Introduction: Incidence of fungal infections is reducing in the last years due to wider use of effective antifungal prophylaxis. On this basis, we evaluated clinical characteristics and outcome of ...patients (pts) with hematological malignancies (HMs) and fungal bloodstream infections (FBSI).
Patient and Methods: This retrospective/prospective study gathered consecutive documented FBSI observed among HMs diagnosed between January 2011 and June 2015 in 19 Italian Hematology Departments that refer to SEIFEM (Sorveglianza Epidemiologica Infezioni Fungine Emopatie Maligne) group.
Results: We collected overall 100 patients including retrospective pts and those observed in the first six months of the prospective study with FBSI among 16 centers; further 3 centers reported no cases of FBSI. Regarding patients' characteristics male/female ratio was 1, median age was 55 yeras. (IQR 18-88). Two-third of FBSI were detected in AML (43 - 43%) and NHL (27 - 27%); the remaining pts were affected by ALL (9 - 9%), MM (6 - 6%), MDS (5 - 5%), MDS/MPN (5 - 5%), CLL (3 - 3%) and HL (2 - 2%). Thirty-five pts had FBSI at the onset of HM or after the first induction, 47 after treatment for refractory/relapsed disease, 13 when in remission, 28 pts during transplant procedures (17 from allogeneic donor, 11 from autologous cells). Fifty-nine pts were receiving antifungal prophylaxis at FBSI breakthrough: 26 posaconazole, 16 fluconazole, 6 itraconazole, 3 amphotericin B, 3 caspofungin, 1 voriconazole, and 4 combination of amphotericin B/azoles; 4 pts were treated with secondary prophylaxis after previous fungal infection. Eighty-nine pts had a central venous catheter. Eighty-four pts presented a neutrophils count < 500/mmc for a median time of 7 days before FBI onset (0-70 d); 50 pts received steroids and other 17 immunosuppressive treatment for allo-HSCT.
Yeasts were the most common agent detected. Candida spp. represent the most represented yeast, counting for 77% of all infections; (21 albicans and 56 non albicans); 8% of FBI were due to 8% Geotrichum, 3% Trichosporon and 2% Rhodotorula, Molds were rare but not infrequent: 8% were caused by Fusarium and 1% by Scedosporium.
Three patients died before starting any antifungal. Fifty-two received echinocandins (49 caspofungin and 3 anidulafungin), 22 liposomal amphotericin B (L-AmB), 15 azoles (7 fluconazole, 3 posaconazole, 3 voriconazole and 2 itraconazole) and 8 pts combo therapy (5 posa+L-AmB, 2 Caspo+L-AmB, 1 vori+caspo).
Thirty-eight pts died within 30 days from FBSI diagnosis, 28 (74%) of whom due to infection. Among these 12 (43%) suffered from AML (1 in induction, 1 in CR, 10 had refractory/relapsed disease), 2 (7.2%) from ALL (all with refractory/relapsed disease), 7 (25%) from NHL (2 in induction, 2 in CR, 3 with refractory/relapsed disease), 4 (14%) from refractory/relapsed MM, 1 (3.6%) from MDS in remission, 2 (7.2%) from newly diagnosed MDS/MPN. In 8 pts (21%) for whom we cannot discriminate if death was subsequent to FBSI only or to uncontrolled HMs, fungal isolates were all rare yeast or molds except 2. Mortality was related only with advanced phase of underlying HM (p<0.0001), molds fungemia (p<0.06) and rare fungi isolation (p<0.06). There is no difference in overall mortality rate among pts treated with echinocandins or azole or amphotericin B compounds or combo.
Conclusions: Nowadays FBSI represents a rare complication of HMs, as a consequence of wider availability of effective antifungal prophylaxis. Candidemia still represents the most important cause of FBSI, although about 25% of FBSI are due to rare yeast or molds. Regardless a lowering incidence, the observed mortality remains high even with target treatment.
No relevant conflicts of interest to declare.
OBJECTIVES
Aim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients ...affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia.
PATIENTS AND METHODS
From January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases.
RESULTS
1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study.
Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded.
Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy.
IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment.
A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S.
Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified.
DISCUSSION
In our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted.
No relevant conflicts of interest to declare.
β1C and β1A integrins are alternatively spliced variants of the human β1-subunit; the former has been shown to inhibit cell proliferation, and the latter to promote it. Although some components of ...the β1 integrin subfamily are expressed in human endometrial and decidual cells during the menstrual cycle and early pregnancy, to date no information is available about the expression of β1C integrin in endometrial and decidual tissues and its possible roles during implantation and pregnancy. To gain further insight on this subject, we have explored β1C integrin expression in endometrial (proliferative, secretory, and atrophic) and decidual (from the first and third trimesters of pregnancy) tissue samples at both gene and protein levels by Northern and Western blotting analyses and by immunohistochemistry. β1A protein levels were also measured in the same tissues as a control. The results of this study demonstrate that both β1C- and β1A-subunits are expressed in the endometrium and decidua. In the former, maximal β1C expression was detected in atrophic endometria, whereas β1A expression levels were increased in secretive and decreased in atrophic endometrial tissues compared with proliferative endometria. In addition, whereas β1A levels were significantly increased in decidual tissues, compared with proliferative endometria, β1C expression was dramatically reduced in the same tissues, thus pointing to selective down-regulation of β1C expression in the decidua.
These data suggest that the expression of β1C integrin, a very efficient inhibitor of cell proliferation, may be modulated by the maternal microenvironment and may play a fundamental role in mediating trophoblast outgrowth and migration during pregnancy.
beta(1C) and beta(1A) integrins are alternatively spliced variants of the human beta(1)-subunit; the former has been shown to inhibit cell proliferation, and the latter to promote it. Although some ...components of the beta(1) integrin subfamily are expressed in human endometrial and decidual cells during the menstrual cycle and early pregnancy, to date no information is available about the expression of beta(1C) integrin in endometrial and decidual tissues and its possible roles during implantation and pregnancy. To gain further insight on this subject, we have explored beta(1C) integrin expression in endometrial (proliferative, secretory, and atrophic) and decidual (from the first and third trimesters of pregnancy) tissue samples at both gene and protein levels by Northern and Western blotting analyses and by immunohistochemistry. beta(1A) protein levels were also measured in the same tissues as a control. The results of this study demonstrate that both beta(1C)- and beta(1A)-subunits are expressed in the endometrium and decidua. In the former, maximal beta(1C) expression was detected in atrophic endometria, whereas beta(1A) expression levels were increased in secretive and decreased in atrophic endometrial tissues compared with proliferative endometria. In addition, whereas beta(1A) levels were significantly increased in decidual tissues, compared with proliferative endometria, beta(1C) expression was dramatically reduced in the same tissues, thus pointing to selective down-regulation of beta(1C) expression in the decidua. These data suggest that the expression of beta(1C) integrin, a very efficient inhibitor of cell proliferation, may be modulated by the maternal microenvironment and may play a fundamental role in mediating trophoblast outgrowth and migration during pregnancy.
The study investigates the circadian rhythm (CR) of urinary 6-sulphatoxy-melatonin (aMT6s) in long-living (longevous) subjects and their progeny. The aim is to detect whether or not the melatonin CR ...is a physiological feature associated with healthy longevity. The aMT6s CR was investigated in 10 longevous subjects, 8 of their children and 9 of their grandchildren, all in good health. Control data were obtained respectively from 13 adult subjects and 9 young subjects, in good health, but characterized by a negative family history for longevity. All the subjects were born and living in the same city. The study was performed in the summer of 1996. The aMT6s CR was found to persist in longevous subjects, being characterized by a lower mesor and amplitude. The aMT6s CR was found not to show properties consistently different in children and grandchildren as compared respectively to their adult and young controls. Because of its preservation in longevous subjects, it can be argued that the melatonin CR is a physiological feature associated with healthy longevity. Because of the comparability of aMT6s CR in children and grandchildren, with respect to their controls without a positive family history of longevity, it can be argued that the melatonin CR is not a marker that can be used for an earlier identification of the candidates for longevity. (Chronobiology International, 18(1), 99-107, 2001)
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