The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma

Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.

Complex Tears, Extrusion, and Larger Excision Are Prognostic Factors for Worse Outcomes 1 and 2 Years After Arthroscopic Partial Meniscectomy for Degenerative Meniscal Tears: A Secondary Explorative Study of the Surgically Treated Group From the Odense-Oslo Meniscectomy Versus Exercise (OMEX) Trial

Background: Few studies have examined morphological findings from preoperative magnetic resonance imaging (MRI) and arthroscopic findings as prognostic factors for outcomes 1 and 2 years after arthroscopic partial meniscectomy (APM). Purpose/Hypothesis: The purpose was to evaluate prognostic factors of preoperative findings from MRI and arthroscopic evaluation on lower extremity performance at 1 year and patient-reported outcomes at 1 to 2 years after APM. The hypothesis was that medial compartment abnormalities would be prognostic for 1- and 2-year functional outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: This secondary analysis from the OMEX (Odense-Oslo Meniscectomy Versus Exercise) trial included 40 patients treated surgically. Regression analyses with adjustments for age, sex, and body mass index explored associations between MRI findings (tear complexity and extrusion), arthroscopic findings (tear length, cartilage injury, and amount of excised meniscal tissue), and the following: lower extremity performance tests and thigh muscle strength at 1 year and the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales at 1 and 2 years. Results: A complex meniscal tear was a significant and clinically relevant prognostic factor for worse KOOS Symptoms subscores at 2 years (mean, 14.1 points [95% CI, 6.1-22.2]). Meniscal extrusion of at least 11%, 25%, and 20% were significant and clinically relevant prognostic factors for worse KOOS Activities of Daily Living (ADL) subscores at 1 year and worse KOOS Sports and Recreation (Sports/Rec) subscores at 1 and 2 years, respectively. Tear lengths of at least 7.0 mm, 6.7 mm, and 6.5 mm were significant and clinically relevant prognostic factors for better KOOS Symptoms subscores at 1 year and better KOOS Sports/Rec subscores at 1 and 2 years, respectively. A cartilage injury in the medial compartment was a significant and clinically relevant prognostic factor for worse KOOS ADL and Quality of Life (QoL) subscores at 2 years (mean, 10.4 and 19.4 points, respectively [95% CI, 3.4-17.4 and 7.7-31.1, respectively]). More than 20% meniscal tissue excised was a significant and clinically relevant prognostic factor for worse KOOS Pain, Symptoms, ADL, and Sports/Rec subscores at 1 and 2 years (mean, 8.9-41.5 points [95% CI, 2.2-15.5 to 21.0-62.0]) and worse KOOS QoL subscores at 2 years (mean, 25.3 points [95% CI, 13.6-37.0]). Conclusion: Complex meniscal tears, larger extrusion, cartilage injuries, and larger meniscal excision were significant and clinically relevant prognostic factors for worse outcomes 1 and 2 years after APM. Registration: NCT01002794 (ClinicalTrials.gov identifier)

Maintenance with weekly carfilzomib in elderly newly diagnosed multiple myeloma (IFM 2012-03).

8029 Background: Prolonged treatments have significantly improved survival in newly diagnosed multiple myeloma (NDMM). Lenalidomide (IMiDs), is currently approved in this indication, but remains a daily treatment, although oral, and may favor side effects in the long run. Furthermore, the use of a proteasome inhibitor (PI) is warranted in certain type of MM, such as high-risk. Carfilzomib, a second generation PI, has proved active combined with an acceptable security profile but its added benefit when given continuously is unknown. We thought to study maintenance Carfilzomib for elderly NDMM (eNDMM). Methods: The IFM 2012-03 multicenter phase I KMP (Carfilzomib, Melphalan, Prednisone) weekly study for eNDMM (≥ 65 years old) determined the maximal tolerated dose of weekly Carfilzomib at 70mg/m². We focus herein on the second part of the study with IV Carfilzomib monotherapy given at 36mg/m² for 13 cycles maintenance on an every 2 weeks schedule. Results: Thirty eNDMM were recruited in IFM 2012-03. Median age is 75, with 56% R-ISS 2 or 3 and 11% high-risk cytogenetic. With K weekly from 36 to 70mg/m², OS is reported at 93.3%, including 46.7% ≥CR; median PFS is 35.8 months and median OS was not reached. Twenty-two (73%) patients started K maintenance and 16 (73%) completed it. Four patients progressed and 2 stopped for AEs (renal amylosis, sensory neuropahty) during the maintenance phase. At maintenance completion, 50% were ≥CR. From the start of maintenance, in landmark analysis, median PFS is 28.1 months and the estimated 36-months OS approximately 70%. Conclusions: Carfilzomib monotherapy can be used safely in maintenance for 1 year in eNDMM, including for patients above 75 years. K maintenance may lead to deep response rate, certainly a most relevant prognostic factor for prolonged survival. Therefore, Carfilzomib maintenance, characterized with a simple administration modality, might be considered as an alternative to Lenalidomide and integrate the armamentarium of prolonged therapy in eNDMM. Clinical trial information: NCT02302495.

Spinal cord lesions: A modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor

Background: The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial. Objective: To assess the value of SC lesions for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS. Methods: Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases ( n = 207), non-SC CIS ( n = 143), non-SC CIS with abnormal brain MRI ( n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS ( n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases ( n = 207), non-SC CIS ( n = 143) and SC CIS ( n = 64). Performance at 2 years was assessed for all outcomes. Results: The presence of SC lesions increased MS risk 2.0–2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4–3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0. Conclusion: SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis.