Splenic artery transposition for hepatic arterial reconstruction in a locally advanced pancreatic cancer: a case report and literature review.

OBJECTIVE: During pancreatic surgery for malignancies, hepatic revascularization is needed in case of en bloc resection with hepatic artery involvement. In these cases, the use of the splenic artery is described in the literature, including transposition and interposition techniques. PATIENTS AND METHODS: We report the case of pancreatic cancer resection with involvement of the right hepatic artery, anomalous arising from the superior mesenteric artery, and hepatic revascularization with splenic artery reconstruction. A literature review to analyze the use of splenic artery in hepatic revascularization during pancreatic cancer surgery was performed. RESULTS: A 61-year-old man with a 55-mm hypovascular tumor in the pancreatic head, in wide contact with the right hepatic artery, underwent total pancreatectomy and splenectomy. Right hepatic artery was resected, and the distal part of the splenic artery was transposed to the right hepatic artery with a termino-terminal anastomosis. Histopathological examination revealed R0 resection. CONCLUSIONS: Hepatic revascularization with splenic artery should be considered in patients suitable to extend resectability in pancreatic cancer surgery. A multidisciplinary approach and careful pre-operative planning are essential.

Management of mycotic aorto-iliac aneurysms: a 30-year monocentric experience.

OBJECTIVE: This study aims to analyze the early and late outcomes of our 30-year experience with mycotic aneurysms of the abdominal aorta and iliac arteries. PATIENTS AND METHODS: This retrospective cohort study compared the outcomes of all the patients with mycotic aneurysm, by analyzing prospectively collected data between September 1989 and October 2019 from the Unit of Vascular Surgery of Fondazione Policlinico Universitario Gemelli - IRCCS in Rome, Italy. RESULTS: Twenty-three patients with mycotic aneurysm were included. Twenty-two patients underwent surgery; one patient arrived at the emergency room with unstable clinical conditions and died before being treated. Fourteen cases (60.9%) were located at the infrarenal aorta, while three cases (13.0%) were pararenal aortic aneurysms. Six cases (26.1%) had an iliac arteries localization. Seventeen patients (77.3%) underwent open surgical repair aneurysmectomy with in situ reconstruction, while three cases (13.6%) underwent extra-anatomic revascularization. Three patients (13.6%) underwent the placement of an endoprosthesis, of whom two underwent hybrid procedures, and one EVAR. The latter underwent an early conversion to open repair due to a type I endoleak. The mean length of hospital stay was 35 ± 18.7 days. Five patients (22.7%) died in the immediate postoperative period. In the follow-up of 45.5 ± 41.3 months (range 2-156), we documented six deaths (35.3%), of whom two (11.8%) were aortic-related for a 34.8% overall aortic-related mortality. Eleven patients were alive, with an overall survival of 47.8%. CONCLUSIONS: Mycotic aneurysm is an extremely rare and varied pathology. Open surgical repair showed to be a safe approach because of a complete and aggressive debridement of local infected tissues, with an acceptable long-term mortality rate.

Conditioning regimens for allogeneic hematopoietic stem cell transplants in acute myeloid leukemia.

AML is currently the first indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as shown by international transplant registries. The conditioning regimens are classified as myeloablative conditioning, non-myeloablative or reduced intensity conditioning. Targeted radioimmunotherapy such as anti-CD45 antibody have also been added to the conditioning regimen in an attempt to improve tumor cell kill. Refinement of standard regimens has led to a reduction of non-relapse mortality, also in the older age group over 60 or 70 years of age. Relapse post allo-HSCT remains an important issue, especially for patients who undergo transplant with residual or refractory disease. In these patients, pre- and post-transplant interventions need to be considered.

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.

BACKGROUND: Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. PATIENTS AND METHODS: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. RESULTS: A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. CONCLUSIONS: Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.

Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

PO-54 - Clinical and laboratory characterization of platelet dysfunction caused by ibrutinib treatment in patients with chronic lymphocytic leukemia.

INTRODUCTION: Ibrutinib treatment in patients with chronic lymphatic leukemia (LLC) is associated with bleeding-related adverse events. About 50% of treated patients display minor bleedings and about 5% major bleedings. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein (GP) VI, which is the receptor for collagen, has been previously described. Ibrutinib-associated bleedings and platelet dysfunction may be relevant in the context of aged patients, who are often under antithrombotic treatments. AIM: Aim of this study is to investigate and characterize the effect of ibrutinib on platelet function in vitro in patients with CLL. MATERIALS AND METHODS: Nine patients recruited in ongoing ibrutinib clinical trials were studied. Assessment of spontaneous bleeding was performed using the WHO bleeding scale. The following tests were performed before and after initiation of treatment with ibrutinib: 1) Light transmission aggregometry (LTA) using platelet-rich-plasma (ADP 2-4µM, PAR1-AP 25 µM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2mg/mL) 2) Measurement of vWF antigen and ristocetin cofactor activities by chemiluminescent immunoassay. RESULTS: I) Five patients displayed grade 1 bleeding (cutaneous bleeding) and one patient grade 2 bleeding (rectal bleeding) (66.7%) after initiation of ibrutinib treatment. II) Eight patients displayed abnormalities of the aggregation by 10 ug/ml collagen after initiation of ibrutinib treatment. At high collagen concentration, only significant prolongation of the lag phase was measured (60.4±10.6sec vs basal 38.4±17sec), whereas the maximal aggregation was not impaired (67.9±21.4% vs basal 85.5±5.8%). Compared to previous reports, these results confirmed an impairment of collagen induced aggregation, but at these concentrations only the lag phase was affected. III) Five patients displayed a significant improvement of the aggregation by 2 uM (91.25±5.26% vs basal 39.3±24.62%) and 4 uM (91±2.83% vs basal 65.42±19.43%) ADP after initiation of ibrutinib treatment. IV) vWF antigen and ristocetin cofactor activity were measured in 3 patients. In all patients vWF levels were higher at the onset of the disease (169±38%) and reduced up to normal values under Ibrutinib treatment (111.4±47%). CONCLUSIONS: Ibrutinib treatment in LLC patients causes a mild bleeding phenotype most probably due to platelet dysfunction. In this study, collagen induced aggregation resulted impaired, whereas the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected. On the contrary, the aggregation by ADP was improved upon ibrutinib treatment. The levels of vonWillebrand factor are significantly higher in LLC patients before treatment and were normalized by ibrutinib.

Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy.

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P=0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P=0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT.

Identification of prognostic factors predicting outcome in Hodgkin's lymphoma patients relapsing after autologous stem cell transplantation.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with relapsed Hodgkin's lymphoma (HL). However, there is currently little information on the predictors of outcome for patients whose disease recurs after ASCT. METHODS: Five hundred and eleven adult patients with relapsed HL after ASCT from EBMT-GITMO databases were reviewed. RESULTS: Treatments administered following ASCT failure included conventional chemotherapy and/or radiotherapy in 294 (64%) patients, second ASCT in 35 (8%), and alloSCT in 133 (29%). After a median follow-up of 49 months, overall survival (OS) was 32% at 5 years. Independent risk factors for OS were early relapse (<6 months) after ASCT, stage IV, bulky disease, poor performance status (PS), and age ≥50 years at relapse. For patients with no risk factors OS at 5 years was 62% compared with 37% and 12% for those having 1 and ≥2 factors, respectively. This score was also predictive for outcome in each group of rescue treatment after ASCT failure. CONCLUSION(S): Early relapse, stage IV, bulky disease, poor PS, and age ≥50 years at ASCT failure are relevant factors for outcome that may help to understand the results of different therapeutic approaches.

Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib.

Health-related quality of life (HRQOL) is an important goal of therapy for chronic myeloid leukemia (CML) patients treated with current molecular-targeted therapies. The main objective of this study was to investigate factors associated with long-term HRQOL outcomes of CML patients receiving imatinib. Analysis was performed on 422 CML patients recruited in an observational multicenter study. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Key socio-demographic and clinical data were investigated for their association with HRQOL outcomes. Chronic fatigue and social support were also investigated. Univariate and multivariate linear regression analyses were used to identify independent factors associated with HRQOL outcomes. Fatigue was the only variable showing an independent and consistent association across all physical and mental HRQOL outcomes (P<0.01). Differences between patients reporting low versus high fatigue levels were more than eight and seven times the magnitude of a clinically meaningful difference, respectively, for the role physical (Δ=70 points) and emotional scale (Δ=63 points) of the SF-36. Fatigue did not occur as an isolated symptom and was most highly correlated with musculoskeletal pain (r=0.511; P≤0.001) and muscular cramps (r=0.448; P≤0.001). Chronic fatigue is the major factor limiting HRQOL of CML patients receiving imatinib.

Outcome of patients activating an unrelated donor search: the impact of transplant with reduced intensity conditioning in a large cohort of consecutive high-risk patients.

An unrelated donor (UD) search was submitted to the Italian Bone Marrow Donor Registry between February 2002 and December 2004, for 326 consecutive patients with hematological malignancies, eligible for a reduced intensity conditioning (RIC) UD transplant. Only two regimens were allowed: melphalan, alemtuzumab, fludarabine and total body irradiation of 200 cGy (regimen A) and thiotepa, cyclophosphamide, anti-thymocyte globulin (regimen B). The outcome of patients receiving an UD transplant (n=121) was compared with patients who did not find a donor (n=205), in a time dependent analysis, correcting for time to transplant. The median follow up from activation of donor search was 6.1 years. UD transplant was associated with a significantly better survival in patients with acute leukemia and non-Hodgkin's lymphoma (NHL) whereas only a favorable trend was documented for Hodgkin's disease. No survival benefit was registered for chronic leukemias. The outcome of the two different conditioning regimens was comparable, in terms of survival, transplant-related mortality and graft versus host disease. In conclusion, finding an UD and undergoing a RIC transplant significantly improves survival of patients with acute leukemia and NHL. The advantage is less clear for HD and chronic leukemias. The role of different conditioning regimens remains to be elucidated by prospective clinical trials.

The role of HLA--G 14-bp polymorphism in allo-HSCT after short-term course MTX for GvHD prophylaxis.

HLA-G molecules are HLA class Ib antigens characterized by tolerogenic and immunoinhibitory functions. The HLA-G 14-bp insertion/deletion (ins/del) polymorphism controls protein expression and seems to be implicated in both MTX treatment response and SCT outcome. The aim of our study is to evaluate the role of HLA-G 14 bp polymorphism in subjects affected by hematological malignancies undergoing allo-SCT and receiving MTX therapy for GvHD prophylaxis. We performed a retrospective analysis of HLA-G 14 bp polymorphism using a specific PCR in 47 recipients and in their respective donors, and evaluated the correlation with the incidence of aGvHD, OS and disease-free survival (DFS) after allo-SCT. We did not observe any correlation between this polymorphism and the risk of aGvHD occurrence. On the contrary, we found that the recipients with a 14 bp ins/14 bp ins genotype were characterized by a lower OS and DFS in univariate and multivariate analysis (OS=OR: 3.235; DFS=OR: 3.302). These data indicate a role for recipient HLA-G 14 bp polymorphism in allo-SCT immunotolerance status and follow-up.

New and old monoclonal antibodies for the treatment of chronic lymphocytic leukemia.

Over the last few years, several new agents have been under evaluation in preclinical studies and clinical trials, showing promise in treating chronic lymphocytic leukemia (CLL). Among these agents, monoclonal antibodies (mAbs) such as rituximab and alemtuzumab have changed the natural course of the disease. Nowadays there are several new promising monoclonal antibodies under investigation against the CD20, CD23, CD37 and CD40 molecules. Application of newer monoclonal antibodies represents an area of ongoing clinical research in CLL.

Molecular characterization of adenovirus from clinical samples through analysis of the hexon and fiber genes.

Human adenoviruses (HAdVs) are common pathogens associated with a variety of clinical manifestations. Although most infections are self-limiting, HAdVs can cause severe or lethal infections in immunocompromised as well as in healthy individuals. Several HAdVs have recently been characterized as emerging pathogens. In Italy, epidemiological, and especially molecular epidemiological, information on this pathogen is scarce. This study describes the characterization by cell culture, PCR and phylogenetic analysis of HAdV strains originating from a small collection of clinical samples gathered between 2008 and 2009. The distribution of different HAdV species was studied and the possible presence of newly emerging types was ascertained. A broad-range primer pair was used, targeting a portion of the hexon gene, in combination with species-specific primer pairs targeting a portion of the fiber gene. Human and animal reference AdV strains were included in the study. The broad-range assay identified all HAdV strains (study and reference samples), as well as three out of four animal AdV reference strains. Seven different types belonging to three HAdV species (B, C and F) were identified in the study samples. Species C was by far the most frequent. Two co-infections were detected, each with two serotypes within species C (types 1/2 and 2/6). The combined use of these two PCR assays--allowing not only the identification of known types but also, potentially, the discovery of newly emerging ones--can provide valuable epidemiological information on the spread of HAdVs.