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Background: Maxillary transverse discrepancy is often diagnosed in childhood. The evaluation of morphological characteristics of the maxilla is crucial for appropriate treatment of this condition, however conventional diagnostic method is based on visual inspection and transversal linear parameters. In this paper, we described a user-friendly diagnostic digital workflow based on the surface-to-surface analysis. We also described a case report., Case Report: A 6-year-old female patient presenting mild transversal maxillary deficiency associated with functional posterior crossbite was treated by using maxillary removable appliance. In this respect, the appliance was designed in accordance to the morphological characteristics of the maxilla obtained by using the diagnostic digital work-flow and the maxillary surface-to-surface analysis., Conclusion: The present user-friendly diagnostic digital workflow based on surface-to-surface analysis helps clinicians to detect specific morphological characteristics of the maxilla, such as shape and area of asymmetry, in order to reach a comprehensive diagnosis and choose the correct biomechanics for treating the condition.

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.

Chronic hepatitis E virus (HEV) infection in hematopoietic stem cell transplantation (HSCT) recipients is an emerging threat. The aim of this study was to provide data on the HEV burden in an Italian cohort of HSCT recipients and analyze risk factors for HEV seropositivity. This retrospective study reports data from 596 HSCT recipients compiled between 2010 and 2019. It included patients who underwent transplantation between 2010 and 2015 for whom pretransplantation (n = 419) and post-transplantation (n = 161) serum samples were available and tested retrospectively, as well as patients in whom prospective HEV testing was performed during the standard care: pre-HSCT IgG screening in 144, pre-HSCT HEV-RNA screening in addition to IgG screening in 60, and HEV-RNA testing in case of clinical suspicion of HEV infection in 59 (26 of whom were also included in the IgG screening cohorts). The rate of pre-HSCT HEV-IgG positivity was 6.0% (34 of 563). Older age was an independent risk factor for seropositivity (P = .039). None of the 34 HEV-IgG-positive patients had detectable HEV-RNA. One case of transient HEV-RNA positivity pre-HSCT was identified through screening. Two patients were diagnosed with chronic HEV hepatitis, and 1 patient was successfully treated with ribavirin. The burden of HEV infection in HSCT recipients in Italy is limited, and pre-HSCT screening appears to be of no benefit. Timely diagnosis of HEV infection with HEV-RNA is mandatory in cases of clinical suspicion., (Copyright © 2020. Published by Elsevier Inc.)

This is an update on acute and chronic graft-versus-host disease (GvHD) in 425 patients with hematologic malignancies, undergoing an unmanipulated haploidentical (HAPLO) graft from related donors, with a modified post-transplant cyclophosphamide (PT-CY) regimen. All patients received a myeloablative conditioning regimen, either based on thiotepa busulfan fludarabine (TBF), or on full-dose total body irradiation (TBI). The cumulative incidence of acute GvHD-grade II-IV was 29%, and the CI of GvHD-grade III-IV was 4%. We found older donors and older patients to have higher rates of grade II-IV acute GvHD; female donors, diagnosis, disease phase, year of transplant, and the conditioning regimen had no predictive effect on acute GvHD. There was no impact of grade II GvHD, but a significant impact of grade III-IV acute GvHD, on overall survival. The CI of moderate-severe chronic GvHD was 18%: the major predictor was a previous acute GvHD, followed by combined donor and recipients age. In conclusion, PT-CY given on days+3 + 5 results in a relatively low, but not insignificant risk of acute and chronic GvHD, in patients grafted from the related HAPLO donors. The use of young donors appears to reduce this risk.

Purpose: Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with hematological malignancies, even in case of resolved infection. Prophylaxis of HBV reactivation is universally recommended in stem cell transplant (SCT) recipients and patients treated with anti-CD20 agents (i.e., rituximab). Despite its well-established favorable safety profile, lamivudine (LAM) use in prophylaxis has been debated because of the possible emergence of resistant viral strains. The aim of this study was to investigate the efficacy of LAM in preventing HBV reactivation in allogeneic SCT recipients with a resolved HBV infection., Methods: Patients who received first allogeneic SCT in years 2009-2016 were evaluated. Sixty-three patients with resolved infection received LAM prophylaxis and were included in the study. Baseline and post-SCT characteristics were recorded, including rituximab exposure, length of LAM prophylaxis, and time from transplant to the last clinical and virological follow-up., Results: Overall, 39 patients (62%) were male, 39 (62%) had acute myeloid leukemia, 38 (60%) received transplant from haploidentical donor, 29 (53%) received myeloablative conditioning, and 15 (24%) received rituximab post-transplant. Median clinical follow-up was 24 months after SCT (range 0.3-97); median virological follow-up 16 months (range 0.3-78), and median length of LAM prophylaxis of 14.5 months (range 0.3-78). No patient experienced HBV reactivation while on LAM prophylaxis. One patient experienced reactivation 8 months after discontinuing prophylaxis., Conclusions: In this high-risk population, LAM prophylaxis was effective in preventing HBV reactivation in patients with resolved infection. It should be considered a reasonable first-line prophylactic agent to be administered in this setting.

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age., (Copyright © 2018. Published by Elsevier Inc.)

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Two-hundred and sixty-nine females aged ≤42 and undergoing an allogeneic stem cell transplant were retrospectively studied to assess the effect of age, conditioning regimen and chronic graft-versus-host disease (cGVHD) on resumption of stable menstrual cyclicity. Overall, a stable menstrual cyclicity was observed in 22% of cases. The cumulative probability of menses resumption was significantly age and conditioning regimen related. A statistically significant inverse correlation between cGVHD severity and menses resumption was observed only in univariate analysis. In patients with residual ovarian function, infertility was found in 43% and early menopause in 45%. An increased incidence of prematurity and low birth weight (LBW) was observed among the single spontaneous pregnancies. Follicle-stimulating hormone (FSH) and 17 beta-oestradiol levels were found to be inadequate to detect both early signs of menses resumption and menstrual stability. Our study confirms the crucial role of full dose total body irradiation (TBI) and age on menses recovery and fertility after haematopoietic stem cell transplantation (HSCT). The impact of severe cGVHD remains unclear.

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 ≥ 180 copies/10(4) Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and ≥ 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT. The cumulative incidence (CI) of relapse was 76% in WT1-180 (n = 17) versus 29% in WT1-100 patients (n = 23) receiving IT (P = .006); the leukemia-free survival from MRD positivity was 23% versus 74%, respectively (P = .003). We then looked at the entire AML patient population (n = 207). WT1-180 and WT1-100 patients were comparable for disease phase and age. The overall 4-year CI of transplantation-related mortality was 13% in both groups; the CI of leukemia relapse was 38% in the WT1-180 and 28% in the WT1-100 patients (P = .05) and leukemia-free survival was 56% versus 48%, respectively (P = .07). In conclusion, we suggests that WT1-based pre-emptive immunotherapy is feasible in patients with undergoing an allogeneic HSCT. The protective effect on relapse is greater when IT is triggered at lower levels of WT1., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

This is a retrospective analysis of 95 patients with myelofibrosis who were allografted between 2001 and 2014. The aims of the study were to assess whether the outcome of alternative donor grafts has improved with time and how this compares with the outcome of identical sibling grafts. Patients were studied in 2 time intervals: 2000 to 2010 (n = 58) and 2011 to 2014 (n = 37). The Dynamic International Prognostic Scoring System score was comparable in the 2 time periods, but differences in the most recent group included older age (58 versus 53 years, P = .004), more family haploidentical donors (54% versus 5%, P < .0001), and the introduction of the thiotepa-fludarabine-busulfan conditioning regimen (70% of patients versus 2%, P < .0001). Acute and chronic graft-versus-host disease were comparable in the 2 time periods. The 3-year transplantation-related mortality (TRM) in the 2011 to 2014 period versus the 2000 to 2010 period is 16% versus 32% (P = .10), the relapse rate 16% versus 40% (P = .06), and actuarial survival 70% versus 39% (P = .08). Improved survival was most pronounced in alternative donor grafts (69% versus 21%, P = .02), compared with matched sibling grafts (72% versus 45%, P = .40). In conclusion, the outcome of allografts in patients with myelofibrosis has improved in recent years because of a reduction of both TRM and relapse. Improvement is most significant in alternative donor transplantations, with modifications in donor type and conditioning regimen., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Therapeutic options for patients with relapsed or refractory acute leukemia are still undefined and often unsatisfactory. We report the outcome of 79 patients with relapsed-refractory acute leukemia treated with fludarabine, cytarabine, and liposomal daunorubicin (FLAD regimen) followed by hematopoietic stem cell transplantation (HSCT), when clinically indicated, between May 2000 and January 2013. Forty-one patients had acute myeloid leukemia (AML), and 38 had acute lymphoblastic leukemia (ALL). Two patients with myeloid blast crises of CML and three with lymphoid blast crises were included in the AML and ALL subgroups, respectively. Median age was 48 years (range 13-77). FLAD was well tolerated with negligible, nonhematological toxicity. Six patients (7.5 %) died before response evaluation. Forty-seven patients achieved hematologic complete response (CR). Complete remission rate was 53 and 65 % among AML and ALL patients, respectively. No CR was recorded among 11 refractory AML patients. Twenty-four patients (30 %) underwent HSCT. Nine patients received stem cells from an HLA identical sibling, and 15 from an alternative donor (3 unrelated matched, 12 haploidentical sibling). Median overall survival in AML and ALL patients receiving FLAD therapy was 9 and 8 months, respectively. A 5-year projected OS for patients receiving the whole program (FLAD + HSCT) was 24 % for AML patients (median survival 43 months), 28 % for ALL patients treated in relapse (median survival 15 months), and 0 % for ALL patients treated for refractory disease. In this paper, we show that FLAD seems to be an effective bridge therapy to HSCT for a part of poor prognosis acute leukemia patients. However, prospective studies are needed to confirm our results.

We studied 459 consecutive patients with hematologic malignancies, median age 44 years (range, 15 to 71 years), who underwent transplantation with grafts from identical sibling donors (SIB; n = 176), matched unrelated donors (MUD; n = 43), mismatched unrelated donors (mmUD; n = 43), unrelated cord blood (UCB; n = 105) or HLA-haploidentical family donors (HAPLO; n = 92). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in the SIB recipients; antithymocyte globulin for the MUD, mmUD, and UCB recipients; and post-transplantation cyclophosphamide, cyclosporine, and mycophenolate in the HAPLO recipients. Conditioning regimens were mostly myeloablative (69%). Advanced disease phase was more frequent, but not significantly so, in the HAPLO and mmUD groups (P = .08). Acute GVHD grade II-IV was significantly less frequent in the HAPLO, UCB, and MUD groups (14% to 21%) compared with the SIB (31%) and mmUD (42%) groups (P < .001), and there was a trend toward less moderate-severe chronic GVHD in the HAPLO and UCB groups (P = .053). The proportion of patients off cyclosporine at 1 year ranged from 55% for the SIB group to 81% for the HAPLO group (P < .001). Transplantation-related mortality at 2 years was lower in the HAPLO and SIB groups (18% to 24%) compared with the MUD, mmUD, and UCB groups (33% to 35%; P = .10). Relapse rate was comparable in the 5 groups (P = .80). The 4-year actuarial survival was 45% in the SIB group, 43% in the MUD group, 40% in the mmUD group, 34% in the UCB group, and 52% in the HAPLO group (P = .10). In multivariate analysis, advanced disease was a negative predictor of survival (hazard ratio [HR], 2.4; P < .0001), together with a diagnosis of acute leukemia (HR, 1.8; P = .0001); HAPLO grafts were comparable to SIB (P = .80), whereas UCB had inferior survival (P = .03). In conclusion, unmanipulated haploidentical family donor transplants are an additional option for patients lacking a matched sibling donor., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Poor graft function (PGF) is characterized by pancytopenia and a hypoplastic marrow, with complete donor chimerism, usually without severe graft-versus-host disease (GVHD). We report 41 patients with PGF, treated with granulocyte colony-stimulating factor-mobilized CD34 selected cells, at a median interval from transplant of 140 days, without conditioning and without GVHD prophylaxis. Donors were HLA matched siblings (n = 12), unrelated donors (n = 18), or mismatched family members (n = 11). The median number of infused CD34(+) cells was 3.4 × 10(6)/kg. The rate of trilineage recovery was 75%: 83% for HLA matched siblings and 72% for unrelated and mismatched family members (P = .3). The cumulative incidence of acute grade II GVHD was 15%, and no patient developed de novo chronic GVHD. The actuarial 3-year survival is 63%: 76% and 25% for patients with or without trilineage recovery. These data confirm the role of CD34(+) selected cells from the same donor in the treatment of PGF and warrant the request for a second donation also when the donor is unrelated., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Malignant melanoma is characterized by metastases also to the gastrointestinal tract, especially in the small bowel. The diagnosis is often delayed because unspecific clinical presentation (frequently as chronic iron deficiency anemia, rectal bleeding or intestinal obstruction). We present a case of melanoma of unknown primary site, with clinical presentation of intestinal obstruction. A segmental resection of the ileum was performed including mesentery with lymph nodes. Histology revealed metastatic melanoma from unknown primary. PET and MRI confirmed disseminated disease without brain metastasis.

Viral respiratory tract infections (VRTI) are an important cause of morbidity and mortality in haematology patients, particularly after haematopoietic stem cell transplantation (HSCT). The incidence, clinical presentation and outcome of symptomatic and asymptomatic VRTI in HSCT outpatient unit were prospectively evaluated during a single influenza season (January-March 2011). Pharyngeal swabs were performed at the first visit and if new symptoms were present. Molecular multiplex assay for 12 respiratory viruses was performed by the regional reference laboratory. Among 264 swabs from 193 outpatients, 58 (22 %) resulted positive for 61 viruses (influenza, n = 20; respiratory syncytial virus [RSV], n = 21; rhinovirus, n = 12; coronavirus, n = 4; adenovirus, n = 3; parainfluenza, n = 1). VRTI were detected more frequently in the presence of symptoms than in asymptomatic patients: 49 out of 162 (30 %) vs. 9 out of 102 (9 %), p < 0.001. Influenza-like illness syndrome (ILI) was significantly associated with a VRTI if compared to other presentations (42 %), while the European Centre for Disease Prevention and Control definition was not (30 %). Positive predictive value (PPV) of ILI for influenza was 17 %. Influenza and RSV peak periods were contemporary. Influenza prophylaxis was given to 25 patients following exposure. Low rate of progression from upper to lower respiratory tract infection (approximately 5 % for influenza and RSV), no nosocomial epidemics and no VRTI-related deaths were observed. VRTI are very frequent in high-risk haematology outpatients, but symptoms are aspecific and PPV of ILI is low. Symptoms of influenza and RSV overlap. Thus, microbiological diagnosis and contact preventive measures are crucial. Rather than universal influenza prophylaxis, prompt diagnosis and treatment of only documented infections could be pursued.

We assessed WT1 expression (expressed as messenger copies/10(4) ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15-69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34-2833). Relapse was higher in 67 patients with WT1 expression, at any time post-HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post-HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5-year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post-HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post-HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy., (© 2013 Blackwell Publishing Ltd.)

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is an increasingly common form of cancer. Although its spontaneous rupture is rare in Western countries, it constitutes a surgical emergency and is associated with high mortality. There is a lack of consensus as to the best approach and what parameters to use in choosing it. The three main approaches are conservative, endovascular and resection - the treatment of choice for acute abdominal bleeding. We report a case of hemoperitoneum following the spontaneous rupture of an unrecognized HCV-related HCC in a patient with no history of liver disease. The patient was successfully treated by emergency surgery, with resection of two segments of the left liver.

We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies., (Published by Elsevier Inc.)

Blood stream infections (BSI) are a well-known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. The aim of this study was to analyze etiology and microbial resistance of BSI in patients undergoing allogeneic HSCT in a single center over a 4-year period (2004-2007). There were 168 episodes of BSI in 132 patients (median 10 days after HSCT) and 182 pathogens were isolated. Gram-positive bacteria (GPB) accounted for 57% of 182 isolates. Gram-negative rods (GNR) for 37% and fungi for 6%. All patients received routine fluoroquinolone prophylaxis. There was a significant decrease in GPB/GNR ratio over time, from 2.4 in 2004 to 1 in 2007 (P = .043). Among GPB, staphylococci decreased from 37 of 68 (64%) in 2004-2005 to 8 of 35 (23%) in 2006-2007 (P < .002). The Enterococcus faecalis/E. faecium ratio decreased from 4.5 in 2004 to 0.33 in 2007 (P = .006), whereas the total number of enterococcal strains per year did not change. The incidence of Escherichia coli among GNR increased from 3 of 15 (20%) in 2004 to 13 of 21 (62%) in 2007 (P = .003). Fluoroquinolone-resistance was common, both among GPB and GNR (81% and 74%, respectively). Mortality rate at 7 days after BSI was 11% (19 of 168), reaching 39% for Pseudomonas aeruginosa BSI (7 of 18). BSI remains a frequent and potentially life-threatening complication of allogeneic HSCT, the causative organism influencing 7- and 30-day mortality rate. BSI etiology may change rapidly, requiring implementation of new empirical-therapy schemes.

Background and Objectives: A proportion of patients develop poor graft function (PGF) following an allogeneic hemopoietic stem cell transplant (HSCT). It is uncertain whether a boost of donor marrow or blood cells is beneficial in terms of trilineage recovery and non-relapse-related mortality (NRM)., Design and Methods: The aim of this study was to compare outcomes in patients with PGF and full donor chimerism following an allogeneic HSCT who did or did not receive a boost of donor stem cells. The study included patients with primary PGF--i.e. those failing to achieve sustained graft function- and secondary PGF--i.e. those developing PGF after complete hematologic recovery. We studied 54 patients with PGF: 20 patients received no further donor cell infusion (group A), 14 received a boost of unmanipulated marrow or blood cells from the original donor, without further conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C). The three groups were comparable for disease phase, patients' age, donor type, primary or secondary PGF, full donor chimerism and duration of PGF., Results: Trilineage recovery was seen in 40%, 36% and 75% of the patients in, respectively, groups A, B and C (p=0.02). In multivariate Cox analysis trilineage recovery was more frequent in patients with secondary PGF (RR of complete recovery 2.82, p=0.01) and in patients receiving CD34+-selected cells (RR of complete recovery 3.0; p=0.007). There was no effect of donor type on hematologic recovery. The rate of NRM was 55%, 64%, 20% in groups A, B and C, respectively (p=0.06) and was highly correlated with trilineage recovery (RR 0.36, p<0.0001). PGF was the primary cause of death in 30%, 21% and 10% of the patients in the three groups, graft-versus-host disease (GVHD) in 5%, 36%, and 10%., Interpretations and Conclusions: In patients with poor graft function (a) a boost of CD34+-selected peripheral blood donor cells is associated with a high chance of trilineage recovery and a low risk of acute GVHD; (b) a boost of unmanipulated donor cells does not seem to offer a survival advantage over no infusion of cells; and (c) NRM is lower when using peripheral blood cells for the boost. These data may be useful when discussing second stem cell donations for patients with poor graft function.

Background and Objectives: Transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to be related to disease stage, duratiion of disease and type of donor. Furthermore, the outcome of transplants performed in the 1990s appears to be better than that of transplants done in the previous decade. The aims of this study were to determine whether these relationships still hold and whether the outcome of transplants is continuing to improve., Design and Methods: We analyzed 1180 consecutive patients with leukemia (n=979) or other hematologic malignancies (n=201) undergoing HSCT in 4 time periods: before 1990, 1991-1995, 1996-2000, and 2001-2002. Changes during these eras include increasing patient age, more unrelated transplants, more patients with advanced disease, different graft-versus-host disease (GvHD) prophylaxis, and different management of infections., Results: The actuarial 2-year transplant-related mortality (TRM) differed significantly between the transplant eras (p<0.001) with a significant interaction with disease phase (p=0.018). In patients in first remission (n=585) TRM was 34%, 25%, 21% and 6% in the four transplant eras. The reduction in TRM was less evident in patients in second remission (n=284) (37%, 35%, 30%, 25%) and absent in relapsed patients (n=311) (TRM=45%, 41%, 29%, 51%). This is a consequence of reductions in GvHD, infections and multiorgan failure among patients in remission but not among those who relapse. The actuarial 2-year survival has improved significantly in patients in first remission (54%, 66%, 72%, 78%) but not in those in second remission (38%, 46%, 52%,45%), or relapsed patients (31%, 25%, 36%, 21%)., Interpretation and Conclusions: In conclusion, TRM has been significantly reduced in first remission patients, suggesting an allograft should be considered in this phase, when appropriate, without delay. There has been no improvement in survival for patients beyond first remission, due to persisting high risk of infections and organ toxicity, a possible consequence of prolonged pre-transplant chemotherapy and neutropenia.

We have studied the impact of cell dose on short- and long-term graft function and outcome in 905 patients undergoing an unmanipulated allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling (n = 735), a one-antigen mismatched related donor (n = 35), or a matched unrelated donor (n = 135). Median number of nucleated cells infused was 3.4 x 10(8)/kg (25th percentile 2.4 x 10(8)/kg, 75th percentile 5 x 10(8)/kg). Patients were stratified according to cells infused in 3 groups: < or = 2.4 x 10(8)/kg (n = 247; low dose); >2.4 x 10(8)/kg and < or = 5 x 10(8)/kg (n = 452; intermediate dose); and >5 x 10(8)/kg (n = 206; high dose). Patients receiving high cell dose had significantly higher platelet counts on days +20, +50, +100, +180, and +365 after BMT (P <.01) and higher white blood cell counts on days +50, +100, and +180 after BMT (P <.01) as compared with other patients. The actuarial 5-year transplant-related mortality (TRM) was 41% versus 36% versus 28% (P =.01); overall survival was 45% versus 51% versus 56% (P =.0008); and disease-free survival was 41% versus 42% versus 48%, respectively, (P =.04) in patients receiving low, intermediate, or high cell dose. The cell dose effect was more pronounced in patients older than 30 years of age, with advanced disease, with chronic myeloid leukemia, and with alternative donors. In multivariate Cox analysis on TRM, cell dose was a significant predictor (P =.002; relative risk 0.6) together with donor type (P =.0001), year of transplantation (P =.0001), conditioning regimen (P =.02), and recipient age (P =.02). In conclusion, transplantation of high marrow cell dose is associated with reduced transplant mortality and improved survival and results in improved graft function both short and long term.

Background and Objectives: The efficacy of antithymocyte globulin (ATG) in the treatment of graft-versus-host disease (GvHD) is controversial. In the present study we report on the use of low dose ATG (thymoglobuline, Sangstat) and steroids in 28 patients with moderate to severe acute GvHD., Design and Methods: Fifteen patients received ATG as first-line treatment within 14 days of the diagnosis of GvHD (median 8 days, range 4-13). Twelve patients received ATG as second-line therapy, more than 14 days after diagnosis (median 32 days, range 14 to 98). The proportion of patients with severe (grade III-IV) GvHD at the time of ATG therapy was 4/15 in the former group and 7/13 in the latter (p=0.1)., Results: On day 30 after ATG the overall proportion of responders was 80% in the group administered ATG early and 38% in those given it later (p=0.03). The overall actuarial 3-year transplant-related mortality was 40% vs 74% for the early vs late ATG groups (p=0.03); the actuarial 3-year survival was, respectively, 49% vs 23% (p=0.04). For patients with GvHD grade III-IV the actuarial 1-year TRM was 47% for those given ATG early, 87% for the late ATG group and 82% for a concurrent control group of 26 patients not treated with ATG., Interpretation and Conclusions: In conclusion, ATG may be considered for early treatment of acute GvHD, within a few days from the onset of the disease. A prospective trial has been started to test whether, in this setting, low dose ATG with steroids is superior to steroids alone.

Background and Objectives: During the last decade an epidemiological association between hepatitis C virus (HCV) and B-cell lymphoproliferative disorders (B-LPD) has been reported; the same association has not been observed for Hodgkin's disease (HD). Hepatitis G virus (HGV) shares genetic and biological features with HCV, thus it might also be involved in lymphomagenesis., Design and Methods: The aim of this study was to compare the prevalence of HCV and HGV infection in patients at diagnosis of B-LPD or HD., Results: We tested 227 consecutive untransfused patients (127 with B-LPD and 100 with HD) and 110 healthy controls. The prevalence of HCV infection was significantly higher in B-LPD patients than in controls (17.3% vs. 1.8%, p<0.002 ), whereas it was the same in HD patients as in controls. In contrast, the prevalence of HGV was significantly higher in patients, both those with B-LPD (7.8% vs. 0.9%, p<0.03) and those with HD (13% vs. 0.9%, p<0.002), than in controls. Among the various B-LPD tested, HGV infection was more frequent in B-NHL (11.5%)., Interpretation and Conclusions: Our data support the hypothesis that HGV infection may play a role in lymphomagenesis and that this role is different and separate from that of HCV.

Background and Objectives: The risk of relapse after autologous bone marrow transplantation (ASCT) is high and is related to the type of malignancy and phase of the disease. The outcome for the patient who relapses after an autologous transplant is poor. Some of these patients achieve a remission with conventional chemotherapy, but it is usually short-lasting. Most of them succumb to the original disease. One further therapeutic possibility is an allogeneic transplant which would confer the potential advantage of a graft-versus-leukemia effect in addition to the lack of tumor contamination of the graft and to a high-dose intensity conditioning regimen., Design and Methods: We have studied the outcome of 31 patients with hematologic malignancies who underwent an allogeneic hematopoietic stem cell transplant (HSCT) after failing an autologous transplant because of relapse (n=29) or persistent aplasia (n=2). The median age at allograft was 36 years (18-55) and the interval from autograft to allograft was 21 months (3-141). The source of stem-cells was unmanipulated bone marrow (n=26) or growth-factor-mobilized peripheral blood (n=5). The donor was an HLA-identical sibling (n=7), or an alternative donor (n=24) (family mismatched n=11, or matched unrelated n=13). The conditioning regimen was cyclophosphamide and thiotepa (n=22), or cyclophosphamide and total body irradiation (n=9) Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CyA) + methotrexate (MTX)., Results: Acute GvHD was scored as 0-I, II, or III-IV in 39%, 48%, and 13% of the patients, respectively. Sixteen patients died of transplant-related complications and one of progressive disease. With a median follow-up of 220 days (9-2104) the actuarial 2-year transplant-related mortality (TRM) was 51%, the actuarial relapse risk 37%, the actuarial survival 46%. Fifteen patients (48%) are alive in complete remission, with a median follow-up of 32 months (range 2-71)., Interpretation and Conclusions: These data suggest that patients relapsing after an autotransplant should be screened for potential related or unrelated donors: although TRM remains high there is a definite chance of long-term disease-free survival if these patients are allografted.

Preparative regimens without total body irradiation (TBI) have been reported for alternative donor hemopoietic stem cell transplants (HSCT). Between 7 September 1994 and 7 June 1999 48 patients with advanced hematologic malignancies were conditioned with thiotepa (THIO) 15 mg/kg, cyclophosphamide (CY) 150 mg/kg and antithymocyte globulin (ATG). Donors were HLA mismatched family members (1-2 antigens) (FAM) (n = 24, median age 31 years) or HLA matched unrelated donors (UD) (n = 24, median age 34 years). GVHD prophylaxis was cyclosporine and methotrexate. Stem cell source was peripheral blood (n = 8) or bone marrow (n = 40). Hematologic recovery was seen in 42/46 (91%) evaluable patients and complete chimerism in 31/37 patients (85%). Acute GVHD grades III-IV were seen in 10/46 patients surviving 10 days (21%) and extensive chronic GVHD in 2/36 patients surviving 100 days (5%). Twenty-six patients died (54%), eight of recurrent disease (17%) and 18 of transplant-related complications (37%): main causes of TRM were GVHD (15%), infections (15%) and graft failure (4%). Twenty-two patients (46%) survive with a median follow-up of 877 days (287-1840). The actuarial 3-year survival is 49% for FAM and 42% for UD transplants. Results obtained with this regimen in unrelated grafts for advanced CML (n = 15) were not significantly different when compared to 21 concurrent UD grafts for advanced CML prepared with CY-TBI. In conclusion, the combination of THIO-CY-ATG allows engraftment of alternative donor hemopoietic stem cells. Results are similar when using unrelated matched donors or partially mismatched family donors, and not significantly different when compared to patients conditioned with CY-TBI.

Background and Objective: Fanconi's anemia (FA) is a rare autosomal recessive syndrome characterized by skeletal abnormalities, late onset bone marrow failure and susceptibility to neoplasias. Reduced defense against oxidative stress is thought to be one of the cell damaging mechanisms. We investigated in vitro the effects of oxidative stress on red blood cells (RBC) and on hematopoietic progenitor growth of normal donors and of FA patients., Design and Methods: The effects of hydrogen peroxide (H2O2) on RBC and hematopoietic progenitors were studied in vitro by erythrophagocytosis assay and by hematopoietic progenitor colony assay, respectively., Results: In an erythrophagocytosis assay using normal monocytes, RBC from nine FA patients showed increased binding index (defined as the percentage of monocytes with adherent or phagocytosed RBC) compared to that obtained with RBC from nine normal controls. Upon exposure to H2O2, the binding index of normal RBC increased, while that of FA RBC remained unchanged. In a set of different experiments, H2O2 treatment of peripheral blood mononuclear cells (PBMNC) caused a significant decrease of the number of colonies from circulating progenitor cells in all normal subjects; the inhibition was dose-dependent and direct as proven by using normal purified CD34+ cells. In nine FA patients colony assays from intact cells showed a decreased number of circulating progenitors as compared to normal subjects; however, H2O2 treatment of FA PBMNC did not cause any further decrease of the plating efficiency., Interpretation and Conclusions: Untreated FA cells behave as normal cells after exposure to the toxic effects of H2O2. However, since H2O2 exposure is inoffensive to circulating FA RBC and hematopoietic progenitors, it seems that a selection for cells resistant to further oxidative stress has taken place in the residual hematopoiesis of FA patients. We may surmise that the survival of cells that have suffered from oxidative damage may have increased the risk of their leukemic transformation.

The in vitro sensitivity of human hematopoietic progenitors to PUVA, 8-MOP and UVA alone was investigated. 8-MOP alone at final concentrations of 150, 200, 600 and 1,000 ng/ml did not modify colony growth of circulating and bone marrow erythroid (BFU-E), myeloid (CFU-GM) and immature (CFU-GEMM) hematopoietic progenitors obtained from normal controls. The exposure of the same progenitors to increasing doses of UVA, up to 12 J/cm2, progressively decreased hematopoietic colony growth (with estimated 50% inhibition occurring at about 5 J/cm2). In vitro PUVA treatment (8-MOP 200 ng/ml followed by UVA 5 J/cm2) caused 90% growth inhibition of circulating and bone marrow hematopoietic progenitors. In addition, the treatment completely inhibited the formation of spontaneous erythroid colonies, obtained from 5 polycythemic patients, that are considered to be a marker of this neoplastic disease. PUVA cytotoxicity was assessed by the colorimetric MTT assay. The percentage of cell death after PUVA exposure was 29 +/- 10% for both peripheral and bone marrow mononuclear cells. Our findings indicate that 8-MOP alone is not toxic to hematopoietic progenitors whereas UVA treatment determines in vitro a dose-dependent inhibition of the clonogenic capacity of normal hematopoietic cells. PUVA treatment enhances this effect, causing a quite complete inhibition of hematopoietic progenitors colony formation from normal donors and spontaneous BFU-E colony formation from polycythemic patients.