Université d'été de Boulogne-sur-Mer

In human, an association between bone loss and increased marrow adipose tissue suggests that medullary adipocytes could play a role in osteoporosis by acting on neighboring bone-forming osteoblasts. Supporting this hypothesis, we previously showed, using coculture and conditioned medium models based on human bone marrow stromal cells of commercial origin, that factors secreted by adipocytes induced the transdifferentiation of osteoblasts towards an adipocyte-like phenotype. The aim of this study was to confirm the involvement of medullary adipocyte secretion products in the alteration of osteoblasts in pathophysiological conditions. To this end, two new cellular models were developed from human bone biopsies representing the aging skeleton. In the first model, outgrowth from trabecular bone fragments were used to isolate primary cells that displayed a specific osteoblast phenotype. We confirmed the transdifferentiation of these primary osteoblasts following their incubation with adipocyte conditioned medium as evidenced by the increase in the levels of adipogenic mRNA markers (PPARG, Leptin and HSD11B1, P<0,001) and the decrease of osteogenic transcript (BGLAP, P<0.05). The second model was based on primary adipocyte isolation through collagenase treatment followed by ceiling and 2D culture. Oil red O staining confirmed the isolation of fully-differentiated primary adipocytes from bone biopsies. Experiments performed with their conditioned medium validated what had been observed with primary osteoblasts: the effect of the adipocyte secretome on osteoblast fate. Overall, our results supported the relevance of these models to examine paracrine interactions between osteoblasts and adipocytes and confirmed the role played by adipocyte-secreted factors in osteoblast transdifferentiation.

Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. NCT02970526 (2016-11-22). https://classic. gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

Chronic kidney disease-associated pruritus (CKD-aP) is a disabling symptom which is frequent and often underestimated. Pa-MRC has a negative impact on quality of life, and is frequently accompanied by sleep disorders and depression. The approval of difelikefalin – a kappa opioid receptor agonist – in this indication requires updated recommendations. As a first step, secondary causes of pruritus without skin lesions must be ruled out, and general measures taken (emollients, psychological support, optimization of dialysis, normalization of serum calcium, phosphate and PTH in the range proposed by the KGIDO guidelines, treatment of iron deficiency). A therapeutic test with a non-sedating oral antihistamine may be proposed. If this test is negative, Pa-MRC must be strongly suspected, and its intensity (WI-NRS scale) and impact on quality of life assessed. In the case of mild Pa-MRC (WI-NRS ≤ 3), only general measures are implemented. If Pa-MRC is moderate to severe (WI-NRS ≥ 4), specific treatment with difelikefaline can be initiated for 6 months in addition to general measures. At 3 months, if the response is complete (WI-NRS score ≤ 1) or partial (decline ≥ 3 points), treatment is continued. At 6 months, if the response is complete, treatment may be discontinued with the patient’s agreement; treatment is maintained if the response is partial. At 3 or 6 months, if response is insufficient (decline < 3 points) and/or in the event of intolerance, treatment is discontinued and an alternative treatment (e.g., gabapentinoids, UVB) may be considered after dermatological consultation.