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Introduction. Multiresistant (multiR) bacteria are emerging pathogens in hematologic cancer patients (pts) and may negatively impact on the outcome of bloodstream infections (BSI). The antibiotic ...pressure, including fluoroquinolones (Fq) prophylaxis, may be one of the factors responsible for this phenomenon. In order to better define the very recent epidemiology and outcome of BSI in a real-life setting, we planned a prospective study collecting all consecutive febrile/infectious episodes occurring in acute leukemia (AL) pts admitted to 9 hematological institutions participating to REL, representing about 75% of the entire AL population treated in Lombardy.
Patients and Methods. From Dec-2012 to Jul-2014, all febrile/infectious episodes were recorded. The following data concerning BSI were analysed: age, gender, type and phase of leukemia, neutropenia, Fq prophylaxis, presence of central venous catheter (CVC), concomitant pulmonary infiltrates, antibiotic resistance.
Results. In 218 AL pts (M/F 131/87; median age 54y, range 17-80; AML/ALL 181/37), 314 BSI were diagnosed. In 180 (57.3%) BSI occurred in pts on Fq prophylaxis. In 71 (22.6%) pneumonia was also present. Gram-positive cocci (GPC) were isolated in 145/314 BSI (46.2%); Gram-negative rods (GNR) in 117 (37.3%), polymicrobial (PMB) aetiology in 48 (15.3%) and fungi (F) in 4 (1.3%). Coagulase-negative staphylococci (CoNS) were the most frequent GPC (105/314, 33.4%); S. aureus, S. viridans and enterococci were observed in 7 (2.2%), 17 (5.4%) and 37 (11.8%) cases, respectively. Methicillin-resistant strains accounted for 75.9% of all staphylococci and vancomycin-resistant strains for 2.7% of enterococci. CVC-related BSI, which accounted for 31.4% of BSI occurring in pts with CVC, was independently correlated with GPC aetiology (OR 1.9, CI 1.1-3.1, p=0.01). Considering GNR, Enterobacteriaceae were isolated in 113/314 BSI (36%) and P. aeruginosa in 31 (9.9%). GNR occurred more frequently during consolidation cycles (45.8% vs 31.1%) and in pts not on Fq prophylaxis (44.2% vs 32.2%). Both conditions were independent risk factors at multivariate analysis (p=0.002 and p=0.02, respectively). Frequency of Enterobacteriaceae BSI was also higher during consolidation cycles in comparison with other AL phases (48.1% vs 27.3%, p=0.0005), but Fq prophylaxis was no longer a protective factor (35% vs, 37.3%). Fq resistance was observed in 63/113 (55.7%) of Enterobacteriaceae; in 84.1% of cases were detected during Fq prophylaxis. ESBL+ strains, which accounted for 24.8% of Enterobacteriaceae, were also associated with Fq prophylaxis (OR 2.8, CI 1.1-7.1, p=0.02) at multivariate analysis. Carbapenemase producing (CP) strains occurred in 8.8% of Enterobacteriaceae. Among P. aeruginosa strains, 19.4% were multiR. Thirty-day mortality was 7.6% (24/314); it was lower for GPC (5.5%) in comparison with GNR (9.4%) and PMB BSI (11.6 %). CP Enterobacteriaceae or multiR P. aeruginosa BSI (30d mortality: 33.3%; OR 21.3, CI 4.4-102.4, p=0.0001) but not ESBL+ strains were independent predictors of death. Furthermore, having relapsed/resistant AL (18.2%; OR 9, CI 2.7-30.7, p=0.0004), and the presence of concomitant pulmonary infiltrates (26.8%; OR 15, CI 4.8-46.8, p<0.001) significantly correlated with the risk of death at multivariate analysis.
Conclusions. The proportion of multiresistant GNR is becoming a major problem in our real-life prospective study. Fq prophylaxis reduced the proportion of GNR BSI as a whole, but not those incurred by Enterobacteriaceae, mainly observed during consolidation phases. Moreover, Fq exposure was associated with ESBL+ aetiology, which also occurred during consolidation cycles. While ESBL+ did not impact on survival, both multiR- and CP-bacteria correlated with a higher risk of death. Interestingly, also a concomitant diagnosis of pneumonia during BSI was a strong predictor of a poorer outcome. The usefulness of Fq prophylaxis has to be reanalysed in this new epidemiologic scenario.
No relevant conflicts of interest to declare.
Background:
TKIs discontinuation has become a safe and feasible option for selected CML patients (pts). Sokal risk score, longer treatment and deep molecular response (DMR) duration were associated ...with lower probability of major molecular responde (MMR) loss after stopping TKIs (Etienne, 2010‐Saussele, 2018). Moreover, the impact of bcr‐abl transcript type on outcome and, particularly, on TFR probability and duration has been recently demonstrated (Claudiani, 2017‐D’Adda, 2019). Previous INF therapy > 12 months was associated with a better outcome after imatinib discontinuation (Ross, 2013).
Aims:
We retrospectively evaluated our CML pts who stopped TKI after sustained DMR (sDMR) in order to assess whether the type of previous treatment could influence the probability of a durable TFR.
Methods:
Bcr‐abl transcripts were determined by RQ‐PCR analysis performed in accordance with EAC protocol (Gabert, Leukemia 2003) and to the standards of the Italian National Network Labnet. Criteria for TKI discontinuation was sustained DMR (MR4 or better) for at least 2 years. After TKI withdrawal, RQ‐PCR for bcr‐abl was performed every month during the first year and every 2 months thereafter. TKI treatment was reintroduced if DMR loss occurred.
Results:
Sixty‐seven pts discontinued TKIs, 18 of them after less than 5 years of treatment because of pregnancy desire (3), intolerance (6), patient's desire/non compliance with therapy (5), enrollment in study protocol with preplanned discontinuation programs (4). At discontinuation, median age was 63 years (30–85), median time from TKI start 85 months (30–190), median duration of sDMR 48 months (24–153). Sokal distribution was 49%, 31% and 18% for low, intermediate and high risk (one pt was not evaluable). Thirty‐eight pts stopped imatinib, 24 nilotinib (19 as first line, 5 as second line treatment), 5 dasatinib. Before imatinib, 15 pts received INF, for a median time of 60 months (3–256). Median follow up after TKI stop was 34 months (4–100, > 24 in 49 pts, <12 in only 2 pts). Twenty‐seven (40 %) pts lost DMR. Median time off‐therapy for these pts was 3 months (1–19), only 2 lost DMR after 6 months (+16 and +19 month). One pt aged 87 years has not yet resumed therapy because of age and severe kidney failure; he remains in MR3 at 47 months after TKI discontinuation. Therapy was restarted in 26 pts (14 in MR3, 11 in MR2, 1 in MR1), 24 achieved a second DMR after a median interval of 2 months (1–18); 2/26 pts are in M3 after 20 and 22 months. Neither cytogenetic relapses, nor progression were documented. One pt died in DMR for pancreatic cancer. Univariate analysis showed no difference in relapse risk according to age, gender, type of TKI (imatinib vs 2GTKI), duration of sDMR and Sokal score risk, while the e14a2 vs e13a2 transcript type (p = 0.02), duration of TKI therapy > 60 months (p = 0.03) and prior INF therapy (p = 0.02) were significantly associated with better outcome after TKI discontinuation, particularly for e13a2 transcript pts whose 12 months probability of TFR increased from 20% to 80% for INF pretreated pts (figure 1). At multivariate analysis the type of bcr‐abl transcript (p = 0.014) and prior INF (p = 0.035) remained independently significant prognostic factors.
Summary/Conclusion:
The e14a2 transcript confirmed as a favorable prognostic factor for TFR maintenance in CML pts receiving TKIs. However INF treatment before TKI improved TFR rate after TKI withdrawn, particularly in e13a2 transcript pts, and actually reverses the e13a2 transcript type negative prognostic impact on TFR maintenance in pts treated with TKI only
Oral cavity lymphoma (OCL) seems to occur more frequently in HIV-positive patients, but it is presently unknown whether HIV-related immune deficit plays a role in modifying the prevalence and the ...characteristics of these lymphomas. To clarify this issue, we compared OCL occurring in immunocompetent and HIV-positive patients. A comparison was made between cases of OCL occurring among 543 and 123 NHL consecutively diagnosed at a single center in immunocompetent and HIV-positive patients respectively. The prevalence of oral cavity involvement at diagnosis was significantly lower in the immunocompetent subgroup (HIV-negative: 1.66%; HIV-positive: 7.3%, P = 0.002). Extranodal T/NK nasal-nasal-type lymphoma (ET/NK-NL) was observed in 3 of 9 immunocompetent patients, whereas plasmablastic lymphoma (PBL) was observed in 3 of 9 HIV-positive patients. EBV expression correlated with HIV-positivity. Response to treatment was similar between the two subgroups, but the overall prognosis was significantly worse among HIV-positive patients. Median survival was 34 months in immunocompetent vs. 9 months in HIV-positive patients (P < 0.01). A higher frequency of oral cavity lymphoma was associated with HIV infection. ET/NK-NL and PBL seemed to be clinical entities characteristically related to immunocompetent and HIV-positive subgroups, respectively. Chemotherapy was feasible and effective in both subgroups, although a poor prognosis was associated with immunodeficiency.
Background:
Mutations in DNA and chromatin regulation genes have been associated with clonal hematopoiesis (CH) in older healthy subjects, but are also involved in leukemogenesis occurring as early ...events. In AML patients, the prognostic role of CH‐mutations detected at diagnosis has been assessed mainly by investigating single mutations, with diverging results. Thus, the significance of pre‐treatment CH‐mutations as a group remains to be elucidated.
Aims:
To investigate the distribution and clinical impact of CH‐mutations detected at diagnosis in AML patients with normal karyotype and treated with chemotherapy eventually followed by allogeneic hematopoietic stem cell transplant (alloHSCT) within the prospective NILG trial 02/06 ClinicalTrials.gov Identifier: NCT00495287.
Methods:
Out of 572 newly diagnosed AML patients enrolled into the trial, 270 had a normal karyotype. For 213 of them, a molecular profile was obtained at diagnosis with standard approach and targeted NGS on peripheral blood and bone marrow samples. CH‐mutations were defined as DNMT3A, TET2, ASXL1, IDH1 and IDH2. Based on the available data, 209 patients were re‐classified as per the 2017 European Leukemia Net (ELN) guidelines. All patients were treated with intensive chemotherapy eventually followed by consolidative alloHSCT.
Results:
At least one CH‐mutation was reported for 131 out of 213 evaluable patients (61.5%), while 82 patients had no CH‐mutations (38.5%). Patients carrying CH‐mutations were older in comparison with patients without CH‐mutations (median age 53 vs 47 years, P = 0.0003). No preferential association was found in respect of AML type (i.e. de novo vs secondary AML, P = 0.25). The most recurrent CH‐mutation was DNMT3A (83/131), followed by TET2 (32/131), IDH2 (26/131), IDH1 (20/131) and ASXL1 (18/131). A single CH‐mutation was observed in 65% of patients, while 33.5% had a double mutation and 1.5% a triple mutation. Overall, CH‐mutations were detected across all ELN risk groups. The likelihood of carrying a CH‐mutation was significantly increased in patients with a NPM1 mutation (P < 0.0001), while the opposite was reported for patients with a biallelic CEBPa mutation (P < 0.0001). Taken together, CH‐mutations did not affect the 5‐years disease free survival (DFS) and overall survival (OS) (46% vs 54%, P = 0.45; and 50% vs 55%, P = 0.21). However, within the ELN risk categories, the presence of CH‐mutations negatively affected the 5‐years DFS (86% vs 59%, P = 0.03) and OS (86% vs 71%, P = 0.09) in patients in the favorable risk group, while these outcomes were not affected in the intermediate and adverse risk groups. By analyzing each CH‐mutation separately, TET2 emerged as an independent risk factor for the achievement of CR OR 0.25 (95% CI 0.08–0.7), P = 0.008, but not for OS OR 1.56 (95% CI 0.89–2.75), P = 0.12. Finally, 186 patients who received a consolidative alloHSCT in first CR were investigated, 107 of them carrying CH‐mutations. AlloHSCT provided a significant benefit in terms of OS for the whole study population (P = 0.001), irrespective of the presence of CH‐mutations (P = 0.87).
Summary/Conclusion:
CH‐mutations are frequently detected at diagnosis in AML patients with normal karyotype across all ELN risk groups, but more likely in NPM1 mutated patients. Overall, the presence of CH‐mutations is not associated with worse outcomes except for patients within the ELN favorable risk group. These findings suggest that an active search of these mutations might refine the risk of relapse in patients considered at favorable risk, while their role is limited in patients with more aggressive disease profile.
Panossas – Les Buissières Poux, Matthieu; Borlenghi, Aldo
ADLFI. Archéologie de la France - Informations,
08/2021
Journal Article
Odprti dostop
Les résultats de cette troisième et dernière campagne de fouille du programme de recherche pluriannuel mené sur le site antique des Buissières ne correspondent que partiellement à ses objectifs ...initiaux, qui ont été fortement revus à la baisse à la demande de la Cira Auvergne-Rhône-Alpes et de la Conservation régionale des monuments historiques. Dans l’attente de solutions pérennes de conservation des vestiges, il a en effet été décidé de ne pas poursuivre l’extension du chantier au-delà de s...
Hemophagocytic syndrome (HS) may occur as a consequence of herpes viral infections. Human herpesvirus 8 (HHV‐8)/Kaposi sarcoma‐associated herpesvirus has so far been recognized as a trigger of HS ...only in immunosuppressed subjects or in patients with Kaposi sarcoma and/or HHV‐8‐related lymphoproliferative diseases. We report two Italian human immunodeficiency virus (HIV)‐negative elderly men who developed an HS with a rapidly fatal course, following treatment with corticosteroids for autoimmune hemolytic anemia. An overwhelming active infection with HHV‐8 was unequivocally documented by molecular and immunohistochemical methods, in the absence of HHV‐8‐related tumors. The occurrence of HHV‐8‐associated HS, although rare, may be considered, even out of the HIV or the transplantation settings, at least in areas endemic for HHV‐8 infection.
Dans ses aspects aussi bien théoriques que matériels, le système du vote dans les mondes grec et romain a depuis longtemps été exploré au sein d’études plus générales sur les institutions ou les ...différents types de régimes politiques. Il n’a cependant jamais fait l’objet de publications réunissant à la fois les témoignages textuels et les résultats des fouilles archéologiques, dans l’optique d’une compréhension globale de cette pratique. De ce constat est né le projet d’une synthèse portant sur les modalités, les lieux et les finalités du vote en Grèce, à Rome et en Gaule, dans une perspective comparatiste. Menée dans le cadre d’un programme de recherche interdisciplinaire soutenu par l’université Lumière Lyon 2 et la Maison de l’Orient et de la Méditerranée, cette recherche a suscité, selon les régions et les périodes concernées, des questionnements spécifiques mais elle a aussi fait émerger des points de convergence. La collaboration de chercheurs issus de plusieurs disciplines – l’histoire, la philologie et l’archéologie – a permis de cerner la pratique du vote à travers ses implications politiques, ses modalités procédurales et la place qui lui a été réservée dans l’espace civique par les différentes sociétés antiques qui l’ont mise en œuvre. Le présent ouvrage, qui présente une synthèse sur chacune des aires géographiques étudiées et rassemble vingt et une contributions issues de séminaires ou de journées d’études qui se sont tenus à Lyon, à la Maison de l’Orient et de la Méditerranée, de la fin de l’année 2012 au printemps 2014, propose une approche inédite de l’acte de vote dans l’Antiquité.
U.O. Ematologia, I Divisione Anatomia Patologia, Spedali Civili, Cattedra di Anatomia Patologica, Universita di Brescia, Brescia, Italy.
BACKGROUND AND OBJECTIVES: Distinct types of lymphoma may ...develop in the same patient either simultaneously or sequentially. The frequency and clinical significance of this phenomenon are still only partially known. DESIGN AND METHODS: We conducted a retrospective analysis of all cases of lymphomas of different histology occurring in the same patient, denoting these cases as multiple histology lymphoma (MHL). The clinicopathologic characteristics of these cases were compared with those of cases with a single histology (SHL). The histologic classifications were made according to the REAL classification by the same pathologists throughout the study period. RESULTS: MHL were identified in 46 of 347 (13%) consecutive cases of lymphoma diagnosed at a single institution. They presented more frequently in stage III-IV (p=0.008), but the age, sex, and IPI score of patients with MHL did not differ from those of patients with SHL. Small lymphocytic/lymphoplasmacytic subtype was more frequent (16.1% vs 3%, p
Only few acute myeloid leukaemia (AML) relapsed patients achieve a long term survival after allogeneic haematopoetic stem cell transplantation (alloSCT). Adequate prognostic criteria are required for ...selecting patients (pts) who can benefit from this procedure. Aim of this study was to assess prognostic factors affecting OS in a cohort of 50 AML pts who received alloHSCT as salvage treatment after a risk-oriented frontline chemotherapy (NILG AML01-00). Fifty out of 140 pts in first relapse received allograft as salvage therapy. Median age was 50 yr (14 pts were >55). At diagnosis 31(62%) pts had high risk AML, defined by clinical and cytogenetic characteristics according to the NILG protocol. Median time from 1st CR to relapse (TTR) was 10 months (mo) and from relapse to allo was 3 mo. At alloSCT 34 pts (85%) were in 2nd CR, and 16 were transplanted with disease. The donor was matched related for 19 pts, matched unrelated for 22 and haploidentical for 9. Stem cell source was PB in 31, BM in 12 and CB in 7 pts. The conditioning regimen was myeloablative (MA) in 38 (74%) and reduced intensity (RIC) in 12. The impact of risk factors on OS was analyzed by univariate and multivariate analyses. The clinical outcome of the 50 transplanted pts was compared with 90 consecutive pts receiving other intensive salvage treatment. After alloSCT 44/50 (88%) achieved a 2nd CR. Relapse occurred in 22 pts at a median time of 8 mo from alloSCT, and all died. Among the 16 pts transplanted with disease 3 are in CCR. Acute (grade>II) or chronic GVHD occurred in 23 pts (46%). The 100dy- and 1-yr TRM was 6% and 20%. Among transplant related deaths, 75% were attributable to MA regimens. After a median follow up of 10 mo (range 3-68), median OS was 13 mo. The projected 1 yr- and 3-ys OS was 60 and 33%. Thirteen (28%) were in CCR at the end of follow-up. The 90 non transplanted pts showed a median OS of 3 mo, with a 1-yr OS of 16% (p=0.000). Univariate analysis performed on the 50 transplanted pts showed that high risk AML, TTR<6mo, ECOG-PS>0 and disease status at transplant were predictive of a poor outcome (p<0.05). By Cox multivariate analysis TTR<6mo and PS>0 were independent adverse prognostic factors for OS (p=0.04 and 0.01). Our data confirm that allograft can offer a better clinical outcome than other intensive regimen. Allograft should be proposed preferentially to pts with a TTR?6 mo and a very good PS.RIC seems to be as effective and less toxic than MA conditioning regimen, but larger prospective studies are required for confirming the role of RIC in AML salvage strategies.
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