Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the
Ataxia Telangiectasia Mutated
(
ATM
) gene. The aim of this paper is to better define the ...immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.
A new possible scenario for the origin of the molecular collective behaviour associated with the emergence of living matter is presented. We propose that the transition from a non-living to a living ...cell could be mapped to a quantum transition to a coherent entanglement of condensates, like in a multigap BCS superconductor. Here the decoherence-evading qualities at high temperature are based on the Feshbach resonance that has been recently proposed as the driving mechanism for high T(c) superconductors. Finally we discuss how the proximity to a particular critical point is relevant to the emergence of coherence in the living cell.
Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy.
Institutional registries across three academic medical ...centers were retrospectively reviewed. Kaplan-Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables.
Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3-4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p < 0.001), tumor burden (p = 0.01) and lymphocyte-to-monocyte ratio (p =0.02) were independent predictors of survival.
Third-line chemotherapy displayed limited activity in this real-world cohort, although prognostic factors have been identified that may assist in treatment decision. The results of this multicenter experience, highlight the need for more effective therapies and provide a benchmark for future trials in this setting.
Pancreatic endocrine tumors (PETs) are usually small, benign or low-grade malignant, and surgery should preserve the pancreatic parenchyma as much as possible. The aim of the study was to evaluate ...the postoperative and long-term survival of patients undergoing enucleation in small PETs.
Of 82 patients having PETs, 46 with tumor less than 4 cm in diameter, without distant metastases and with R0 resection by final pathologic examination, were included in this study. Enucleation was performed when the tumor did not involve the main pancreatic duct and in the absence of peripancreatic lymphadenopathy (group A); a typical resection was carried out in all other cases (group B). The 2 groups were compared regarding postoperative mortality and morbidity, pancreatic fistula, postoperative hospital stay, reoperation, World Health Organization classification, TNM stage, recurrence, and long-term survival.
There were 15 patients (32.6%) in group A and 31 (67.4%) in group B. Postoperative and long-term results were similar in the 2 groups, whereas World Health Organization classification was significantly different; enucleation was performed more frequently than typical R0 resection in benign tumors (P = 0.009).
Enucleation should be reserved for patients having benign PETs less than 4 cm in diameter and far from the main pancreatic duct.
The RIDART I study found a 13.6% prevalence of anemia in Italian patients with inflammatory bowel disease (IBD); most cases were due to iron-deficiency anemia (IDA).
To evaluate changes in hemoglobin ...concentration during a 24-week follow-up of anemic patients with IBD.
Follow-up laboratory and clinical data were obtained from RIDART I study patients with anemia. Factors affecting hemoglobin concentration, the impact of anemia on fatigue and quality of life (QoL), and its relationship with treatment, disease activity and disease complications were investigated.
Hemoglobin was 108 g/L at baseline, increased to 121 g/L at follow-up week 12 (p < 0.001) and then stabilized until week 24, but most patients remained anemic, with IDA, throughout the study. Hemoglobin improvement was greater in patients receiving either oral or parenteral iron supplementation. Following hemoglobin normalization, anemia relapse rate during follow-up was 30%. Oral iron did not cause disease reactivation. Lower follow-up hemoglobin was associated with a higher probability of having active disease, clinical complications, increased fatigue and reduced QoL.
In anemic patients with IBD, anemia represents a long-lasting problem, in most cases persisting for up to 24 weeks, with high relapse rate and a negative impact on fatigue and QoL.
Abstract Backgound In 2010, the World Health Organization (WHO) modified the classification for pancreatic neuroendocrine tumours (NETs). Recently, some modifications were proposed to improve its ...prognostic value. The aim of this study was to test the prognostic value of both the original and the modified 2010 WHO grading systems. Methods One hundred and twenty consecutive patients surgically resected for well-differentiated NETs were evaluated in multivariate Cox regression models. Age, sex, hormonal status, size, lymph node ratio, stage, margin status and grading were evaluated in order to predict disease-free survival (DFS). Four models were evaluated: model 1: grading according to the 2010 WHO; model 2: modified grading with cut-off at 5% of the Ki-67 index; model 3: modified grading in which the G2 category was divided into two subgroups (2–5% and 5–20%) and model 4: the Ki-67 index as a continuous variable. Decision curve analysis (DCA) was carried out to evaluate the clinical utility of the various cut-offs. Results All the grading systems remained independent factors in predicting DFS. Model 2 (c index = 0.814 and P = 0.012) and model 3 (c index = 0.865 and P = 0.015) showed higher predictive powers with respect to model 1 (c index = 0.799). Model 4 had a high predictive value (c index 0.848, P = 0.013). Decision curve analysis confirmed that biological behaviour represented the best prognostic parameter. Conclusion This study presented some limitations: single centre, retrospective design and a long period of enrolment. The result showed that, by increasing the cut-off of the G2 category to 5% or by creating two subgroups in the G2 category, it was possible to obtain a better stratification of patients.
Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) is the commonest subtype of PTCL. NF–kB related molecules have been found to be variably expressed in PTCL/NOS, suggesting a potential ...involvement of the NF–kB system in their pathogenesis. However, the actual contribution of NF–kB molecular programs to the PTCL/NOS landscape has not been investigated yet.
In this study, we assessed in a large series of PTCL/NOS, the activation status of NF–kB programs and investigated the prognostic impact of such NF–kB expression. Moreover, we explored the possible role of NF–kB inhibitors. We studied the gene expression profiles of 180 PTCL cases and tested two different drugs, the IKK inhibitor BMS-345541 and the proteasome inhibitor Bortezomib, in four PTCL cell lines.
We found that most cases (84%) presented with some degree of NF–kB activation, based on the expression of
REL
and
RELA
. Functionally, the latter was strictly related with TCR signaling activation, while REL was at least partially TCR independent. We also identified genes related with NF–kB activation in this setting that were mainly involved in cell proliferation and apoptosis inhibition. Further, by reverse engineering we defined the transcriptional network of both REL and RELA in PTCLs that only partially overlapped. On the clinical ground, we found that RELA expression was related to a significantly poorer overall survival, with similar trends for REL. However, most remarkably, when all the three genes were considered together, cases with at least one gene over-expressed, showed a dramatically inferior overall survival (28.67 vs. 56.018 months;
p
= 0.004). Finally, we showed that NF–kB pharmacological inhibition was associated with cell cycle arrest and cell death in NF–kB positive PTCL cells.
In conclusion, we extensively explored NF–kB activation in PTCL/NOS, documenting its negative prognostic role. Further, we showed that NF–kB inhibition might represent a rational therapeutic approach in selected cases.
The 2019 Geomorphological Field Camp at San Domino Island (Tremiti Islands, Southern Adriatic Sea) is the result of geological and geomorphological field work activities carried out by a group of ...students attending the Geomorphological field mapping course of the Master's Degree in Geological Science and Technology (University of Chieti-Pescara). The main map (1:5000 scale) was obtained through an integrated approach that incorporates morphometric analysis, geological and geomorphological field mapping, and geomorphological profiles drawing. Activities were carried out by all students, divided into six working groups of three to four persons each. The field camp and field work activities made it possible to produce a detailed thematic map, as a scientific tool to depict the San Domino Island landscape, and to outline some geomorphological issues in terms of possible constraints to landscape evolution, geomorphological processes distribution, and natural hazard assessment.
Introduction: The programmed cell death 1 (PD-1) monoclonal antibodies (MoAbs) nivolumab and pembrolizumab induce response rates exceeding 70% in relapsed/refractory (R/R) classical Hodgkin lymphoma ...(cHL). The lack of response to PD-1 MoAbs, and the relapse occurring in most patients who had responded to PD-1 blockade suggest that tools to identify the determinants of response/resistance to PD-1 MoAbs are urgently required. We hypothesized that the characterization of the mutational profile of circulating tumor DNA (ctDNA) could represent a valuable tool to track clonal evolution-driven resistance to checkpoint inhibitors.
Patients and Methods: 21 R/R cHL (median age, 32 years; range, 19-51) who had received a median of 5 (range, 3-7) chemotherapy lines, including autologous stem cell transplantation (77%) and brentuximab vedotin (100%), were treated with PD-1 MoAbs. Blood samples were profiled by CAPP-Seq strategy. We analyzed ctDNA and paired DNA from peripheral blood mononuclear cells (PBMCs), as source of germline DNA to filter out polymorphism and sequencing errors. A targeted resequencing panel optimized to include the coding exons and splice sites of 133 genes (320 Kb) that are recurrently mutated in B-cell lymphomas was used. Libraries were prepared from ctDNA and germline gDNA according to the CAPP-seq targeted enrichment strategy (Nimblegen-Roche) and subjected to ultra-deep-next generation sequencing (NGS) using the Nextseq 500 platform (Illumina). The sequencing was performed to obtain a depth of coverage >2000x in >80% of the target region in all samples, which allowed a sensitivity of 3x10-3. A stringent and completely automated bioinformatic pipeline was applied to call non-synonymous somatic mutations, using the somatic function of VarScan2.
Results: After a median of 26 (range, 9-63) cycles of PD-1 inhibitors best response was complete remission (CR) for 9 patients (42%), partial remission (PR) for 6 (29%) and progressive disease (PD) for 6 (29%). Patients achieving PR experienced a disease control lasting for 4.5 to 24 months and subsequently underwent PD. Plasma and PBMC samples were collected at baseline, every five cycles of therapy, and end-of-therapy (EOT). At baseline, 18 of 21 patients could be successfully genotyped, whereas three were not. Evaluable patients showed a mean (±SD) number of mutated genes and mutations per patient of 7.3±5.1 (range, 2-22) and 9.9±8.4 (range, 2-37), respectively. Genes recurrently affected by non-synonymous somatic mutations in >20% of R/R cHL included STAT6 (45%), SOCS1 (40%), ITPKB (35%), GNA13 (35%), TP53 (20%), TNFAIP3 (15%). At baseline, no association of distinct DNA mutations with resistance to PD-1 inhibitors could be demonstrated. Signaling pathways targeted by DNA mutations included JAK-STAT, NF-κB, PI3K-AKT, cytokine, NOTCH, immune evasion. The concentration of ctDNA reported as haploid genome equivalent per ml (hGE/ml) was 592.2 (range, 2-2,746), with values of hGE/ml detected in PD patients being significantly higher as compared to CR patients (P=.0437). As compared to cycle 0, the hGE/ml of ctDNA at cycle 5 showed a significant reduction (592.2 vs. 67, P<.0008) which was followed by further hGE/ml decline in CR patients (to 14 P=.05) and further hGE/ml increase in PD patients (to 1,300 P=.1). At cycle 5, all CR/PR patients showed complete disappearance of baseline mutations, which were replaced by completely novel clones. In all CR/PR patients, this pattern of “clonal reshaping” was repeatedly detected over time. In striking contrast, at cycle 5, PD patients showed the persistence of baseline mutations. In all PD patients, this pattern of “clonal persistence”, was repeatedly detected over time. In 4 patients, resistance to PD-1 inhibitors was associated with the appearance of a TP53 mutated clone. Although, a formal correlation of circulating DNA mutations with standard FDG-PET imaging was outside the objective of this study, both the “clonal reshaping” and “clonal persistence” patterns could be demonstrated to correlate with the results of FDG-PET.
Conclusions: Analysis of ctDNA allows detecting tumor-specific mutations in R/R cHL. The longitudinal tracking of circulating DNA mutations in these patients identifies two different patterns of clonal evolution associated with sensitivity (clonal reshaping) or resistance (clonal persistence) to checkpoint blockade.
Santoro:Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; BMS: Consultancy; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Carlo-Stella:ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Research Funding; Janssen Oncology: Honoraria; MSD: Honoraria; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Amgen: Honoraria; Boehringer Ingelheim: Consultancy; Novartis: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations; Rhizen Pharmaceuticals: Research Funding; AstraZeneca: Honoraria; Genenta Science srl: Consultancy.
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