Treatment of older patients with mantle-cell lymphoma.

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents.

Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4-15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years, N = 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.

Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma.

BACKGROUND: A combination of bortezomib (1.3 mg/m(2)), melphalan (5 mg/m(2)), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated. PATIENTS AND METHODS: Fifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, 'base' schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, 'weekly' schedule). RESULTS: Side-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in 'weekly' schedule (36% versus 66% in 'base' schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7-50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months). CONCLUSION: Taken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.

The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi.

BACKGROUND: The role of [¹8F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cell (MSC) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes in MSC epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1.1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU-Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation, and cell metabolism networks in MDS-MSCs.

BRIT1/MCPH1 expression in chronic myeloid leukemia and its regulation of the G2/M checkpoint.

BRIT1 (BRCT-repeat inhibitor of hTERT expression), also known as microcephalin (MCPH1), is a crucial gene in the complex cellular machine that is devoted to DNA repair and acts as a regulator of both the intra-S and G2/M checkpoints. The most important role of BRIT1/MCPH1 in the regulation of cell cycle progression appears to be the G2/M checkpoint. The K562 and peripheral blood cells of chronic myeloid leukemia (CML) patients at diagnosis were found to downregulate BRIT1/MCPH1. However, we could not find any correlation between bcr/abl activity and the BRIT1/MCPH1 level. In order to study the genomic instability of CML cells, we evaluated the ability of these cells to arrest mitotic division after exposure to hydroxyurea, a known genotoxic agent. We showed that CML cells continue to proliferate without the activation of the G2/M cell cycle checkpoint arrest or of the apoptotic mechanism. This behavior may predispose the cells to accumulate genomic defects. In conclusion, we found that CML cells have a low BRIT1/MCPH1 level and show a defective G2/M arrest, confirming that these cells have a constitutive genomic instability.

Consequences of metaphase II oocyte cryopreservation on mRNA content.

INTRODUCTION: We studied the consequences of freezing/thawing processes on mRNA contents in MII oocytes after slow-freezing/rapid thawing (SF/RT) and vitrification/warming (V/W) protocols, and compared the results to fresh MII oocytes. We quantified the nuclear transcript mRNA responsible for the translation of proteins belonging either to trans-regulatory protein family or to functional structural proteins such as proteins involved in DNA structural organization (NAP1L1, TOP1, H1F0H1), chromosomal structure maintenance (SMC, SCC3, RAD21, SMC1A, SMC1B, STAG3, REC8), mitochondrial energetic pathways (ATP5GJ, SDHC), cell cycle regulation and processes (CLTA, MAPK6, CKS2) and staminal cell potency-development competence stage (DPPA3, OCT4, FOXJ2). MATERIAL AND METHODS: Surplus MII oocytes were donated from patients in IVF cycles and divided in three groups of 15 oocytes. Group 1 was comprised of non-cryopreserved oocytes and Groups 2 and 3 underwent SF/RT and V/W procedures, respectively. RESULTS: There was an overall decrease of mRNA extracted from cryopreserved oocytes compared to control group. Only 39.4% of mRNA content were preserved after SF/RT while 63.3% of mRNA content were maintained after V/W. CONCLUSIONS: Oocyte cryopreservation is associated with molecular injury associated with the decrease of stored mRNA. However the V/W protocol is more conservative than SF/RT resulting in a level of mRNA sufficient to maintain biologic functions in the subsequent fertilized oocyte.

Phylogenetic analysis in the clinical risk management of an outbreak of hepatitis C virus infection among transfused thalassaemia patients in Italy.

BACKGROUND: Occurrence of hepatitis C virus (HCV) infection is reduced by effective risk management procedures, but patient-to-patient transmission continues to be reported in healthcare settings. AIM: To report the use of phylogenetic analysis in the clinical risk management of an HCV outbreak among 128 thalassaemia outpatients followed at a thalassaemia centre of an Italian hospital. METHODS: Epidemiological investigation and root-cause analysis were performed. All patients with acute hepatitis and known chronic infection were tested for HCV RNA, HCV genotyping, and NS3, NS5A, and NS5B HCV genomic region sequencing. To identify transmission clusters, phylogenetic trees were built for each gene employing Bayesian methods. FINDINGS: All patients with acute hepatitis were infected with HCV genotype 1b. Root-cause analysis, including a lookback procedure, excluded blood donors as the source of HCV transmission. The phylogenetic analysis, conducted on seven patients with acute infection and eight patients with chronic infection, highlighted four transmission clusters including at least one patient with chronic and one patient with acute HCV infection. All patients in the same cluster received a blood transfusion during the same day. Two patients with acute hepatitis spontaneously cleared HCV within four weeks and nine patients received ledipasvir plus sofosbuvir for six weeks, all achieving a sustained virological response. CONCLUSION: Combined use of root-cause analysis and molecular epidemiology was effective in ascertaining the origin of the HCV outbreak. Antiviral therapy avoided the chronic progression of the infection and further spread in care units and in the family environment.

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

Expert Panel Consensus Statement for Proper Evaluation of First Relapse in Multiple Myeloma.

PURPOSE OF REVIEW: A working group of six expert physicians convened to assess the spectrum of multiple myeloma relapse presentations, discussed the features that can define the disease as aggressive and not aggressive, and established whether this information could help in selecting treatment together with the characteristics of disease and of patients and type of prior therapy. RECENT FINDINGS: The working group agreed that relapse should be distinguished between biochemical and clinical according to IMWG. Moreover, the expert panel defined "aggressive disease" as a clinical condition that requires therapy able to induce a rapid and as deep as possible response to release symptoms and to avoid impending danger of new events. According to this definition, relapse was considered aggressive if it presents with at least one of the following features: doubling of M protein rate over 2 months, renal insufficiency, hypercalcemia, extramedullary disease, elevated LDH, high plasma cell proliferative index, presence of plasma cells in peripheral blood, or skeletal-related complications. Moreover, the panel agreed that this classification can be useful to choose therapy in first relapse together with other patient, disease, and prior therapy characteristics. So, this item was included in a new therapeutic algorithm. The treatment choice in MM at relapse is wider than in the past with the availability of many new therapeutic regimens leading to increased diversity of approaches and relevant risk of inappropriate treatment decisions. A practical classification of relapses into aggressive or non-aggressive, included in a decisional algorithm on MM management at first relapse, could help to make the appropriate treatment decisions.

NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways.

In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

The efficacy of rituximab plus Hyper-CVAD regimen in mantle cell lymphoma is independent of FCgammaRIIIa and FCgammaRIIa polymorphisms.

Mantle cell lymphoma (MCL) accounts for 3-10% of all non-Hodgkin's lymphomas, with median overall survival not exceeding 3-4 years. Rituximab in combination with the Hyper-CVAD regimen appears the most promising regimen; thus, we adopted it as a first-line treatment strategy in a series of 24 patients. In addition to evaluation of clinical success of the regimen, we investigated a possible role of polymorphism in IgG Fc receptors, FCgammaRIIIa and FCgammaRIIa. The frequencies of FCgammaRIIIa-158 were as follows: V/V=4/24 (17%); V/F=16/24 (66%); F/F=4/24 (17%). Those of the FCgammaRIIa-131 polymorphism were H/H=11/24 (46%), H/R=9/24 (37%), R/R=4/24 (17%). The overall response rate was 62.5%, with 33% of complete responses (CRs) after four cycles of R-Hyper-CVAD. Two-year progression-free survival (PFS) was 78% for 158V/V patients vs 75% for cases carrying phenylalanine (p=0.88). When the FCgammaRIIa polymorphism was assessed, the 2-year PFS was 82% for 131H/H patients vs 75% for those carrying arginine (p=0.26). Eighty-three percent of cases achieved Polymerase Chain Reaction (PCR)-negativity: the progression rate was significantly influenced by the minimal residual disease clearance, with 12% progression in the subgroup of PCR-negative cases versus 67% progression in PCR-positive cases (p=0.008). The achievement of PCRnegativity was not significantly influenced by FCgammaR polymorphisms. Results confirm that rituximab plus Hyper-CVAD is an effective regimen for the induction of prolonged remission in patients with aggressive MCL and suggest that rituximab efficacy is independent of the FCgammaR polymorphisms.

NOTCH1-mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin 1 and ribosome-associated components.

In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1-mutated (NOTCH1-mut) versus NOTCH1 wild-type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by the upregulation of genes related to ribosome biogenesis, such as nucleophosmin 1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by ethylenediaminetetraacetic acid or by coculture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as a mediator of NOTCH1 effects over NPM1 and RNP expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Clinical and endoscopic presentation of primary gastric lymphoma: a multicentre study.

BACKGROUND: Although the stomach is the most frequent site of intestinal lymphomas, few data are available on both clinical endoscopic presentation of gastric lymphoma and possible differences between low-grade and high-grade lymphomas. METHODS: Clinical, histological and endoscopic records of consecutive patients with primary low-grade or high-grade lymphoma diagnosed were retrieved. Symptoms were categorized as 'alarm' or 'not alarm'. The endoscopic findings were classified as 'normal' or 'abnormal'. RESULTS: Overall, 144 patients with primary gastric lymphoma were detected, including 74 low-grade and 70 high-grade lymphoma. Alarm symptoms, particularly persistent vomiting and weight loss, were more frequently present in patients with high-grade lymphoma than in those with low-grade lymphoma (54% vs. 28%; P = 0.002). Low-grade lymphomas presented as 'normal' appearing mucosa (20% vs. 0%; P = 0.0004) or petechial haemorrhage in the fundus (9% vs. 0%; P = 0.02) more frequently than high-grade lymphomas, being also more often confined to the antrum (47% vs. 27%, P = 0.03) and associated with Helicobacter pylori infection (88% vs. 52%, P < 0.0001). On the contrary, high-grade lymphomas presented more commonly as ulcerative type (70% vs. 52%; P = 0.03), being also more frequently diagnosed in stage >I when compared with low-grade lymphomas (70% vs. 21%, P < 0.0001). CONCLUSIONS: The overall prevalence of alarm symptoms is quite low and may be absent in more than 70% of patients with low-grade lymphoma.

lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.