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Background: Adrenalectomy for pheochromocytoma (PHEO) is challenging because of the high risk of intraoperative hemodynamic instability (HDI). This study aimed to compare the incidence and risk factors of intraoperative HDI between laparoscopic left adrenalectomy (LLA) and laparoscopic right adrenalectomy (LRA). Methods: We retrospectively analyzed two hundred and seventy-one patients aged > 18 years with unilateral benign PHEO of any size who underwent transperitoneal laparoscopic adrenalectomy at our hospitals between September 2016 and September 2023. Patients were divided into LRA (N= 122) and LLA (N= 149) groups. Univariate and multivariate logistic regression analyses were used to predict intraoperative HDI. In multivariate analysis for the prediction of HDI, right-sided PHEO, PHEO size, preoperative comorbidities, and preoperative systolic blood pressure were included. Results: Intraoperative HDI was significantly higher in the LRA group than in the LLA (27% vs. 9.4%, p< 0.001). In the multivariate regression analysis, right-sided tumours showed a higher risk of intraoperative HDI (odds ratio [OR] 5.625, 95% confidence interval [CI], 1.147–27.577, p= 0.033). The tumor size (OR 11.019, 95% CI 3.996–30.38, p< 0.001), presence of preoperative comorbidities [diabetes mellitus, hypertension, and coronary heart disease] (OR 7.918, 95% CI 1.323–47.412, p= 0.023), and preoperative systolic blood pressure (OR 1.265, 95% CI 1.07–1.495, p= 0.006) were associated with a higher risk of HDI in both LRA and LLA, with no superiority of one side over the other. Conclusion: LRA was associated with a significantly higher intraoperative HDI than LLA. Right-sided PHEO was a risk factor for intraoperative HDI.

•An improved pegaspargase-modified MRD and risk-oriented regimen was prospectively tested in adults aged 18-65 years with Ph–ALL/LL.•Three-year survival rates were >60% with HCT or chemotherapy, further improved by MRD negativity and age ≤40 years.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.

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ABSTRACTIntroduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, ‘combined’ approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.

Background: Placement of central venous access devices is a clinical procedure associated with some risk of adverse events and with a relevant cost. Careful choice of the device, appropriate insertion technique, and proper management of the device are well-known strategies commonly adopted to achieve an optimal clinical result. However, the environment where the procedure takes place may have an impact on the overall outcome in terms of safety and cost-effectiveness.Methods: We carried out a retrospective analysis on pediatric patients scheduled for a major neurosurgical operation, who required a central venous access device in the perioperative period. We divided the patients in two groups: in group A the central venous access device was inserted in the operating room, while in group B the central venous access device was inserted in the sedation room of our Pediatric Intensive Care Unit. We compared the two groups in terms of safety and cost-effectiveness.Results: We analyzed 47 central venous access devices in 42 children. There were no insertion-related complications. Only one catheter-related bloodstream infection was recorded, in group A. However, the costs related to central venous access device insertion were quite different: €330–€540 in group A versus €105–€135 in group B.Conclusion: In the pediatric patient candidate to a major neurosurgical operation, preoperative insertion of the central venous access device in the sedation room rather than in the operating room is less expensive and equally safe.

The unexpected outbreak of Corona Virus Disease 19 had several consequences worldwide and on the Italian Health System. We report our experience in the reorganization of our Pediatric Department to prevent the risk of infection for both children and staff. We strongly believe that the need to face an unpredictable emergency situation should not affect the quality of the assistance to the non–Corona Virus Disease patients.

T-cell acute lymphoblastic leukemia (T-ALL) results from deregulation of a number of genes via multiple genomic mechanisms. We designed a comprehensive fluorescence in situhybridization (CI-FISH) assay that consists of genomic probes to simultaneously investigate oncogenes and oncosuppressors recurrently involved in chromosome rearrangements in T-ALL, which was applied to 338 T-ALL cases. CI-FISH provided genetic classification into one of the well-defined genetic subgroups (ie, TAL/LMO, HOXA, TLX3, TLX1, NKX2-1/2-2, or MEF2C) in 80% of cases. Two patients with translocations of the LMO3transcription factor were identified, suggesting that LMO3activation may serve as an alternative to LMO1/LMO2activation in the pathogenesis of this disease. Moreover, intrachromosomal rearrangements that involved the 10q24 locus were found as a new mechanism of TLX1activation. An unequal distribution of cooperating genetic defects was found among the six genetic subgroups. Interestingly, deletions that targeted TCF7or TP53were exclusively found in HOXAT-ALL, LEF1defects were prevalent in NKX2-1rearranged patients, CASP8AP2and PTENalterations were significantly enriched in TAL/LMOleukemias, and PTPN2and NUP214-ABL1abnormalities occurred in TLX1/TLX3. This work convincingly shows that CI-FISH is a powerful tool to define genetic heterogeneity of T-ALL, which may be applied as a rapid and accurate diagnostic test.

Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.

In pediatric patients, the choice of the venous access device currently relies upon the operator’s experience and preference and on the local availability of specific resources and technologies. Though, considering the limited options for venous access in children if compared to adults, such clinical choice has a great critical relevance and should preferably be based on the best available evidence. Though some algorithms have been published over the last 5 years, none of them seems fully satisfactory and useful in clinical practice. Thus, the GAVePed—which is the pediatric interest group of the most important Italian group on venous access, GAVeCeLT—has developed a national consensus about the choice of the venous access device in children. After a systematic review of the available evidence, the panel of the consensus (which included Italian experts with documented competence in this area) has provided structured recommendations answering 10 key questions regarding the choice of venous access both in emergency and in elective situations, both in the hospitalized and in the non-hospitalized child. Only statements reaching a complete agreement were included in the final recommendations. All recommendations were also structured as a simple visual algorithm, so as to be easily translated into clinical practice.

•Integrating key risk factors (genetics, WCC, and MRD) predicts outcome more accurately than using traditional risk factors independently.•The EWALL-PI strongly correlates with relapse and death and defines clinically relevant risk groups in adult ALL.

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Introduction. Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) employed in relapsed/refractory (R/R) and, more recently, also in newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ph-like ALL is a genetically heterogenous subgroup that shares a common transcriptional profile, similar to that of true Ph+ ALL, though lacking the BCR::ABL1rearrangement. Ph-like ALL is characterized by a poor prognosis, a high relapse rate and a worse overall survival if treated with standard chemotherapy. Several molecular pathways are involved, including JAK/STAT, CRLF2and ABL-class mutations, providing a heterogeneous genetic landscape with very limited data on the subsequent clinical outcome. Few isolated cases of successful treatment of R/R Ph-like ALL with ponatinib have been reported, including also patients with lesions different from ABL-class mutations. Currently, ponatinib prescription in Italy is not allowed for Ph-like ALL.

Introduction. Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are commonly treated with tyrosine kinase inhibitors (TKI) in combination with either steroids, chemotherapy and more recently also immunotherapy. In the past, allogeneic transplant (SCT) was considered the only curative option; however, with the introduction of more potent TKIs as well as immunotherapy this milestone is nowadays debated, mostly for patients who achieve a molecular response. Moreover, as in chronic myeloid leukemia (CML), it is becoming relevant to understand if patients may over time discontinue TKI treatment. For this purpose, it is pivotal to report the outcome of Ph+ ALL patients who, for any reason, stopped TKI treatment.

Introduction.The outcome of adult patients with acute lymphoblastic leukemia (ALL) has markedly improved following the introduction of a pediatric inspired chemotherapy backbone coupled with minimal residual disease (MRD) monitoring at well-defined timepoints (TP), translating into a rational patients' stratification for allogeneic transplantation (Tx). Immunotherapy, in particular blinatumomab, represents a further advancement in the management of ALL. We designed a phase II trial (GIMEMA LAL2317) for adult Ph- CD19+ B-lineage ALL (Ph- B-ALL) consisting of a pediatric chemotherapy backbone - with dose adjustment in patients >55 years - to which 2 cycles of blinatumomab were added, the first after early consolidation cycle 3 (high-dose methotrexate and Ara-C) and the second after late consolidation cycle 6. Tx allocation was based on MRD assessment, carried out in most cases by RQ-PCR and by flow cytometry when a sensitive molecular marker was not identified. The primary objective of the trial was to assess the impact of blinatumomab in increasing the rate of early MRD negativity at end of week 14 (TP3).

The BCR::ABL1fusion gene is a hallmark of chronic myeloid leukemia (CML) but is also found in patients with acute lymphoblastic leukemia (ALL). There are two main breakpoint clusters in BCR- “minor” (between exons 1-2, resulting in p190 fusion protein, prevalent in ALL and scarce in CML) and “Major” (between exons 13-15, resulting in p210 protein). On the ABL1side, the breakpoints are mostly localized between exons 1-3. Due to large intronic areas where the breakpoints occur, only a few papers have been published focusing on the structure of BCR::ABL1fusions. Moreover, with a single exception, these studies included only the Major- BCR::ABL1patients. Here, we focused on the analysis of BCR::ABL1breakpoints involving CML and ALL, children and adults, and Major and minor forms of fusion. To our knowledge, we present data on the largest cohort of patients with BCR::ABL1fusion identified at the DNA level described to date.

BackgroundThe Italian national program of pediatric-inspired chemotherapy GIMEMA LAL1913 trial for adult Ph- acute lymphoblastic leukemia (Ph- ALL) has reported favorable results particularly in the younger subgroup of patients (pts) aged 18-40 years (Bassan et al, Blood Adv 2023). After the closure of the trial, this treatment scheme was adopted in the clinical practice by many Italian hematology centers for the treatment of newly diagnosed adult Ph- ALL. The safety of this intensive treatment in terms of infectious complications deserves to be investigated in the real life.

Introduction.The outcome of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved in the last decade, due with the introduction in the clinical practice of tyrosine kinase inhibitors (TKIs). A further improvement has been obtained with the use of blinatumomab as a consolidation strategy in newly diagnosed patients. We previously designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA); the preliminary results showed that after 2 cycles of blinatumomab (primary endpoint), molecular responses were achieved in 60% of cases and that, with a median follow-up of 18 months, overall survival (OS) and disease (DFS) were 95% and 88% (Foà et al, NEJM 2020). An updated follow-up at 53 months (Foà et al, under revision and ASH 2023) confirmed the favorable long-term outcomes with OS and DFS of 75.8% and 80.7%, respectively. A total of 9 relapses occurred. The median time to relapse was 4.4 months (1.9-25.8); 4 were at the central nervous system (CNS). To further improve the outcome of these patients, we designed a phase III trial (GIMEMA ALL2820) in which in the experimental arm dasatinib was substituted with ponatinib, followed - in the consolidation phase - by at least 2 cycles of blinatumomab. The trial is currently enrolling.

Introduction.In 2000, the GIMEMA cooperative study group launched the first frontline protocol with a tyrosine kinase inhibitor (TKI) alone plus steroids and without systemic chemotherapy for elderly (>60 years) Ph+ acute lymphoblastic leukemia (ALL) patients (LAL0201-B; Vignetti et al, Blood 2007). Thereafter, 4 academic clinical trials were conducted for adult patients (>18 years). In all studies, the induction was always based on a TKI alone plus steroids and CNS prophylaxis without systemic chemotherapy. In the GIMEMA LAL0904 trial, patients (18-60 years) received imatinib followed by chemotherapy in the post-induction phase (Chiaretti et al, Haematologica 2016). In the GIMEMA LAL1205 trial (no upper age limit), patients received dasatinib plus steroids, while the post-induction treatment was left to the investigator's choice (Foà et al, Blood 2011). In the GIMEMA LAL1509 total therapy protocol, patients (18-60 years) received dasatinib plus steroids followed by dasatinib alone in patients in complete molecular response (CMR) or chemotherapy and/or allogeneic transplant for those who did not reach a CMR (Chiaretti et al, Haematologica 2021). In the last LAL2116 trial, dasatinib plus glucocorticoids were administered in induction followed by at least two blinatumomab cycles as consolidation (Foà et al, N Engl J Med 2020). The rates of hematologic CR were comparable in the four trials, ranging from 96 to 100%.

Introduction.The prognosis of Ph+ acute lymphoblastic leukemia (ALL) has changed profoundly following the advent of tyrosine kinase inhibitors (TKIs). Since 2000, the GIMEMA frontline studies for adult Ph+ ALL patients have been based on a TKI plus steroids in induction without systemic chemotherapy. This has allowed complete hematologic remission (CHR) rates of 94-100%, irrespective of age, with virtually no deaths in induction 1-5. We then designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA). The preliminary results 6,7showed a CHR rate of 98% with 60% of molecular responses at the primary endpoint of the study (after 2 blinatumomab cycles); the OS and DFS were 95% and 88% at 18 months. Here we present the final long-term results of the study.

Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification.

Invasion leading to the formation of metastasis is one of the hallmarks of cancer. Analysis of different human cancers has led to the identification of the PPFIA1 gene encoding the protein liprin-1, a possible player in cancer. The PPFIA1 gene is amplified in malignant tumors, including about 20% of breast cancers. Also the liprin-1 protein is found overexpressed in tumors. Liprin-1 belongs to the liprin family of cytosolic scaffold proteins that includes four liprin-, two liprin- members, and liprin-γ/kazrinE. In this review we will discuss the available evidence on the role of different members of the liprin family in distinct aspects of tumor cell migration and invasion. Evidence from in vitro studies indicates that the widely expressed liprin-1 protein regulates the migration and invasion of human breast cancer cells. Liprin-α1 affects cell migration and invasion by regulating the organization of lamellipodia and invadopodia, two structures relevant to cell invasion. In the cell liprin-1 forms a complex with liprin-1, ERC1/ELKS and LL5 proteins, which localizes at the front of migrating cells and positively regulates lamellipodia stability, and integrin–mediated focal adhesions. On the other hand, liprin-2 appears to play a role as tumor suppressor by inhibiting breast cancer cell motility and invasion. The available data indicate that liprins are central players in the regulation of tumor cell invasion, therefore representing interesting targets for anti-metastatic therapy.

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL, and increases progressively with age. The introduction of tyrosine kinase inhibitors (TKIs) has enabled to obtain complete hematologic remissions (CHRs) in virtually all patients, including the elderly, to improve disease-free survival and overall survival, as well as to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo-SCT). The current management of adult Ph+ ALL patients relies on the use of a TKI with or without chemotherapy followed by an allo-SCT, which still remains the only curative option. Minimal residual disease screening is permitting not only a better stratification of patients, but has also allowed to reconsider the role of autologous stem cell transplant for a set of patients who do not have a donor or are not eligible for an allo-SCT. At present, clinical challenges are represented by the emergence of resistant mutations, particularly the gatekeeper T315I, for which alternative approaches, comprising novel TKIs or therapies based on the combination of TKI with immunotherapeutic strategies, are being considered in order to overcome resistance.

MYCtranslocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ∼6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYCtranslocations were significantly associated with the TAL/LMOsubtype of T-ALL (P= .018) and trisomies 6 (P< .001) and 7 (P< .001). Within the TAL/LMOsubtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYCtranslocations; specifically, 77 were upregulated and 71 downregulated in those with MYCtranslocations. The poor prognostic marker, CD44, was among the upregulated genes. MYCtranslocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse.

Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ∼70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL.

Previous assessments of soil organic carbon (SOC) stocks have used soil maps and other tacit knowledge from soil survey to aggregate and extrapolate data without assessing the relationship between SOC and the tacit information used. The objective of this paper is to outline a process that translates tacit class‐based knowledge into semiquantitative information about SOC stocks. This information was used to create a soil‐based strata for sample selection to inventory SOC stocks. The process was completed in three steps: (i) official series descriptions (OSDs) were used to compile comprehensive soil information, (ii) an ordinal scoring system was developed and applied to link soil properties to likely SOC stocks, and (iii) hierarchical clustering was applied to cluster soils into groups for sampling. The scores and groups were tested using pedon SOC stocks from the National Cooperative Soil Survey laboratory database. Expert soil scientists interpreted individual terms used in Soil Taxonomy and OSDs for their explicit or implicit relationships with SOC stocks. Taxa, soil moisture regime, and temperature regime were separated as individual factors. Other information from the OSDs including family particle size class, depth to restrictive layer, and drainage class were used to translate qualitative information into ordinal scores. Classes for taxonomic order, soil moisture regimes, and drainage class were significantly different in pedon SOC stocks across and within regions. Scores within each factor (taxonomy, moisture regime, drainage class, temperature regime, and soil depth) were also significantly different from one another in pedon SOC stocks. Ordinal scores were used to cluster soils within each of 17 regions. Soil groups were significantly different from one another in SOC stocks in each of the 17 sampling regions. The process was considered satisfactory and was used to stratify soils for SOC stock sampling in the conterminous United States. A similar process could be applied to any soil property over any area of interest to evaluate tacit knowledge for communicating soil information, grouping soils for interpretation, or creating strata for distributing samples.

Buckypaper (BP) is the general definition of a macroscopic assembly of entangled carbon nanotubes. In this paper, a new property of a BP film produced from oxidized multiwalled carbon nanotubes was investigated. In particular, BP shows to be able to promptly and strongly adhere to animal internal soft and wet tissues, as evaluated by peeling and shear tests. BP adhesion strength is higher than that recorded for a commercial prosthetic fabric (sealed to the tissue by fibrin glue) and comparable with that of other reported optimized nanopatterned surfaces. In order to give an interpretation of the observed behavior, the BP composition, morphology, porosity, water wettability, and mechanical properties were analyzed by AFM, X-ray photoelectron spectroscopy, wicking tests, contact angle, and stress–strain measurements. Although further investigations are needed to assess the biocompatibility and safety of the BP film used in this work, the obtained results pave the way for a possible future use of buckypaper as adhesive tape in abdominal prosthetic surgery. This would allow the substitution of conventional sealants or the reduction in the use of perforating fixation.

The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored, although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis, the LR condition was an independent predictor of shorter time-to-first treatment. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells.

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-κB signaling, was investigated in different CLL clinical phases. BIRC3lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3abnormalities, suggesting that BIRC3genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3disruption identified patients with a poor outcome similar to that associated with TP53abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3as a negative regulator of NF-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53abnormalities.

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-κB signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities.

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P = .046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL.

Increased expression or aberrant activation of c-Myc plays an important role in leukemogenesis. Here, we show that in acute myeloid leukemia (AML), c-Myc directly controls the expression of EZH2, a component of the Polycomb repressive complex 2, and miR-26a. miR-26a is downregulated in primary blasts from AML patients and, during myeloid differentiation of AML cells, is induced together with a decrease in c-Myc and Ezh2 levels. Previously, EZH2 was shown to be regulated by miR-26a at the translational levels in lymphomas. However, we demonstrate that in AML, the variation of EZH2 mainly depends on c-Myc transcriptional control. We also show that enforced expression of miR-26a in AML cells is able to inhibit cell cycle progression by downregulating cyclin E2 expression. In addition, increased levels of miR-26a potentiate the antiproliferative effects of 1,25-dihydroxyvitamin D3(VitD) and stimulate myeloid differentiation. Our results identify new molecular targets of c-Myc in AML and highlight miR-26a attractiveness as a therapeutic target in leukemia.