Combined Reverse-Transcriptase Multiplex Ligation-Dependent Probe Amplification and Next-Generation Sequencing Analyses to Assign Unclassified BCL2-/BCL6- Nonrearranged Small B-Cell Lymphoid Neoplasms as Follicular or Nodal Marginal Zone Lymphoma.

Distinguishing between follicular lymphoma (FL) and nodal marginal zone lymphoma (NMZL) can be difficult when morphologic and phenotypic features are unusual and characteristic cytogenetic rearrangements are absent. We evaluated the diagnostic contribution of ancillary techniques-including fluorescence in situ hybridization (FISH)-detected 1p36 deletion; reverse-transcriptase, multiplex, ligation-dependent probe amplification (RT-MLPA); and next-generation sequencing (NGS)-for tumors that remain unclassified according to standard criteria. After review, 50 CD5-negative small B-cell lymphoid neoplasms without BCL2 and BCL6 FISH rearrangements were diagnosed as FLs (n = 27), NMZLs (n = 5), or unclassified (n = 18) based on the 2016 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. FISH helped identify the 1p36 deletion in 3 FLs and 1 unclassified tumor. Most classified FLs had an RT-MLPA germinal center B-cell (GCB) signature (93%) or were noncontributive (7%). Classified NMZLs had an RT-MLPA activated B-cell signature (20%), had an unassigned signature (40%), or were noncontributive (40%). Among unclassified tumors, the RT-MLPA GCB signature was associated with mutations most commonly found in FLs (CREBBP, EZH2, STAT6, and/or TNFRSF14) (90%). An RT-MLPA-detected GCB signature and/or NGS-detected gene mutations were considered as FL identifiers for 13 tumors. An activated B-cell signature or NOTCH2 mutation supported NMZL diagnosis in 3 tumors. Combining the RT-MLPA and NGS findings successfully discriminated 89% of unclassified tumors in favor of one or the other diagnosis. NGS-detected mutations may be of therapeutic interest. Herein, we detected 3 EZH2 and 8 CREBBP mutations that might be eligible for targeted therapies.

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity.

Positron emission tomography-imaging assessment for guiding strategy in patients with relapsed/refractory large B-cell lymphoma receiving CAR T cells.

The aim of this study was to evaluate the prognostic impact of the F-fluorodeoxyglucose positron emission tomography response at 1 month (M1) and 3 months (M3) after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in a multicenter cohort of 160 patients with relapsed/refractory large B-cell lymphomas (R/R LBCL). In total, 119 (75%) patients reached M1 evaluation; 64 (53%, 64/119) had a complete response (CR); 91% were Deauville Score (DS) 1-3. Progressionfree survival (PFS) and overall survival (OS) were significantly worse in patients with DS-5 at M1, than in patients with DS 1-3 (PFS hazard ratio [HR]=6.37, 95% confidence interval [CI]: 3.5-11.5 vs. OS HR=3.79, 95% CI: 1.7-8.5) and DS-4 (PFS HR=11.99, 95% CI: 5.0-28.9 vs. OS HR=12.49, 95% CI: 2.8-55.8). The 1-year PFS rates were 78.9% (95% CI: 58.9-89.9) for DS-4 at M1, similar to 67.3% (95% CI: 51.8-78.8) for patients with DS 1-3 at M1, very different to 8.6% (95% CI: 1.8-22.4) for DS-5, respectively. Only eight of 30 (26%) patients with DS-4 progressed. Response at M3 evaluated in 90 (57%) patients was prognostic for PFS with lower discrimination (HR=3.28, 95% CI: 1.5-7.0; P=0.003) but did not predict OS (HR=0.61, 95% CI: 0.2-2.3; P=0.45). Patients with a high baseline total metabolic tumor volume (TMTV) >80 mL had worse PFS (HR=2.05, 95% CI: 1.2-3.5; P=0.009) and OS (HR=4.52, 95% CI: 2.5-8.1; P<0.001) than patients with low TMTV. Multivariable analyses identified baseline elevated lactate dehydrogenase, DS-5, CAR T cells at M1 for PFS and baseline elevated lactate dehydrogenase, TMTV >80 mL, and DS-5 at M1 for OS. In conclusion, baseline TMTV and response at M1 strongly predicts outcomes of patients with R/R LBCL undergoing CAR T-cell therapy.

VANDA regimen followed by blinatumomab leads to favourable outcome in patients with Philadelphia chromosome-negative B-precursor acute lymphoblastic leukaemia in first relapse.

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia (R/R BCP-ALL) have very poor outcome. Blinatumomab as single agent has shown activity in R/R BCP-ALL. We aimed to assess the activity of blinatumomab in concomitant association with intensive chemotherapy. Seventeen patients with R/R BCP-ALL were treated with combination of blinatumomab and VANDA (etoposide, cytarabine, mitoxantrone, dexamethasone and asparaginase) regimen. Complete remission (CR) was achieved in 14/17 patient (82%) and 11/17 (65%) were transplanted. One-year leukaemia-free survival was 58.8% for the whole cohort and 90.9% for transplanted patients. These preliminary data suggest that the VANDA-blinatumomab salvage regimen leads to a very high rate of CR and HSCT in suitable patients.

Epidemiological landscape of young patients with multiple myeloma diagnosed before 40 years of age: the French experience.

Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing <2% of all patients with MM. Little is known about the disease characteristics and prognosis of these patients. In this study, we examined 214 patients diagnosed with MM at age ≤40 years over 15 years, in the era of modern treatments. Among them, 189 patients had symptomatic MM. Disease characteristics were similar to older patients: 35% had anemia, 17% had renal impairment, and 13% had hypercalcemia. The staging was ISS-1 in 52.4%, ISS-2 in 27.5%, and ISS-3 in 20.1%. Overall, 18% of patients had high-risk cytogenetics [del 17p and/or t(4;14)]. Ninety percent of patients received intensive chemotherapy followed by autologous stem cell transplant, and 25% of patients had allogeneic stem cell transplant predominantly at time of relapse. The median follow-up was 76 months, the estimated median overall survival was 14.5 years, and the median progression free-survival was 41 months. In multivariate analysis, bone lesions (hazard ratio [HR], 3.95; P = .01), high ISS score (HR, 2.14; P = .03), and high-risk cytogenetics (HR, 4.54; P < .0001) were significant risk factors for poor outcomes. Among predefined time-dependent covariables, onset of progression (HR, 13.2; P < .0001) significantly shortened overall survival. At 5 years, relative survival compared with same age- and sex-matched individuals was 83.5%, and estimated standardized mortality ratio was 69.9 (95% confidence interval, 52.7-91.1), confirming that MM dramatically shortens the survival of young patients despite an extended survival after diagnosis.

Myasthenia gravis and paroxysmal nocturnal hemoglobinuria after thymectomy: A rare association.

Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare clonal autoimmune disease manifesting with hemolysis, thrombosis, or bone marrow failure. We present an atypical association of myasthenia gravis, aplastic anemia, and PNH occurring years after thymectomy. While this association might be extremely rare, it may not be coincidental as there is a common pathophysiology between PNH and aplastic anemia, with the latter reported in several thymoma/thymectomy cases. Eculizumab was introduced with good efficacy and without safety concern in our patient, leading to long-term control of PNH without worsening of myasthenia gravis.

Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome.

Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.

A fossil peronosporomycete oogonium with an unusual surface ornament from the Carboniferous of France.

A new fossil peronosporomycete from the upper Visean (Mississippian) of France occurs as a globose oogonium at the tip of a thin-walled hypha. The oogonium surface is prominently ornamented by densely spaced, long and subtle, straight or once to several times furcated thread-like extensions; many possess an opaque, bulb-like swelling at base. Antheridia adpressed to the oogonium are clavate and paragynous. This fossil represents only the third record of an unequivocal peronosporomycete from the Carboniferous, and thus provides important details about the evolutionary history of this group of organisms.

Scanning electron microscopy and synchrotron radiation x-ray tomographic microscopy of 330 million year old charcoalified seed fern fertile organs.

Abundant charcoalified seed fern (pteridosperm) pollen organs and ovules have been recovered from Late Viséan (Mississippian 330 Ma) limestones from Kingswood, Fife, Scotland. To overcome limitations of data collection from these tiny, sometimes unique, fossils, we have combined low vacuum scanning electron microscopy on uncoated specimens with backscatter detector and synchrotron radiation X-ray tomographic microscopy utilizing the Materials Science and TOMCAT beamlines at the Swiss Light Source of the Paul Scherrer Institut. In combination these techniques improve upon traditional cellulose acetate peel sectioning because they enable study of external morphology and internal anatomy in multiple planes of section on a single specimen that is retained intact. The pollen organ Melissiotheca shows a basal parenchymatous cushion bearing more than 100 sporangia on the distal face. Digital sections show the occurrence of pollen in some sporangia. The described ovule is new and has eight integumentary lobes that are covered in spirally arranged glandular hairs. Virtual longitudinal sections reveal the lobes are free above the pollen chamber. Results are applied in taxonomy and will subsequently contribute to our understanding of the former diversity and evolution of ovules, seeds, and pollen organs in the seed ferns, the first seed-bearing plants to conquer the land.

Combresomyces cornifer gen. sp. nov., an endophytic peronosporomycete in Lepidodendron from the Carboniferous of central France.

Structurally preserved periderm of the lycophyte Lepidodendron rhodumnense from the Visean (Mississippian) of central France contains a peronosporomycete (Combresomyces cornifer gen. sp. nov.) that occurs in the form of pyriform to subglobose terminal oogonia. On the surface is a conspicuous ornamentation, which may have formed through condensation of a mucilaginous extra-oogonial wall secretion. Some oogonia contain thin-walled spherules, which may represent (walled) oospheres or spores of an endoparasitic fungus (?chytrid), whereas single, large spheres in the interior are interpreted as oospores. Antheridia adpressed to several of the specimens are clavate and paragynous. This discovery sheds light on the morphology and biology of peronosporomycetes in a terrestrial ecosystem some 330My ago. Although the organism occurs exclusively in the periderm of L. rhodumnense, it is not known whether it represents a symptomless endophyte, pathogen, or saprotroph.

Tyloses and ecophysiology of the early carboniferous progymnosperm tree Protopitys buchiana.

Trunk woods of Early Carboniferous Protopitys buchiana show the earliest example of tylose formation and the first record for a progymnosperm. Protopitys tyloses are more densely located in inner trunk woods and near growth layer boundaries. We suggest, therefore, that an altered physiological state of living ray cells, during dormancy and/or following water stress, was necessary to make the woods vulnerable to tylose formation. Coupled with the distribution and proximity of abundant wood ray parenchyma to large xylem conducting cells, the positions of conduits filled with tyloses can be interpreted as ecophysiological responses of the plant to changes in local environment. In addition, some xylem conducting cells might have functioned as vessels. Fungal hyphae are present in some tracheary cells and in some areas with tyloses, but there is no evidence for wood trauma; we conclude, therefore, that these particular cases of tyloses are probably not induced by wound trauma. Protopitys buchiana wood thus shows structure/function similarities to modern woods with vessels, such as those of dicot angiosperms. This implies that ancient and modern plant ecophysiological responses correlate well with the physical parameters of their cellular construction.