics between comatose and noncomatose BAO patients, as well as clinical outcomes (modified Rankin scale, mRS 0-3 at 3 months). Using a multivariate logistic regression, we examined the population of comatose patients for baseline predictive factors of mortality.We included 269 patients, 72 (27%) comatose and 197 (73%) non-comatose. Despite similar recanalization rates between comatose and non-comatose patients (83% vs. 90% p = 0.221), comatose patient long-term outcomes were dramatically worse (11% mRS 0-3 vs. 54%, p 0.0001) and mortality was higher (64% vs. 34%, p 0.0001). Baseline predictors of mortality at 3 months among comatose BAO patients after multivariate analysis were the following: male sex (odds ratio, OR 31.20, 2.57-378.52, p = 0.007), older age (OR 1.13, 1.04-1.24, p = 0.007) and higher serum glucose levels (OR 1.54, 1.07-2.21, p = 0.019).Thrombectomy is technically effective for BAO patients presenting with coma; however, the long-term favorable outcome remains poor. Male sex, old age and hyperglycemia were predictors of mortality in these patients.

Background and Purpose: Although the efficacy of endovascular treatment (EVT) in patients with anterior circulation ischemic stroke (AIS) is well documented, early neurological deterioration after EVT remains a serious issue associated with poor outcome. Besides obvious causes, such as lack of reperfusion, procedural complications, or parenchymal hemorrhage, early neurological deterioration may remain unexplained (UnEND). Our aim was to investigate predictors of UnEND after EVT in patients with AIS. Methods: Patients who underwent EVT for AIS, with an initial National Institutes of Health Stroke Scale score >5, Alberta Stroke Program Early CT Score ≥6, and included in a multicenter prospective observational registry were analyzed. Predictors of UnEND, defined as ≥4-point increase in the National Institutes of Health Stroke Scale score between baseline and day 1 after EVT, were determined via center-adjusted analyses. Results: Among the 1925 included in the analysis, 128 UnEND (6.6%) were recorded. In multivariate analysis, predictors of UnEND were diabetes mellitus (odds ratio [OR], 2.17 [95% CI, 1.32–3.56]), prestroke modified Rankin Scale score ≥2 (OR, 2.22 [95% CI, 1.09–4.55]), general anesthesia (OR, 2.55 [95% CI, 1.51–4.30]), admission systolic blood pressure (OR, 1.10 [95% CI, 1.01–1.20]), age (OR, 1.38 [95% CI, 1.14–1.67]), number of passes (OR, 1.16 [95% CI, 1.04–1.28]), direct admission or not to a comprehensive stroke center (OR, 0.49 [95% CI, 0.30–0.81]), and initial National Institutes of Health Stroke Scale score (OR, 0.65 [95% CI, 0.52–0.81]). Conclusions: Severely impaired AIS patients with nonmodifiable factors are more likely to develop UnEND. Some modifiable predictors of UnEND such as the number of EVT passes could be the object of improvement in AIS management.

BACKGROUND AND PURPOSE: Ischaemic stroke has been described in association with COVID-19. Several pathophysiological mechanisms have been suggested, i.e. prothrombotic state, cardiac injury etc. It was sought to assess the potential association between ischaemic stroke associated with SARS-CoV-2 infection and underlying atherosclerotic lesions. METHODS: A retrospective analysis of stroke related to large vessel occlusion was conducted amongst patients with SARS-CoV-2 infection and underlying mild atherosclerotic disease, between 19 March and 19 April 2020 in six different stroke centers in the Ile-de France area, France. RESULTS: The median age was 52 years, median body mass index was 29.5 kg/m2 . All patients displayed previous vascular risk factors such as high blood pressure, diabetes, dyslipidemia or body mass index > 25. The delay between the first respiratory symptoms of COVID-19 and stroke was 11.5 days. At baseline, all had tandem occlusions, i.e. intracerebral and extracerebral thrombus assessed with computed tomography or magnetic resonance imaging. Cases displayed a large thrombus in the cervical carotid artery with underlying mild non-stenosing atheroma, after an etiological workup based on angio-computed tomography or magnetic resonance imaging and/or cervical echography. CONCLUSION: Our study should alert clinicians to scrutinize any new onset of ischaemic stroke during COVID-19 infection, mainly in patients with vascular risk factors or underlying atherosclerotic lesions.

PURPOSE: We performed detailed genomic analysis on 87 cases of de novo diffuse large B-cell lymphoma of germinal center type (GCB DLBCL) to identify characteristics that are associated with survival in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). EXPERIMENTAL DESIGN: The cases were extensively characterized by combining the results of immunohistochemistry, cell-of-origin gene expression profiling (Nanostring), double-hit gene expression profiling (DLBCL90), fluorescence in situ hybridization (FISH) cytogenetic analysis for double/triple-hit lymphoma, copy number analysis (CNA), and targeted deep sequencing using a custom mutation panel of 334 genes. RESULTS: We identified four distinct biologic subgroups with different survivals, and with similarities to the genomic classifications from two large retrospective studies of DLBCL. Patients with the double-hit signature but no abnormalities of TP53, and those lacking EZH2 mutation and/or BCL2 translocation, had an excellent prognosis. However, patients with an EZB-like profile had an intermediate prognosis, whereas those with TP53 inactivation combined with the double-hit signature had an extremely poor prognosis. This latter finding was validated using two independent cohorts. CONCLUSIONS: We propose a practical schema to utilize genomic variables to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies.

Background and Purpose: The efficiency of prehospital care chain response and the adequacy of hospital resources are challenged amid the coronavirus disease 2019 (COVID-19) outbreak, with suspected consequences for patients with ischemic stroke eligible for mechanical thrombectomy (MT). Methods: We conducted a prospective national-level data collection of patients treated with MT, ranging 45 days across epidemic containment measures instatement, and of patients treated during the same calendar period in 2019. The primary end point was the variation of patients receiving MT during the epidemic period. Secondary end points included care delays between onset, imaging, and groin puncture. To analyze the primary end point, we used a Poisson regression model. We then analyzed the correlation between the number of MTs and the number of COVID-19 cases hospitalizations, using the Pearson correlation coefficient (compared with the null value). Results: A total of 1513 patients were included at 32 centers, in all French administrative regions. There was a 21% significant decrease (0.79; [95%CI, 0.76–0.82]; P P P R 2 −0.51; P =0.04). Patients treated during the COVID outbreak were less likely to receive intravenous thrombolysis and to have unwitnessed strokes (both P Conclusions: Our study showed a significant decrease in patients treated with MTs during the first stages of the COVID epidemic in France and alarming indicators of lengthened care delays. These findings prompt immediate consideration of local and regional stroke networks preparedness in the varying contexts of COVID-19 pandemic evolution.

Human immunodeficiency virus (HIV)-infected people and solid organ transplant recipients have elevated risk of anaplastic large cell lymphoma (ALCL). Little is known regarding ALCL risk factors in immunosuppressed populations. We used data from US cancer registries linked to HIV registries (1996-2016) and to the national transplant registry (1992-2017). ALCL risk in HIV-infected people and transplant recipients relative to the general population was calculated as a standardized incidence ratio (SIR). ALCL risk factors were evaluated using Poisson regression. We identified 121 incident ALCL cases in the HIV (n = 86) and transplant (n = 35) populations. We reviewed pathology reports for 45 cases and most (86·7%) were confirmed as ALCL. Epstein-Barr virus tested positive in 1/8 (12·5%) cases. Compared to the general population, ALCL risk was strongly elevated among HIV-infected people [SIR 5·43; 95% confidence interval (CI) 4·27-6·81] and transplant recipients (5·96; 4·03-8·49). Among HIV-infected people, ALCL incidence was strongly related to CD4 count [adjusted incidence rate ratio (aIRR) 0·15 for ≥500 vs.

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.

The number of lung transplantations performed is increasing worldwide. With an improved experience and outcomes, the age of the recipient on its own has ceased to be an absolute contra-indication. We report our first experience with lung transplantation in patients aged 65 years or older.From January 2014 to March 2019, the files of patients aged 65 years or older undergoing lung transplantation were retrospectively reviewed.During the study period, 241 patients underwent lung transplantation in Bichat hospital (Paris, France), including 25 recipients aged 65 years or older. Underlying diagnoses were interstitial (72%) and obstructive (28%) disease. The rate of single lung transplantation was 80%. Sixteen patients required ECMO assistance during the procedure. Early complications were mostly grade III primary graft dysfunction (12%) and cellular rejection (20%). Overall one-year survival rate was 76%.After a careful selection of the recipients, the early results of our retrospective single center series are encouraging. We continue to consider lung transplantation in rigorously selected recipients of aged 65 years and more.

Background: To date, thrombectomy for large vessel occlusion (LVO) strokes can be performed only in comprehensive stroke centers with thrombectomy capacity. We compared the clinical outcome of patients first referred to a primary stroke center to those admitted directly to a comprehensive stroke center and treated on site in the multicentric observational Endovascular Treatment in Ischemic Stroke (ETIS) registry. Methods: From our perspective, multicenter, observational ETIS registry, we analyzed anterior circulation stroke patients, treated within 8 h, who underwent thrombectomy after thrombolysis and were admitted to a comprehensive stroke center either with drip and ship or mothership. Clinical and safety outcomes were compared between 2 groups. Results: A total of 971 patients were analyzed: 298 were treated with the mothership approach and 673 with drip and ship. Significantly more functional independence (90-day modified Rankin Scale [mRS] 0–2) was achieved in mothership (60.1%) than in drip and ship patients (52.6%; adjusted relative risk [RR] 0.87, 95% CI 0.77–0.98, p = 0.018). Excellent outcome (90-day mRS 0–1) was achieved in 45.3% of the mothership group, compared to 37.9% of the drip and ship group (RR 0.84, 95% CI 0.71–0.98; p = 0.026). According to the distance between the primary stroke center and the comprehensive stroke center, greater functional independence was achieved in mothership than in drip and ship >12.5 miles patients (adjusted RR 0.82; 95% CI 0.71–0.94). Results in the drip-ship group stratified according to time between cerebral imaging and groin puncture (categorized according to the median cut-off: 140 min) were similar. Symptomatic intracerebral hemorrhage rate and mortality within 90 days was similar in both groups (7.5 vs. 5.9%, p = 0.40; 17.4 vs. 16.1%, p = 0.63). Conclusions: Our study suggests that LVO stroke patients directly admitted to a comprehensive stroke center present a higher chance of functional independence, especially when the distance between the primary stroke center and comprehensive stroke center is >12.5 miles or when the time between cerebral imaging and groin puncture is ≥140 min.

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case–control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI.Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls.Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04–1.14; P = 0.007]. We observed significant heterogeneity by study design (P = 0.04), noting the BMI–multiple myeloma association only for population-based studies (Ptrend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m2; OR, 1.2; 95% CI, 1.1–1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI (Pinteraction Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood.Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876–85. ©2017 AACR.

Background: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. Methods: We pooled individual-level data from 20 case-control studies (17 471 NHL cases, 23 096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. Results: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. Conclusions: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most established risk factors for NHL. Studies of solid organ transplant recipients and individuals infected with HIV demonstrate that risks are markedly increased for several—but not all—NHL subtypes (8–13). Some infections and autoimmune diseases are associated with a single specific subtype [eg, human T-cell lymphotropic virus, type I (HTLV-I) with adult T-cell leukemia/lymphoma (14), celiac disease with enteropathy-type peripheral T-cell lymphoma (PTCL) (15–17)], whereas others [eg, Epstein–Barr virus, hepatitis C virus (HCV), Sjogren’s syndrome (18–21)] have been associated with multiple subtypes. In the last two decades, reports from individual epidemiological studies of NHL have suggested differences in risks among NHL subtypes for a wide range of risk factors, but most studies have lacked the statistical power to assess any differences quantitatively and have not systematically evaluated combinations of subtypes. One study assessed multiple risk factors and found support for both etiologic commonality and heterogeneity for NHL subtypes, with risk factor patterns suggesting that immune dysfunction is of greater etiologic importance for diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma than for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (22). However, that analysis was limited to approximately 1300 NHL cases and considered only the four most common NHL subtypes. Pooling data from multiple studies through the International Lymphoma Epidemiology Consortium (InterLymph) have provided substantial insight into associations between specific risk factors and NHL subtypes, with evidence that family history of hematologic malignancy, autoimmune diseases, atopic conditions, lifestyle factors (smoking, alcohol, anthropometric measures, and hair dye use), and sun exposure are associated with NHL risk (19,21,23–32). However, no previous study has compared patterns of risk for a range of exposures for both common and rarer NHL subtypes. We undertook the InterLymph NHL Subtypes Project, a pooled analysis of 20 case–control studies including 17 471 NHL cases and 23 096 controls, to advance understanding of NHL etiology by investigating NHL subtype-specific risks associated with medical history, family history of hematologic malignancy, lifestyle factors, and occupation. The detailed risk factor profiles for each of 11 NHL subtypes appear in this issue (15–17,33–40). In this report, we assess risk factor heterogeneity among the NHL subtypes and identify subtypes that have similar risk factor profiles.

Composite lymphomas consist of 2 or more distinct lymphomas occurring in a single anatomical site or simultaneously in different sites and can be composed of any combination of B-cell non-Hodgkin lymphoma (NHL), T-cell NHL, or Hodgkin lymphoma (HL). Cases of composite lymphomas with more than 2 lymphomas are extremely rare, with only 4 reports in the literature. We report the case of a 49-year-old man with a triple composite lymphoma in a single lymph node, consisting of small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma in situ. The patient received multiple courses of chemotherapy and an autologous stem cell transplant, which resulted in complete remission. Then, 6 years after the stem cell transplant, he developed classical HL. This unique case is, to our knowledge, the first report of a patient with triple composite lymphoma consisting of 3 small mature B-cell NHLs, who subsequently developed a fourth lymphoma.

The distribution of non-Hodgkin lymphoma subtypes varies around the world, but a large systematic comparative study has never been done. In this study, we evaluated the clinical features and relative frequencies of non-Hodgkin lymphoma subtypes in five developing regions of the world and compared the findings to the developed world. Five expert hematopathologists classified 4848 consecutive cases of lymphoma from 26 centers in 24 countries using the World Health Organization classification, and 4539 (93.6%) were confirmed to be non-Hodgkin lymphoma, with a significantly greater number of males than females in the developing regions compared to the developed world (P

Background Peppermint oil and caraway oil are established remedies in gastroenterological medicine because of their spasmolytic/analgesic effects. Purpose We investigated whether Menthacarin, a combination of both oils, exerted anti-inflammatory effects in a dextran sodium sulphate (DSS, 2%) murine model of colitis. Study Design and Methods C57BL/6 mice were orally administered Menthacarin in doses of 10, 30, 60, and 120 µg/g body weight (BW), and control mice received 0.2% agar, 10 µl/g BW, during 8 days of DSS-induced colitis. Colitis was monitored by BW measurements and colonoscopies. Colons of euthanised mice were excised for histological staining and ELISA measurements of the cytokines TNFα, IL-6, IL-10, IL-1β, and TGF-β. Results Menthacarin-treated mice compared to controls showed improved macroscopical and microscopical parameters and lower BW loss during the course of colitis. Menthacarin changed the colonic cytokine profile towards a regulatory/anti-inflammatory phenotype. Conclusion Menthacarin attenuates experimental colitis and may be a promising add-on therapy for the treatment of IBD.

Organophosphates and carbamates have been among the most commonly used insecticides, with both agricultural and residential uses. Previous studies have suggested associations of non-Hodgkin lymphoma (NHL) with some of these chemicals; however, many studies have been limited in their ability to evaluate associations with lymphoma subtypes. We evaluated the use of eleven organophosphate and two carbamate insecticides in association with NHL in the North American Pooled Project, which includes data from case-control studies in the United States and Canada (1690 cases/5131 controls). We used unconditional logistic regression adjusting for potential confounders, including use of other pesticides, to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between these chemicals and NHL overall, and NHL subtypes, i.e., follicular (FL), diffuse large B-cell (DLBCL), small lymphocytic lymphoma (SLL) and others. Ever use of malathion was associated with increased risk of NHL overall (OR = 1.43; 95% CI: 1.14–1.81) compared with never users. Categories using tertiles of duration (< 4 yrs., 4–12 yrs., and > 12yrs) also showed a significant exposure-response for increasing years of use of malathion and risk of NHL (OR < 4vsUnex = 1.33 (0.88, 2.03), OR4–12vsUnex = 1.42 (1.02, 1.96), OR > 12vsUnex = 1.55 (1.05, 2.28, p-trend < 0.01)). In addition, malathion use was statistically significantly associated with FL (OR = 1.58; 95% CI: 1.11–2.27) and DLBCL (OR = 1.61; 95% CI: 1.16–2.22) while there were no apparent associations with SLL or other subtypes, the p-value for heterogeneity across subtypes, however, was not significant. These results support previous studies suggesting an association between insecticide use and NHL overall, and provide new information on associations with NHL subtypes.

Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation, the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 × 1 × 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.

Comparative data on the distribution of non-Hodgkin lymphoma (NHL) subtypes in Southern Africa (SAF) is scarce. In this study, five expert haematopathologists classified 487 consecutive cases of NHL from SAF using the World Health Organization classification, and compared the results to North America (NA) and Western Europe (WEU). Southern Africa had a significantly lower proportion of low-grade (LG) B-NHL (34·3%) and a higher proportion of high-grade (HG) B-NHL (51·5%) compared to WEU (54·5% and 36·4%) and NA (56·1% and 34·3%). High-grade Burkitt-like lymphoma was significantly more common in SAF (8·2%) than in WEU (2·4%) and NA (2·5%), most likely due to human immunodeficiency virus infection. When SAF patients were divided by race, whites had a significantly higher frequency of LG B-NHL (60·4%) and a lower frequency of HG B-NHL (32·7%) compared to blacks (22·5% and 62·6%), whereas the other races were intermediate. Whites and other races had a significantly higher frequency of follicular lymphoma and a lower frequency of Burkitt-like lymphoma compared to blacks. The median ages of whites with LG B-NHL, HG B-NHL and T-NHL (64, 56 and 67 years) were significantly higher than those of blacks (55, 41 and 34 years). Epidemiological studies are needed to better understand these differences.

Comparative data regarding the distribution of non-Hodgkin lymphoma (NHL) subtypes in North Africa, the Middle East and India (NAF/ME/IN) is scarce in the literature. In this study, we evaluated the relative frequencies of NHL subtypes in this region. Five expert haematopathologists classified 971 consecutive cases of newly-diagnosed NHL from five countries in NAF/ME/IN. After review, 890 cases (91·7%) were confirmed to be NHL and compared to 399 cases from North America (NA). The male-to-female ratio was significantly higher in NAF/ME/IN (1·8) compared to NA (1·1; P< 0·05). The median ages of patients with low-grade (LG) and high-grade (HG) B-NHL in NAF/ME/IN (56 and 52 years, respectively) were significantly lower than in NA (64 and 68 years, respectively). In NAF/ME/IN, a significantly lower proportion of LG B-NHL (28·4%) and a higher proportion of HG B-NHL (58·4%) were found compared to NA (56·1% and 34·3%, respectively). Diffuse large B-cell lymphoma was more common in NAF/ME/IN (49·4%) compared to NA (29·3%), whereas follicular lymphoma was less common in NAF/ME/IN (12·4%) than in NA (33·6%). In conclusion, we found significant differences in NHL subtypes and clinical features between NAF/ME/IN and NA. Epidemiological studies are needed to better understand the pathobiology of these differences.

Large and systematic studies of non-Hodgkin lymphoma (NHL) in the Far East (FE) with good comparative data are scarce in the literature. In this study, five expert hematopathologists classified 730 consecutive cases of newly-diagnosed NHL from four sites in the FE (excluding Japan) using the World Health Organization classification. The results were compared to 399 cases from North America (NA). We found a significantly higher male to female ratio in the FE compared to NA (1.7 versus 1.1; p

International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Background: The International Peripheral T-cell Lymphoma Project was organized to better understand the T-cell and natural killer (NK) cell lymphomas, and our task is to present the clinicopathologic correlations and therapeutic results for adult T-cell leukemia/lymphoma (ATL). Patients and methods: Among 1153 patients with T-cell or NK cell lymphomas, 126 patients (9.6%) with ATL were represented in this project. All were categorized as aggressive ATL, i.e. acute or lymphoma type, and 87% fell into the lymphoma type. Results: The median age was 62 years and the male to female ratio was 1.2 : 1. Significant prognostic factors for overall survival (OS) by univariate analysis were the presence of B symptoms (P = 0.018), platelet count

Background and Purpose— We aimed to study the intrarater and interrater agreement of clinicians attributing DWI-ASPECTS (Diffusion-Weighted Imaging–Alberta Stroke Program Early Computed Tomography Scores) and DWI-FLAIR (Diffusion-Weighted Imaging–Fluid Attenuated Inversion Recovery) mismatch in patients with acute ischemic stroke referred for mechanical thrombectomy. Methods— Eighteen raters independently scored anonymized magnetic resonance imaging scans of 30 participants from a multicentre thrombectomy trial, in 2 different reading sessions. Agreement was measured using Fleiss κ and Cohen κ statistics. Results— Interrater agreement for DWI-ASPECTS was slight (κ=0.17 [0.14–0.21]). Four raters (22.2%) had a substantial (or higher) intrarater agreement. Dichotomization of the DWI-ASPECTS (0–5 versus 6–10 or 0–6 versus 7–10) increased the interrater agreement to a substantial level (κ=0.62 [0.48–0.75] and 0.68 [0.55–0.79], respectively) and more raters reached a substantial (or higher) intrarater agreement (17/18 raters [94.4%]). Interrater agreement for DWI-FLAIR mismatch was moderate (κ=0.43 [0.33–0.57]); 11 raters (61.1%) reached a substantial (or higher) intrarater agreement. Conclusions— Agreement between clinicians assessing DWI-ASPECTS and DWI-FLAIR mismatch may not be sufficient to make repeatable clinical decisions in mechanical thrombectomy. The dichotomization of the DWI-ASPECTS (0–5 versus 0–6 or 0–6 versus 7–10) improved interrater and intrarater agreement, however, its relevance for patients selection for mechanical thrombectomy needs to be validated in a randomized trial.

The World Health Organization classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into 3 grades (FL1-3) based on the average number of centroblasts per high-power field in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the World Health Organization criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity. The features of FLC include a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1μ, approximately twice that of small lymphocytes and similar to centroblasts. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high Ki67 proliferation (81%). The clinical features of patients with FLC were similar to those with other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. FLC is a variant of follicular lymphoma which should be recognized in future lymphoma classifications because the diagnosis of FLC may be important for the selection of therapy.

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker—the proliferation signature—using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.

Background Occult atrial fibrillation (AF) may, in part, explain cryptogenic stroke. A 22% prevalence of subdiaphragmatic visceral infarction (SDVI) among patients with ischemic stroke (IS) due to AF has been reported, using abdominal MRI. We sought to assess the reproducibility of this method and to confirm that SDVI is more prevalent in cases of AF-caused IS than in IS of other etiologies. Methods In consecutive patients admitted to our hospital, we compared SDVI prevalence in three groups: patients with IS due to AF (IS+/AF+ group), patients with stroke of another determined cause (IS+/AF− group) and patients with AF without stroke (IS−/AF+ group). Results A total of 111 patients were included. The median time between inclusion and abdominal MRI was six days. SDVI was more frequent in the IS+/AF+ group ( n = 10; 21.3%), than in IS+/AF− ( n = 1; 3.3%) and IS−/AF+ ( n = 0) groups, p = 0.002. The most frequent localization was the kidney. Conclusions The prevalence of SDVI was higher among patients with AF-caused IS. In cases of cryptogenic stroke, a positive abdominal MRI may suggest occult AF as the cause and identify a high risk of AF in this subgroup of patients.

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation with different morphological patterns, phenotypes and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. In 2006 the International T-Cell Lymphoma Project launched the T-Cell Project, building on the retrospective study previously carried on by the network, with the aim to prospectively collect accurate data to improve knowledge on this group of lymphomas. Based on previously published reports from International Study Groups it emerged that rendering a correct classification of PTCLs is quite difficult because the relatively low prevalence of these diseases results in a lack of confidence by most pathologists. This is the reason why the T-Cell Project requested the availability of diagnostic material from the initial biopsy of each patient registered in the study in order to have the initial diagnosis centrally reviewed by expert hematopathologists. In the present report the results of the review process performed on 573 cases are presented. Overall, an incorrect diagnosis was centrally recorded in 13.1% cases, including 8.5% cases centrally reclassified with a subtype eligible for the project and 4.6% cases misclassified and found to be disorders other than T-cell lymphomas; 2.1% cases were centrally classified as T-Cell disorders not included in the study population. Thus, the T-Cell Project confirmed the difficulties in providing an accurate classification when a diagnosis of PTCLs is suspected, singled out the major pitfalls that can bias a correct histologic categorization and confirmed that a centralized expert review with the application of adequate diagnostic algorithms is mandatory when dealing with these tumours. Copyright © 2016 John WileySons, Ltd.

Solid organ transplant recipients have elevated cancer risks, owing in part to pharmacologic immunosuppression. However, little is known about risks for hematologic malignancies of myeloid origin. We linked the US Scientific Registry of Transplant Recipients with 15 population-based cancer registries to ascertain cancer occurrence among 207 859 solid organ transplants (1987–2009). Solid organ transplant recipients had a significantly elevated risk for myeloid neoplasms, with standardized incidence ratios (SIRs) of 4.6 (95% confidence interval 3.8–5.6; N=101) for myelodysplastic syndromes (MDS), 2.7 (2.2–3.2; N=125) for acute myeloid leukemia (AML), 2.3 (1.6–3.2; N=36) for chronic myeloid leukemia and 7.2 (5.4–9.3; N=57) for polycythemia vera. SIRs were highest among younger individuals and varied by time since transplantation and organ type (Poisson regression P

The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell–like or activated B cell–like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)–based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and "double-hit" DLBCL, with both MYC and BCL2 translocations has a poor prognosis. In this study, we investigated whether MYC and BCL2 protein expression in tissue would predict survival in DLBCL. The study included 106 cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or CHOP-like regimens. The results were validated on an independent cohort of 205 DLBCL patients. Patients with low expression of BCL2 (≤30%) and MYC (≤50%) had the best prognosis, whereas those with high BCL2 (>30%) and MYC (>50%) had the worst outcome. In multivariate analysis, the combination of the BCL2 and MYC was an independent predictor of overall survival (OS) and event-free survival (EFS) (P = 0·015 and P = 0·005, respectively). The risk of death was nine times greater for patients with high BCL2 and MYC compared to those with low expression. High BCL2 and MYC was a strong predictor of poor OS (P < 0·001) and EFS (P = 0·0017) in patients with the germinal centre B-cell (GCB) type, but not in the non-GCB type. In DLBCL, high co-expression of MYC and BCL2 was an independent predictor of poor survival, and could be used to stratify patients for risk-adapted therapies.