The Consensus Panel 3 (CP3) of the 12th International Workshop on Waldenström macroglobulinemia (IWWM-12) has reviewed and incorporated current data to make recommendations for the management of patients with high-risk WM (HR-WM). Recognizing the considerable heterogeneity in survival outcomes and identifying a subgroup of patients with a very poor prognosis, the key recommendations from CP3 include: (1) Risk stratifying patients with smoldering WM (SWM) and active (symptomatic) WM at diagnosis (2) Using the degree of i) bone marrow lymphoplasmacytosis, ii) serum beta-2 microglobulin (β2M) elevation, iii) IgM increase, iv) serum albumin decrease and the presence of wild-type MYD88 status markers that adversely dictate the time-to-progression from smoldering to active WM to the define HR-SWM. (3) Among patients with active WM, the presenting parameters: advanced chronological age, low serum albumin, elevated serum lactate dehydrogenase, elevated β2M and the presence of TP53 alterations (TP53 mutation or deletion 17p) unfavorably impact the prognosis and should be utilized to risk-stratify patients into the HR category. (4) The panel encourages screening for genetic alterations at diagnosis, prior to initiating therapy and also with rapidly advancing disease or refractoriness to ongoing therapy, which might result from clonal evolution. Although limited data directing the selection and sequencing of therapies exist, a risk-adapted approach and clinical trial participation for patients with HR-WM are highly encouraged.
- MeSH
- beta 2-Microglobulin blood MeSH
- Consensus MeSH
- Humans MeSH
- Disease Management MeSH
- Prognosis MeSH
- Waldenstrom Macroglobulinemia * therapy diagnosis genetics blood MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Consensus Development Conference MeSH
BACKGROUND: Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. METHODS: This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was β2-microglobulin removal rate (β2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. RESULTS: 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest β2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. CONCLUSIONS: The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. TRIAL REGISTRATION: eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).
- MeSH
- beta 2-Microglobulin blood MeSH
- Kidney Failure, Chronic therapy MeSH
- Hemodiafiltration * instrumentation methods MeSH
- Hydrophobic and Hydrophilic Interactions * MeSH
- Cross-Over Studies * MeSH
- Middle Aged MeSH
- Humans MeSH
- Membranes, Artificial * MeSH
- Prospective Studies MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
One of the most common mechanisms of immune evasion in MSI colorectal cancers (CRCs) is loss of HLA class I expression due to mutations in B2M gene which can become a negative predictor for checkpoint blockade therapy. The aim of this study was the determination of prevalence of B2M somatic mutations in MSI CRC patients and relationship between B2M mutations and lymphocytes infiltration and other clinicopathological features as well as detection of methylation changes in B2M promoter region which can be another mechanism of immune escape. In our study, 37 MSI-H and 5 MSI-L patients were selected for screening of B2M mutational and methylation status. The characterization of patients was based on standard histopathological diagnosis and TNM classification; BRAF, KRAS mutations, tumor-infiltrating lymphocytes and peritumoral lymphoid reaction were also determined. MSI analysis was performed using fragment analysis. B2M mutations were identified by Sanger sequencing, and methylation of CpG islands in promoter region was detected by methylation-specific PCR. Heterozygous mutations in the B2M gene were detected in five MSI-H patients (13.5%), while the mutation c.45_48delTTCT was determined in four patients and mutation c.276delC was found in two patients. One of these five patients was compound heterozygote harboring both mutations. Methylation of the promoter region of the B2M gene was observed in one patient with MSI-H colorectal cancer. Detection of genetic and epigenetic changes in B2M gene could be important in personalized therapy for CRC patients as these changes may be one of the mechanisms of secondary resistance of MSI positive tumors to immunotherapy.
- MeSH
- beta 2-Microglobulin genetics MeSH
- CpG Islands MeSH
- Adult MeSH
- Down-Regulation MeSH
- Epigenesis, Genetic MeSH
- Colorectal Neoplasms genetics pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation * MeSH
- Microsatellite Instability * MeSH
- Mutation MeSH
- Promoter Regions, Genetic MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Staging MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
In the majority of human tumors, downregulation of major histocompatibility complex class I (MHC‑I) expression contributes to the escape from the host immune system and resistance to immunotherapy. Relevant animal models are therefore needed to enhance the efficacy of cancer immunotherapy. As loss of β‑2 microglobulin expression results in irreversible downregulation of surface MHC‑I molecules in various human tumors, the β‑2 microglobulin gene (B2m) was deactivated in a mouse oncogenic TC‑1 cell line and a TC‑1/dB2m cell line that was negative for surface MHC‑I expression was derived. Following stimulation with interferon γ, MHC‑I heavy chains, particularly the H‑2Db molecules, were found to be expressed at low levels on the cell surface, but without β‑2 microglobulin. B2m deactivation in TC‑1/dB2m cells led to reduced proliferation and tumor growth. These cells were insensitive to DNA vaccination and only weakly responsive to combined immunotherapy with a DNA vaccine and the ODN1826 adjuvant. In vivo depletion demonstrated that NK1.1+ cells were involved in both reduced tumor growth and an antitumor effect of immunotherapy. The number of immune cells infiltrating TC‑1/dB2m‑induced tumors was comparable with that in tumors developing from TC‑1/A9 cells characterized by reversible MHC‑I downregulation. However, the composition of the cell infiltrate was different and, most importantly, infiltration with immune cells was not increased in TC‑1/dB2m tumors after immunotherapy. Therefore, the TC‑1/dB2m cell line represents a clinically relevant tumor model that may be used for enhancement of cancer immunotherapy.
- MeSH
- beta 2-Microglobulin genetics immunology MeSH
- T-Lymphocytes, Cytotoxic immunology pathology MeSH
- Immunotherapy MeSH
- Interferon-gamma immunology MeSH
- Humans MeSH
- Histocompatibility Antigens Class I genetics immunology MeSH
- Mice MeSH
- Cell Line, Tumor metabolism MeSH
- Neoplasms genetics immunology pathology MeSH
- Gene Expression Regulation, Neoplastic genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The selection of a suitable combination of reference genes (RGs) for data normalization is a crucial step for obtaining reliable and reproducible results from transcriptional response analysis using a reverse transcription-quantitative polymerase chain reaction. This is especially so if a three-dimensional multicellular model prepared from liver tissues originating from biologically diverse human individuals is used. The mRNA and miRNA RGs stability were studied in thirty-five human liver tissue samples and twelve precision-cut human liver slices (PCLS) treated for 24 h with dimethyl sulfoxide (controls) and PCLS treated with β-naphthoflavone (10 μM) or rifampicin (10 μM) as cytochrome P450 (CYP) inducers. Validation of RGs was performed by an expression analysis of CYP3A4 and CYP1A2 on rifampicin and β-naphthoflavone induction, respectively. Regarding mRNA, the best combination of RGs for the controls was YWHAZ and B2M, while YWHAZ and ACTB were selected for the liver samples and treated PCLS. Stability of all candidate miRNA RGs was comparable or better than that of generally used short non-coding RNA U6. The best combination for the control PCLS was miR-16-5p and miR-152-3p, in contrast to the miR-16-5b and miR-23b-3p selected for the treated PCLS. Our results showed that the candidate RGs were rather stable, especially for miRNA in human PCLS.
- MeSH
- beta 2-Microglobulin genetics metabolism MeSH
- beta-Naphthoflavone pharmacology MeSH
- Cytochrome P-450 CYP1A2 genetics metabolism MeSH
- Cytochrome P-450 CYP3A genetics metabolism MeSH
- Dimethyl Sulfoxide pharmacology MeSH
- Adult MeSH
- Liver drug effects metabolism MeSH
- Real-Time Polymerase Chain Reaction standards MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- MicroRNAs genetics metabolism MeSH
- 14-3-3 Proteins genetics metabolism MeSH
- Reference Standards MeSH
- Rifampin pharmacology MeSH
- Aged MeSH
- Gene Expression Profiling standards MeSH
- Cytochrome P-450 Enzyme System pharmacology MeSH
- Transcriptome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce. METHODS: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score. RESULTS: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher β2-microglobulin. The HDF cohort had lower β2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time. CONCLUSIONS: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.
- MeSH
- beta 2-Microglobulin blood MeSH
- Headache etiology MeSH
- C-Reactive Protein MeSH
- Kidney Failure, Chronic blood complications therapy MeSH
- Renal Dialysis adverse effects MeSH
- Child MeSH
- Phosphates blood MeSH
- Hemodiafiltration * adverse effects methods MeSH
- Hemoglobins metabolism MeSH
- Patient Reported Outcome Measures MeSH
- Hospitalization MeSH
- Hypertension etiology MeSH
- Carotid Intima-Media Thickness * MeSH
- Blood Pressure MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Parathyroid Hormone blood MeSH
- Child, Preschool MeSH
- Muscle Cramp etiology MeSH
- Body Height * MeSH
- Dizziness etiology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Comparative Study MeSH
In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and β2-microglobulin [β2m]) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (β2m > 3 mg/L), low (β2m ≤ 3 mg/L without bone marrow involvement), and intermediate (β2m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively (P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively (P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.
- MeSH
- beta 2-Microglobulin metabolism MeSH
- Lymphoma, Follicular * metabolism mortality pathology therapy MeSH
- Immunotherapy * MeSH
- Bone Marrow metabolism pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Survival Rate MeSH
- Neoplasm Proteins metabolism MeSH
- Disease-Free Survival MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Research Support, N.I.H., Extramural MeSH
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.
- MeSH
- B7-H1 Antigen antagonists & inhibitors biosynthesis genetics immunology MeSH
- Programmed Cell Death 1 Receptor antagonists & inhibitors biosynthesis genetics immunology MeSH
- beta 2-Microglobulin biosynthesis genetics immunology MeSH
- Reed-Sternberg Cells drug effects immunology pathology MeSH
- Progression-Free Survival MeSH
- Hodgkin Disease drug therapy genetics immunology pathology MeSH
- Cohort Studies MeSH
- Humans MeSH
- Chromosomes, Human, Pair 9 MeSH
- Histocompatibility Antigens Class II biosynthesis genetics immunology MeSH
- Nivolumab therapeutic use MeSH
- Predictive Value of Tests MeSH
- Antigen Presentation MeSH
- Antineoplastic Agents, Immunological therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Několik publikací z nedávné doby poukazuje na nově objevené mechanismy primární a sekundární rezistence na léčbu monoklonálními protilátkami proti PD-1/PD-L1 (programmed cell death 1, membránový protein programované buněčné smrti 1/programmed cell death ligand 1, ligand membránového proteinu programované buněčné smrti 1). Z patofyziologického hlediska ji lze rozdělit na rezistenci způsobenou změněnou antigenní výbavou nádorových buněk a rezistenci podmíněnou změnami v signálních drahách. Některé z těchto mechanismů rezistence jsou ovlivnitelné cílenými léky.
Several recent studies have identified novel mechanisms of primary and secondary resistance to treatment with anti-PD-1/PD-L1 (programmed cell death 1/programmed cell death ligand 1) antibodies. They can be broadly divided into resistance due to altered antigenic load of tumor cells and mutation-related changes in signaling pathways. Some of these mechanisms of resistance can be influenced by targeted drugs.
- MeSH
- B7-H1 Antigen immunology MeSH
- Programmed Cell Death 1 Receptor immunology MeSH
- Antigens, Neoplasm genetics immunology MeSH
- beta 2-Microglobulin genetics MeSH
- Drug Resistance, Neoplasm * genetics immunology MeSH
- Cytokines immunology MeSH
- Genes, MHC Class I MeSH
- Immunotherapy * MeSH
- Carcinogenesis MeSH
- Cell Cycle Checkpoints immunology MeSH
- Humans MeSH
- Antibodies, Monoclonal * pharmacology MeSH
- Mutation MeSH
- Neoplasms drug therapy genetics immunology MeSH
- Gene Expression Regulation MeSH
- Check Tag
- Humans MeSH
