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Background: Acute recurrent pancreatitis (ARP) is a rare manifestation of Intraductal Papillary Mucinous Neoplasms (IPMN) of the pancreas; ARP is a relative indication for pancreatic surgery in the setting of IPMN. Endoscopic pancreatic sphincterotomy (EPS) has been described as a minimal invasive treatment to reduce the episodes of ARP secondary to mucus migration in IPMN., Methods: patients with IPMN-related ARP treated with ESP from January 2004 to December 2020 were retrospectively selected. Clinical and technical data were recorded. A clinical follow-up (minimum 12 months) was performed to assess the number of episodes of AP occurring after EPS., Results: 25 patients were included. The mean follow-up after ESP was 93.4 months (SD± 56.6). The mean number of AP before and after EPS were respectively 3.29 (SD ± 1.04) and 0.51 (SD ± 0.71). A complete response (no further episodes of AP) and a partial response (>50% reduction of AP episodes) were obtained in 64% and 24% of the cases, respectively, with an overall response rate of 88%. One post-EPS bleeding and one minor-papilla stenosis were reported and were endoscopically managed. Two patients underwent pancreatic resection for the occurrence of high-risk stigmata for cancer progression., Conclusions: EPS is a safe and effective treatment to reduce the number of episodes of AP in selected patients with IPMNs-related ARP. Prospective trials are needed to confirm these data., Competing Interests: Declaration of Competing Interest Andrea Tringali is a consultant for Boston Scientific and Olympus. Ivo Boškoski is a consultant for Apollo Endosurgery, Cook Medical, and Boston Scientific Corp., he holds a research grant from Apollo Endosurgery, and is on the scientific board of EndoTools. Guido Costamagna is on the advisory board for Cook Medical, Olympus, and Ethicon, and holds a research grant from Boston Scientific Corp. and Apollo Endosurgery. The other authors have no financial relationships with a commercial entity producing health-care related products and/or services relevant to this article., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The implementation of multidisciplinary tumor board (MDTB) meetings significantly ameliorated the management of oncological diseases. However, few evidences are currently present on their impact on pancreatic cancer (PC) management. The aim of this study was to evaluate the impact of the MDTB on PC diagnosis, resectability and tumor response to oncological treatment compared with indications before discussion., Patients and Methods: All patients with a suspected or proven diagnosis of PC presented at the MDTB from 2017 to 2019 were included in the study. Changes of diagnosis, resectability and tumor response to oncological/radiation treatment between pre- and post-MDTB discussion were analyzed., Results: A total of 438 cases were included in the study: 249 (56.8%) were presented as new diagnoses, 148 (33.8%) for resectability assessment and 41 (9.4%) for tumor response evaluation to oncological treatment. MDTB discussion led to a change in diagnosis in 54/249 cases (21.7%), with a consequent treatment strategy variation in 36 cases (14.5%). Change in resectability was documented in 44/148 cases (29.7%), with the highest discrepancy for borderline lesions. The treatment strategy was thus modified in 27 patients (18.2%). The MDTB brought a modification in the tumor response assessment in 6/41 cases (14.6%), with a consequent protocol modification in four (9.8%) cases., Conclusions: MDTB discussion significantly impacts on PC management, especially in high-volume centers, with consistent variations in terms of diagnosis, resectability and tumor response assessment compared with indications before discussion., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular complications are included among the systemic effects of tyrosine kinase inhibitor (TKI)-based therapeutic strategies. To test the hypothesis that inhibition of Kit tyrosine kinase that promotes cardiac progenitor cell (CPC) survival and function may be one of the triggering mechanisms of imatinib mesylate (IM)-related cardiovascular effects, the anatomical, structural and ultrastructural changes in the heart of IM-treated rats were evaluated. Cardiac anatomy in IM-exposed rats showed a dose-dependent, restrictive type of remodeling and depressed hemodynamic performance in the absence of remarkable myocardial fibrosis. The effects of IM on rat and human CPCs were also assessed. IM induced rat CPC depletion, reduced growth and increased cell death. Similar effects were observed in CPCs isolated from human hearts. These results extend the notion that cardiovascular side effects are driven by multiple actions of IM. The identification of cellular mechanisms responsible for cardiovascular complications due to TKIs will enable future strategies aimed at preserving concomitantly cardiac integrity and anti-tumor activity of advanced cancer treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL)., Patients and Methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8., Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected., Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration., Registered Clinical Trial Number: NCT01724021 (ClinicalTrials.gov)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in immunocompromised patients. Patients with hematological malignancies undergoing conventional chemotherapy, autologous or allogeneic hematopoietic stem cell transplantation are considered at high risk, and Aspergillus spp. represents the most frequently isolated micro-organisms. In the last years, attention has also been focused on other rare molds (e.g., Zygomycetes, Fusarium spp.) responsible for devastating clinical manifestations. The extensive use of antifungal prophylaxis has reduced the infections from yeasts (e.g., candidemia) even though they are still associated with high mortality rates. This paper analyzes concurrent multiple predisposing factors that could favor the onset of fungal infections. Although neutropenia is common to almost all hematologic patients, other factors play a key role in specific patients, in particular in patients with AML or allogeneic HSCT recipients. Defining those patients at higher risk of IFIs may help to design the most appropriate diagnostic work-up and antifungal strategy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM., (© 2016 by The American Society of Hematology.)

Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donor-vs-recipient natural killer [NK]-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio [HR], 0.25; P = .01; KIR3DS1 present vs absent: HR, 0.18; P = .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P = .011; KIR3DS1 present vs absent: HR, 0.30; P = .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P = .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection., (© 2015 by The American Society of Hematology.)

Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow., (© 2014 by The American Society of Hematology.)

Today human leukocyte antigen-haploidentical transplantation is a feasible option for patients with high-risk acute leukemia who do not have matched donors. Whether it is T-cell replete or T-cell depleted, it is still, however, associated with issues of transplant-related mortality and posttransplant leukemia relapse. After reports that adoptive immunotherapy with T-regulatory cells controls the alloreactivity of conventional T lymphocytes in animal models, tomorrow's world of haploidentical transplantation will focus on new "designed" grafts. They will contain an appropriate ratio of conventional T lymphocytes and T-regulatory cells, natural killer cells, γ δ T cells, and other accessory cells. Preliminary results of ongoing clinical trials show the approach is feasible. It is associated with better immune reconstitution and a quite powerful graft-versus-leukemia effect with a low incidence of graft-versus-host disease and no need for posttransplant pharmacological prophylaxis. Future strategies will focus on enhancing the clinical benefit of T-regulatory cells by increasing their number and strengthening their function.

The electronic surveillance system Hema e-Chart allowed us to prospectively collect data and to perform an analysis of invasive fungal infections (IFI) diagnosed in febrile patients as well as the procedures allowing their diagnosis and outcome according to the treatment given. Every patient admitted to 26 Italian Haematology Units with a new diagnosis of haematological malignancy and who was a candidate for chemotherapy was consecutively registered between March 2007 and March 2009. In all, 147 haematological patients with mycoses were identified. Yeasts were found in 23 infections; moulds were diagnosed in 17 proven, 35 probable and 72 possible mycoses. Galactomannan (GM) antigen was the most important test to diagnose probable mould infection; it was positive (cut-off >0.5) in 27 (77%) probable and in nine (53%) proven mould infections. Among patients with probable/proven mould infection who received no prophylaxis or non-mould-active prophylaxis with fluconazole, more patients (n = 26, 78.8%) had GM antigen positivity compared with patients (n = 10, 52.6%) given prophylaxis with mould-active drugs (p <0.05). First-line antifungal therapy was effective in 11/23 (48%) yeast infections and in 37/52 (71.2%) proven/probable mould infections. Twenty patients (14%) died within 12 weeks. The fungal attributable mortality was 30.4% and 17.3% in yeast and proven/probable mould infections, respectively. Among risk factors only age was independently associated (p 0.013) with mortality; sex, underlying haematological malignancy, previous prophylaxis and presence of neutropenia at diagnosis were not significant. A diagnosis of mould infection seemed to have a trend for a better outcome than the diagnosis of yeast infection (p 0.064)., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8⁺ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8⁺ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4⁺ and CD8⁺ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8⁺ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8⁺ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8⁺ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.

Much progress has been made in the clinical, biological and technical aspects of the T-cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT). Our experience demonstrates that infusing a megadose of extensively T-cell-depleted hematopoietic peripheral blood stem cells after an immuno-myeloablative conditioning regimen in acute leukemia patients ensures sustained engraftment with minimal GvHD without the need of any post-transplant immunosuppressive treatment. Since our first successful pilot study, our efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the post-transplant immunological recovery. The results we have so far achieved in high risk acute leukemia patients show that haploidentical transplantation is now a clinical reality. The present challenge is to reduce post-transplant infectious mortality and several strategies are being tested., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Haploidentical transplantation, with extensive T cell depletion to prevent GvHD, is associated with a high incidence of infection-related deaths. The key challenge is to improve immune recovery with allogeneic donor T cells without triggering GvHD. As T regulatory cells (Tregs) controlled GvHD in pre-clinical studies, the present study evaluated the impact of an infusion of donor CD4/CD25 + Tregs, followed by an inoculum of donor mature T cells (Tcons) and positively immunoselected CD34 + cells in the setting of haploidentical stem cell transplantation., Patients and Methods: Twenty-eight patients were enrolled in this study (22 AML; 5 ALL; 1 NHL). All received immunoselected Tregs (CliniMACS, Miltenyi Biotec) followed by positively immunoselected CD34 + cells together with Tcons 4 days later. No GvHD prophylaxis was administered., Results: 26/28 patients engrafted. No acute GvHD developed in 24/26 patients; 2 developed ≥ grade II acute GvHD. No patient has developed chronic GvHD. CD4 and CD8 counts rapidly increased after transplant. Episodes of CMV reactivation were significantly fewer than in controls., Conclusions: In the setting of haploidentical transplantation infusion of Tregs makes administration of a high dose of T cells feasible. This strategy provides a long-term protection from GvHD and robust immune reconstitution., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Hastening posttransplantation immune reconstitution is a key challenge in human leukocyte antigen (HLA)-haploidentical hematopoietic stem-cell transplantation (HSCT). In experimental models of mismatched HSCT, T-regulatory cells (Tregs) when co-infused with conventional T cells (Tcons) favored posttransplantation immune reconstitution and prevented lethal graft-versus-host disease (GVHD). In the present study, we evaluated the impact of early infusion of Tregs, followed by Tcons, on GVHD prevention and immunologic reconstitution in 28 patients with high-risk hematologic malignancies who underwent HLA-haploidentical HSCT. We show for the first time in humans that adoptive transfer of Tregs prevented GVHD in the absence of any posttransplantation immunosuppression, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect. This study provides evidence that Tregs are a conserved mechanism in humans.

The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.

T cell-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) is an option to treat children with very high-risk acute lymphoblastic leukemia (ALL) lacking an HLA-identical donor. We analyzed 127 children with ALL who underwent haploHSCT in first (n = 22), second (n = 48), or third (n = 32), complete remission or in relapse (n = 25). The 5-year leukemia-free survival (LFS) was 30%, 34%, 22%, and 0%, respectively. A risk-factor analysis was performed for patients who underwent transplantation in remission (n = 102). Five-year nonrelapse mortality (NRM), relapse incidence (RI), and LFS were 37%, 36%, and 27%, respectively. A trend of improved LFS rate and decreased RI was observed for children given a graft with higher number of CD34(+) cells (adjusted P = .09 and P = .07, respectively). In a multivariate analysis, haploHSCT performed in larger centers (performing > or = 231 allotransplantations in the studied period) was associated with improved LFS rate and decreased RI (adjusted P = .01 and P = .04, respectively), adjusting for different patient-, disease-, and transplant-related factors such as number of previous autotransplantations, cytomegalovirus serology status, type of T-cell depletion, and use of total body irradiation and antithymocyte globulin. In conclusion, higher CD34(+) cell dose and better patient selection may improve outcomes of children with ALL who undergo a haploHSCT. Transplant centers initiating programs on haploHSCT for children may collaborate with more experienced centers.

Donor-versus-recipient natural killer (NK) cell alloreactivity has been established as a key therapeutic element in HLA haplotype mismatched hematopoietic transplants in adult AML and pediatric ALL and as a possible beneficial effector in cord blood transplant for AML. It is effected by functional NK cells which express inhibitory killer cell immunoglobulin-like receptor(s) (KIR) for self-class I ligand(s), sense missing expression of donor KIR ligand(s) in the recipient and mediate alloreactions. At present NK cell allotherapy for leukemia is deployed through stem cell transplantation (and ensuing NK cell reconstitution) across KIR ligand mismatches. Studies have been performed to infuse NK cells for immunotherapy outside the fields of transplantation and/or harness the function of endogenous NK cells in patients with hematological malignancies.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. We analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a haplo-HSCT in Europe. All grafts were T cell-depleted peripheral blood progenitor cells from a direct family or other related donor. At transplantation, there were 25 patients with AML in CR1 (complete remission 1), 61 in more than or equal to CR2, and 87 in nonremission, and 24 with ALL in CR1, 37 in more than or equal to CR2, and 32 in nonremission. Median follow-up was 47 months in AML and 29 months in the ALL groups. Engraftment was observed in 91% of the patients. Leukemia-free survival at 2 years was 48% plus or minus 10%, 21% plus or minus 5%, and 1% for patients with AML undergoing transplantation in CR1, more than or equal to CR2, and nonremission, and 13% plus or minus 7%, 30% plus or minus 8%, and 7% plus or minus 5% in ALL patients, respectively. In conclusion, haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor.

We hypothesized that transplacental leukocyte trafficking during pregnancy, which induces long-term, stable, reciprocal microchimerism in mother and child, might influence outcome of patients with acute leukemia given parental donor haploidentical hematopoietic stem cell transplantation (HSCT). We analyzed the outcome of 118 patients who received transplants for acute leukemia in 2 centers. Patients received highly T cell-depleted haploidentical grafts after myelo-ablative conditioning. Five-year event-free survival was better in patients who received transplants from the mother than from the father (50.6% +/- 7.6% vs 11.1% +/- 4.2%; P < .001). Better survival was the result of both reduced incidence of relapse and transplantation-related mortality. The protective effect was seen in both female and male recipients, in both lymphoid and myeloid diseases; it was more evident in patients receiving transplants in remission than in chemotherapy-resistant relapse. Incidences of rejection and acute graft-versus-host disease were not significantly influenced. Multivariate analysis confirmed donor sex in parental donor transplantation as an independent prognostic factor for survival (hazard ratio, father vs mother = 2.36; P = .003). In contrast, in a control cohort of patients who received transplants from haploidentical siblings, donor sex had no influence on outcome. Although obtained in a retrospective analysis, these data suggest that the mother of the patient should be preferred as donor for haploidentical HSCT.

Objective: To evaluate the cost-effectiveness of caspofungin versus liposomal amphotericin B as empiric antifungal treatment in patients with neutropenic fever in Italy., Methods: The cost-effectiveness of caspofungin versus liposomal amphotericin B was evaluated using a decision-tree model. Patients were stratified by presence or absence of baseline infection. Model outcomes included success in terms of resolution of fever, resolution of baseline infection, absence of breakthrough infection, survival, and quality-adjusted life years (QALYs) saved. Discontinuation because of nephrotoxicity or other adverse events were included in the model. Efficacy and safety data were based on a randomized, double-blind, multinational trial of caspofungin compared to liposomal amphotericin B (Walsh 2004). Information on life expectancy, quality of life, medical resource consumption, and costs was obtained from the literature., Results: The caspofungin estimated total treatment cost amounted to 8351 euros (95% uncertainty interval 7801 euros-8903 euros), which is 3470 euros (2575 euros-4382 euros) less than with liposomal amphotericin B. Treatment with caspofungin resulted in 0.25 (-0.11; 0.59) QALYs saved in comparison to treatment with liposomal amphotericin B. Probabilistic sensitivity analysis demonstrated a 93% probability that caspofungin was economically dominant, i.e., cost and QALY saving, and a probability of more than 99% that the costs per QALY saved were below 20,000 euros, a commonly accepted threshold for cost-effectiveness. Additional analyses with alternative doses of liposomal amphotericin B confirmed these findings., Conclusion: Given the underlying assumptions, our economic evaluation demonstrated that caspofungin is cost-effective compared to liposomal amphotericin B in empiric antifungal treatment of patients with neutropenic fever in Italy.

We analyzed 112 patients with high-risk acute myeloid leukemia (61 in complete remission [CR]; 51 in relapse), who received human leukocyte-antigen (HLA)-haploidentical transplants from natural killer (NK) alloreactive (n = 51) or non-NK alloreactive donors (n = 61). NK alloreactive donors possessed HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligand(s) which were missing in the recipients, KIR gene(s) for missing self recognition on recipient targets, and alloreactive NK clones against recipient targets. Transplantation from NK-alloreactive donors was associated with a significantly lower relapse rate in patients transplanted in CR (3% versus 47%) (P > .003), better event-free survival in patients transplanted in relapse (34% versus 6%, P = .04) and in remission (67% versus 18%, P = .02), and reduced risk of relapse or death (relative risk versus non-NK-alloreactive donor, 0.48; 95% CI, 0.29-0.78; P > .001). In all patients we tested the "missing ligand" model which pools KIR ligand mismatched transplants and KIR ligand-matched transplants from donors possessing KIR(s) for which neither donor nor recipient have HLA ligand(s). Only transplantation from NK-alloreactive donors is associated with a survival advantage.

In haplo-identical hematopoietic transplantation, donor vs. recipient natural killer (NK) cell alloreactivity derives from a mismatch between donor NK clones bearing inhibitory killer cell Ig-like receptors (KIR) for self-HLA class I molecules and their HLA class I ligands (KIR ligands) on recipient cells. When faced with mismatched allogeneic targets, these NK clones sense the missing expression of self-HLA class I alleles and mediate alloreactions. KIR ligand mismatches in the GvH direction trigger donor vs. recipient NK cell alloreactions, which improve engraftment, do not cause GvHD and control relapse in AML patients . The mechanism whereby alloreactive NK cells exert their benefits in transplantation has been elucidated in mouse models. The infusion of alloreactive NK cells ablates (i) leukemic cells, (ii) recipient T cells that reject the graft and (iii) recipient DC that trigger GvHD, thus protecting from GvHD.

Aspergillus and cytomegalovirus are major causes of morbidity/mortality after haploidentical hematopoietic transplantation. The high degree of mismatching makes cell immunotherapy impossible as it would result in lethal graft-versus-host disease (GvHD). We generated large numbers of donor T-cell clones specific for Aspergillus or cytomegalovirus antigens. We identified clones potentially responsible for causing GvHD by screening them for cross-reactivity against recipient mononuclear cells. Non-recipient reactive, pathogen-specific clones were infused soon after transplantation. They were CD4+ and produced high levels of interferon-gamma and low levels of interleukin-10. In 46 control transplant recipients who did not receive adoptive therapy, spontaneous pathogen-specific T cells occurred in low frequency 9 to 12 months after transplantation and displayed a non-protective low interferon-gamma/high interleukin-10 production phenotype. In the 35 recipients who received adoptive therapy, one single infusion of donor alloantigen-deleted, pathogen-specific clones in the dose range of 10(5) to 10(6) cells/kg body weight did not cause GvHD and induced high-frequency T-cell responses to pathogens, which exhibited a protective high interferon-gamma/low interleukin-10 production phenotype within 3 weeks of infusion. Frequencies of pathogen-specific T cells remained stable over time, and were associated with control of Aspergillus and cytomegalovirus antigenemia and infectious mortality. This study opens new perspectives for reducing infectious mortality after haploidentical transplantations.

Natural-killer-cell-mediated, donor-vs-recipient alloresponses occur following transplantation of human-leukocyte-antigen (HLA)-haplotype-mismatched haematopoietic stem cells. Natural killer (NK) cell alloreactivity reduces the risk of relapse in acute myeloid leukaemia patients, while improving engraftment and protecting against graft-vs-host disease. NK cells are primed to kill by several activating receptors. NK cell killing of autologous cells is prevented as NK cells co-express inhibitory receptors (killer cell Ig-like receptors, KIR) that recognize groups of (self) major histocompatibility complex class I alleles. As KIRs are distributed clonally, the NK cell population in any individual constitutes a repertoire with different allospecificities. NK cells in the repertoire mediate alloreactions when the allogeneic targets do not express class I alleles that block them. High-resolution molecular HLA typing of recipient and donor, positive identification of donor KIR genes and, in some cases, functional assessment of donor NK clones will identify haplo-identical donors who are able to mount donor-vs-recipient NK alloreactions.

Background: Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the GvL effect. In HLA haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GvHD. This raises the question of whether mismatched transplants exert any GvL effect, and whether it will ever be possible to reduce the intensity of preparative regimens. Natural killer (NK) cells are negatively regulated by MHC Class I-specific inhibitory receptors. Mismatched transplants may therefore trigger NK-cell alloreactivity., Methods: The effects of NK-cell alloreactivity were evaluated in clinical transplantation and in murine transplant models., Results: In clinical hematopoietic stem-cell transplants, HLA Class I disparities driving NK-cell alloreactions in the GvH direction eliminate AML relapse and graft rejection, while protecting patients from GvHD. In murine MHC mismatched transplant models, the pre-transplant infusion of donor-versus-recipient alloreactive NK cells conditioned the recipients to BMT, and reduced GvHD., Discussion: NK-cell alloreactivity may thus provide a novel, powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.

In acute leukemia patients, infusing a megadose of extensively T-cell-depleted hematopoietic stem cells after an immuno-myeloablative conditioning regimen ensures sustained engraftment of full-haplotype mismatched transplants without graft-vs-host disease. Besides the conditioning regimen and the megadose of stem cells donor natural killer cell alloreactivity also plays a role in facilitating engraftment and in preventing relapse. Since our first successful pilot study, our efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the post-transplant immunological recovery. The results we have so far achieved in 112 very high-risk acute leukemia patients show that haploidentical transplantation is now a clinical reality. Because virtually all patients in need of a hematopoietic stem cell transplant have a full-haplotype mismatched donor, who is immediately available, a T-cell depleted mismatched transplant should be offered, not as a last resort, but as a viable option to high risk acute leukemia patients who do not have, or cannot find, a matched donor., (Copyright 2001 Harcourt Publishers Ltd.)

In human leukocyte antigen haplotype-mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4- and IL-10-producing CD4(+) cells not expressing the IL-12 receptor beta(2) chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12-producing dendritic cells (1-3 months after transplantation versus > 12 months in transplant recipients given G-CSF), of CD4(+) cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4(+) cell counts increased in significantly less time. Finally, elimination of G-CSF-mediated immune suppression did not significantly increase the incidence of GVHD (< 15%). Thus, this study found that administration of G-CSF to recipients of T-cell-depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.

The engraftment capacity of bone marrow-derived mesenchymal cells was investigated in 41 patients who had received a sex-mismatched, T-cell-depleted allograft from human leukocyte antigen (HLA)-matched or -mismatched family donors. Polymerase chain reaction (PCR) analysis of the human androgen receptor (HUMARA) or the amelogenin genes was used to detect donor-derived mesenchymal cells. Only 14 marrow samples (34%) from 41 consenting patients generated a marrow stromal layer adequate for PCR analysis. Monocyte-macrophage contamination of marrow stromal layers was reduced below the levels of sensitivity of HUMARA and amelogenin assays (5% and 3%, respectively) by repeated trypsinizations and treatment with the leucyl-leucine (leu-leu) methyl ester. Patients who received allografts from 12 female donors were analyzed by means of the HUMARA assay, and in 5 of 12 cases a partial female origin of stromal cells was demonstrated. Two patients who received allografts from male donors were analyzed by amplifying the amelogenin gene, and in both cases a partial male origin of stromal cells was shown. Fluorescent in situ hybridization analysis using a Y probe confirmed the results of PCR analysis and demonstrated in 2 cases the existence of a mixed chimerism at the stromal cell level. There was no statistical difference detected between the dose of fibroblast progenitors (colony-forming unit-F [CFU-F]) infused to patients with donor- or host-derived stromal cells (1.18 +/- 0.13 x 10(4)/kg vs 1. 19 +/- 0.19 x 10(4)/kg; P >/=.97). In conclusion, marrow stromal progenitors reinfused in patients receiving a T-cell-depleted allograft have a limited capacity of reconstituting marrow mesenchymal cells.

We have shown that addition of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to the marrow inoculum allows engraftment of T-cell depleted, "three loci" HLA-incompatible marrow transplants for acute leukemia. The event-free survival of patients at high risk for potential of this transplant. Tumor-cell lysis by natural killer (NK) cells is regulated by inhibitory receptors for specific HLA class I alleles. Here, we report the postgrafting emergence of a large, donor-type CD3+/CD8+ T-cell receptor (TcR)-alpha beta+ cell population, barely detectable in normal subjects, that expresses 58 kD, "p58," NK receptors for HLA-C locus alleles. Analysis of > 900 clones revealed that 40% to 80% of these T cells exhibit NK-like function, i.e., they lysed class I- targets and were functionally blocked by class I alleles on target cells. Monoclonal antibody-mediated blocking of class I recognition by these cells induced lysis of HLA-protected, autologous targets. The class I-mediated inhibitory signaling through the NK receptors also blocked TcR/CD3-triggered cytotoxicity of these cells, indicating that their antigen-specific responses may be impaired. However, the NK-like function of these cells allows them to discriminate normal cells, protected from lysis, from leukemic cells that were lysed and may be targets for a graft-versus-leukemia effect.

Patients who undergo transplantation with haploidentical "three-loci" mismatched T-cell-depleted bone marrow (BM) are at high risk for graft failure. To overcome the host-versus-graft barrier, we increased the size of the graft inoculum, which has been shown to be a major factor in controlling both immune rejection and stem cell competition in murine models. Seventeen patients (mean age, 23.2 years; range, 6 to 51 years) with end-stage chemoresistant leukemia were received transplants of a combination of BM with recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells from HLA-haploidentical "three-loci" incompatible family members. The average concentration of colony-forming unit-granulocyte-macrophage in the final inoculum was sevenfold to 10-fold greater than that found in BM alone. The sole graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion of the graft by the soybean agglutination and E-rosetting technique. The conditioning regimen included total body irradiation in a single fraction at a fast dose rate, antithymocyte globulin, cyclophosphamide and thiotepa to provide both immunosuppression and myeloablation. One patient rejected the graft and the other 16 had early and sustained full donor-type engraftment. One patient who received a much greater quantity of T lymphocytes than any other patient died from grade IV acute GVHD. There were no other cases of GVHD > or = grade II. Nine patients died from transplant-related toxicity, 2 relapsed, and 6 patients are alive and event-free at a median follow-up of 230 days (range, 100 to 485 days). Our results show that a highly immunosuppressive and myeloablative conditioning followed by transplantation of a large number of stem cells depleted of T lymphocytes by soybean agglutination and E-rosetting technique has made transplantation of three HLA-antigen disparate grafts possible, with only rare cases of GVHD.

We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.

In Hodgkin's disease, Hodgkin and Reed-Sternberg cells consistently express the antigen CD30. We investigated the possible therapeutic role of an immunotoxin prepared by covalent linking of an anti-CD30 monoclonal antibody (Ber-H2) to saporin (SO6), a type-1 ribosome-inactivating protein. The immunotoxin (0.8 mg/kg in one or two doses) was given to four patients with advanced refractory Hodgkin's disease. In three, there was rapid and substantial reduction in tumour mass (50% to greater than 75%). Clinical responses were transient (6-10 weeks). In-vivo binding of the immunotoxin to tumour cells was shown by immunohistology in two patients. Antibodies to both parts of the immunotoxin developed in all patients.