Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Effectiveness of the Combination of Rituximab and Standard Chemotherapeutic Regimens in Previously Untreated Patients with Chronic Lymphocytic Leukaemia in Real-Life: Results from a Noninterventional Study (CILI Study).

Chronic lymphocytic leukemia (CLL) is one of the most common haematological malignancies exhibiting remarkable heterogeneity in clinical course. Rituximab added to standard chemotherapy has been proven to increase response rate and eventually survival among previously untreated CLL patients. CILI was an open-label, non-randomized, single arm, multicentric, observational study aimed to collect real-life effectiveness data for rituximab used according to the current label in combination with standard chemotherapy in previously untreated CLL patients. Overall response rates (ORR) in the entire study population as well as in various subgroups were estimated. Adverse events were recorded during the entire course of the study. A total number of 150 patients were enrolled by 15 Hungarian study sites. Out of these, 82 patients received 6 cycles of rituximab containing treatment. Overall response rates of 88.24% (CI95%: 81.6-93.12%) and 94.59% (CI95%: 86.73-98.51%) were recorded in the intent-to-treat (ITT) and per-protocol (PP) populations, respectively. In both study populations, somewhat higher ORR was observed in patients aged ≥65 years. Subgroups defined according to either chromosomal aberrations (presence of 11q and 17p deletions) showed apparently high ORRs, though these rates were most probably biased by low patient numbers. 144 adverse events were reported during the study, of which 15 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those previously reported by controlled clinical trials.

Efficacy and Tolerability of a 2-Year Rituximab Maintenance Therapy in Patients with Advanced Follicular Lymphoma after Induction of Response with Rituximab-Containing First Line-Regimens (HUSOM Study).

Follicular lymphoma is a lymphoid malignancy commonly showing slow progression which makes the treatment of the disease challenging. Rituximab monotherapy and rituximab added to standard chemotherapy has been proven to increase survival among patients with advanced stage of the disease. However, the benefit of a rituximab maintenance therapy after induction was still unclear at the time of the initiation of this study. HUSOM was a phase III open-label, single-arm, multi-centre study aimed to assess the efficacy and the safety of the 12 cycles of rituximab (375 mg/m2 every 8 weeks) maintenance therapy in patients had already presented partial or complete response to R-CVP or R-CHOP. Efficacy endpoints such as event-free survival and overall survival were estimated. Adverse events were recorded during the entire course of the study. A total number of 124 patients were enrolled by 15 Hungarian study sites. Out of these, 86 patients received 12 cycles of rituximab and 69 patients completed the 3-year follow-up phase as well. The probabilities of the event free survival and progression at 4.3 years were estimated to be 70.3% and 74.4%, respectively. The overall and the disease free survival at 4 years were estimated to be 90.7% and 87.9%, respectively. A total number of 85 adverse events were reported during the study out of which 5 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those reported by controlled clinical trials (EORTC 20981, PRIMA) conducted in parallel with the HUSOM study.

Parallel palaeogenomic transects reveal complex genetic history of early European farmers.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.

BACKGROUND: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. FINDINGS: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. INTERPRETATION: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. FUNDING: CTI BioPharma Corp.

Between the Vinca and Linearbandkeramik Worlds: The Diversity of Practices and Identities in the 54th-53rd Centuries cal BC in Southwest Hungary and Beyond.

Perhaps nowhere in European prehistory does the idea of clearly-defined cultural boundaries remain more current than in the initial Neolithic, where the southeast-northwest trend of the spread of farming crosses what is perceived as a sharp divide between the Balkans and central Europe. This corresponds to a distinction between the Vinca culture package, named for a classic site in Serbia, with its characteristic pottery assemblage and absence of longhouses, and the Linearbandkeramik (LBK), with equally diagnostic but different pottery, and its apparently culturally-diagnostic longhouses, extending in a more northerly belt through central Europe westward to the Dutch coast. In this paper we question the concept of such a clear division through a presentation of new data from the site of Szederkény-Kukorica-dulo. A large settlement in southeast Transdanubia, Hungary, excavated in advance of road construction, Szederkény is notable for its combination of pottery styles, variously including Vinca A, Raziste and LBK, and longhouses of a kind otherwise familiar from the LBK world. Formal modelling of its date establishes that the site probably began in the later 54th century cal BC, lasting until the first decades of the 52nd century cal BC. Occupation, featuring longhouses, pits and graves, probably began at the same time in the eastern and western parts of the settlement, starting a decade or two later in the central part; the western part was probably the last to be abandoned. Vinca pottery is predominantly associated with the eastern and central parts of the site, and Raziste pottery with the west. Formal modelling of the early history of longhouses in the LBK world suggests their emergence in the Formative LBK of Transdanubia c. 5500 cal BC followed by rapid dispersal in the middle of the 54th century cal BC, associated with the 'earliest' (älteste) LBK. The adoption of longhouses at Szederkény thus appears to come a few generations after the start of this 'diaspora'. Rather than explaining the mixture of things, practices and perhaps people at Szederkény with reference to problematic notions such as hybridity, we propose instead a more fluid and varied vocabulary, encompassing combination and amalgamation, relationships and performance in the flow of social life, and networks; this makes greater allowance for diversity and interleaving in a context of rapid change.

Tracing the genetic origin of Europe's first farmers reveals insights into their social organization.

Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis is yet unclear. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starcevo and LBK sites (seventh/sixth millennia BC) from the Carpathian Basin and southeastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early southeastern European and Carpathian Basin farming cultures on Central European populations of the sixth-fourth millennia BC. Comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through southeastern Europe and the Carpathian Basin into Central Europe. However, our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting a system of patrilineal descent and patrilocal residential rules among the early farmers.

[Primary gastrointestinal non-Hodgkin's lymphoma in two Hungarian regions]. / Pimer gastrointestinalis non-Hodgkin-lymphoma két magyarországi régió beteganyaga alapján.

UNLABELLED: Over the past few decades, the occurrence of adult onset non-Hodgkin's lymphoma has significantly increased. The patient population involved is very heterogeneous, with different clinical and morphological manifestations. In addition to the most typical nodal involvement, extra-nodal manifestations are also frequent, affecting, most often, the gastrointestinal tract, the central nervous system and the skin. The treatment strategy for non-Hodgkin's lymphoma has changed over the past decade: chemo-immunotherapy has largely taken over surgical intervention, the dominant treatment option of the past. METHODS: The authors present their experience with 48 patients with non-Hodgkin's lymphoma, affecting the gastrointestinal tract, treated in Kaposvár, in the Kaposi Mór Teaching Hospital and in Gyula, in the Pándy Kálmán County Hospital. Demography: 27 female, 21 male; mean age: 67.8 years. Localization, pathological classification and the international prognostic index (IPI) have been analysed and correlated with the clinical response to different therapeutic strategies. RESULTS: The most frequently involved GI organ was the stomach ( n = 26), with the dominant histological type of diffuse large B-cell lymphoma. Fourty-six patients received chemo-immunotherapy, 6 received radiotherapy, 3 patients were primarily treated with Helicobacter pylori eradication therapy, and 4 patients were referred for stomach resection. A complete remission was achieved in 68% of the patients, a partial remission in 13%, while 19% did not show clinical response. Based on the international prognostic index, the majority of the patients fulfilled criteria of low or high intermediate risk categories, with an IPI average of 2.68. Patients with upper gastrointestinal tract involvement carried the best prognosis (IPI: 2.0); at the same time, patients with stomach lymphoma achieved the highest rate of remission (73%). CONCLUSIONS: With chemo-immunotherapy the chances of a complete remission have significantly improved over the past decade, thus a significant portion of non-Hodgkin's lymphomas involving the gastrointestinal tract can be cured. IPI index represents the most recognised indicator for assessing the prognosis of non-Hodgkin's lymphoma. Patients who achieved complete remission had the lowest prognostic index in this cohort; nevertheless, numerous data indicate that factors other than the IPI can also have an impact on patients' response to treatment.