The role of new technologies in myeloproliferative neoplasms

The hallmark of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is the presence of a driver mutation in JAK2, CALR, or MPL gene. These genetic alterations represent a key feature, useful for diagnostic, prognostic and therapeutical approaches. Molecular biology tests are now widely available with different specificity and sensitivity. Recently, the allele burden quantification of driver mutations has become a useful tool, both for prognostication and efficacy evaluation of therapies. Moreover, other sub-clonal mutations have been reported in MPN patients, which are associated with poorer prognosis. ASXL1 mutation appears to be the worst amongst them. Both driver and sub-clonal mutations are now taken into consideration in new prognostic scoring systems and may be better investigated using next generation sequence (NGS) technology. In this review we summarize the value of NGS and its contribution in providing a comprehensive picture of mutational landscape to guide treatment decisions. Finally, discussing the role that NGS has in defining the potential risk of disease development, we forecast NGS as the standard molecular biology technique for evaluating these patients

SAKK38/07 study: Integration of baseline metabolic heterogeneity and metabolic tumor volume in DLBCL prognostic model

Several functional parameters frombaseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P =.0005), whereas overall survival (OS) was 91%and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P=.0001).MTVwas the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P =.0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P <.0001; validation set: HR, 7.6; 95% CI, 2.0-28; P =.0003). This findingwas confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219

IELSG38: phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma

The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC rituximab maintenance in patients with extranodal marginal zone lymphoma (MZL) who received front-line treatment with chlorambucil plus rituximab. Study treatment was an induction phase with oral chlorambucil 6 mg/m2/day on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and intravenous rituximab 375 mg/m2 on day 1 of weeks 1-4, and 1,400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1,400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI: 78-92), 84% (95% CI: 75-89), and 93% (95% CI: 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that SC rituximab did not improve the CR rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC rituximab maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results

\ua9 2024 by American Society of Clinical Oncology. PURPOSE The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial. METHODS The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned. RESULTS The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, -0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSION This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation

Modeling in vitro osteoarthritis phenotypes in a vascularized bone model based on a bone-marrow derived mesenchymal cell line and endothelial cells

The subchondral bone and its associated vasculature play an important role in the onset of osteoarthritis (OA). Integration of different aspects of the OA environment into multi-cellular and complex human, in vitro models is therefore needed to properly represent the pathology. In this study, we exploited a mesenchymal stromal cell line/endothelial cell co-culture to produce an in vitro human model of vascularized osteogenic tissue. A cocktail of inflammatory cytokines, or conditioned medium from mechanically-induced OA engineered microcartilage, was administered to this vascularized bone model to mimic the inflamed OA environment, hypothesizing that these treatments could induce the onset of specific pathological traits. Exposure to the inflammatory factors led to increased network formation by endothelial cells, reminiscent of the abnormal angiogenesis found in OA subchondral bone, demineralization of the constructs, and increased collagen production, signs of OA related bone sclerosis. Furthermore, inflammation led to augmented expression of osteogenic (alkaline phosphatase (ALP) and osteocalcin (OCN)) and angiogenic (vascular endothelial growth factor (VEGF)) genes. The treatment, with a conditioned medium from the mechanically-induced OA engineered microcartilage, also caused increased demineralization and expression of ALP, OCN, ADAMTS5, and VEGF; however, changes in network formation by endothelial cells were not observed in this second case, suggesting a possible different mechanism of action in inducing OA-like phenotypes. We propose that this vascularized bone model could represent a first step for the in vitro study of bone changes under OA mimicking conditions and possibly serve as a tool in testing anti-OA drugs

Design and fabrication of novel polymeric biodegradable stents for small caliber blood vessels by computer-aided wet-spinning

Biodegradable stents have emerged as one of the most promising approaches in obstructive cardiovascular disease treatment due to their potential in providing mechanical support while it is needed and then leaving behind only the healed natural vessel. The aim of this study was to develop polymeric biodegradable stents for application in small caliber blood vessels. Poly[(R)- 3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate] (PHBHHx), a renewable microbial aliphatic polyester, and poly(ε-caprolactone), a synthetic polyester approved by the US Food and Drug Administration for different biomedical applications, were investigated as suitable polymers for stent development. Anovel manufacturing approach based on computer-aided wet-spinning of a polymeric solution was developed to fabricate polymeric stents. By tuning the fabrication parameters, it was possible to develop stents with different morphological characteristics (e.g. pore size and wall thickness). Thermal analysis results suggested that material processing did not cause changes in the molecular structure of the polymers. PHBHHx stents demonstrated great radial elasticity while PCL stents showed higher axial and radial mechanical strength. The developed stents resulted able to sustain proliferation of human umbilical vein endothelial cells within two weeks of in vitro culture and they showed excellent results in terms of thromboresistivity when in contact with human blood

An in vitro chondro-osteo-vascular triphasic model of the osteochondral complex

The generation of engineered models of the osteochondral complex to study its pathologies and develop possible treatments is hindered by the distinctly different properties of articular cartilage and subchondral bone, with the latter characterized by vascularization. In vitro models of the osteochondral complex have been mainly engineered as biphasic constructs containing just cartilage and bone cells, a condition very dissimilar from the in vivo environment. The different cellular components of the osteochondral complex are governed by interacting biochemical signaling; hence, to study the crosstalk among chondrocytes, osteoblasts, and endothelial cells, we have developed a novel triphasic model of the osteochondral tissue interface. Wet-spun poly(ε-caprolactone) (PCL) and PCL/hydroxyapatite (HA) scaffolds in combination with a methacrylated gelatin (gelMA) hydrogel were used as the polymeric backbone of the constructs. The scaffold components were engineered with human bone marrow derived mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs), and differentiated using a dual chamber microphysiological system (MPS) bioreactor that allows the simultaneous, separate flow of media of different compositions for induced differentiation of each compartment towards a cartilaginous or osseous lineage. Within the engineered Microphysiological Vascularized Osteochondral System, hMSCs showed spatially distinct chondrogenic and osteogenic markers in terms of histology and gene expression. HUVECs formed a stable capillary-like network in the engineered bone compartment and enhanced both chondrogenic and osteogenic differentiation of hMSCs, resulting in the generation of an in vitro system that mimics a vascularized osteochondral interface tissue

A systematic review of contemporary phase I trials in patients with lymphoma.

We performed a systematic review of phase I trials specifically designed for lymphoma patients. PubMed and Cochrane Library databases were searched using (lymphoma*) AND (phase 1) and publication date 2015-2020 to identify phase I dose-finding trials including a majority of lymphoma patients. Eighty-two trials (n = 3289 lymphoma patients) were included: 46 (55%) enrolled only lymphoma patients, 34 (41%) included also other hematologic malignancies, 2 (2%) solid tumors. Forty-six trials (56%) evaluated a combination (in 25 addition of experimental drug to standard therapy). Seven trials (9%) enrolled untreated patients. Among trials reporting activity in lymphoma patients, 74% (n = 57) reported an overall response rate ≥ 30%. All trials reported grade ≥ 3 adverse events; however, rates were not comparable across trials. Thirty-one treatment-related deaths in lymphoma patients were reported (overall treatment-related grade 5 adverse events rate 0.94%). Phase I trials designed for lymphoma patients were generally safe and the majority reported overall response rate ≥ 30%