CANVAS, a rare disorder responsible for late-onset ataxia of autosomal recessive inheritance, can be misdiagnosed. We investigated a series of eight patients with sensory neuropathy and/or an unexplained cough, who appeared to suffer from CANVAS, and we emphasized the clinical clues for early diagnosis. Investigations included clinical and routine laboratory analyses, skin biopsy, nerve biopsy and molecular genetics. The eight patients had clinical and/or laboratory evidence of sensory neuronopathy. All but one had neuropathic pain that had started in an asymmetric fashion in two patients. A chronic cough was a prominent feature in our eight patients and had started years before neuropathic symptoms in all but one. The course of the disease was slow, and ataxia remained mild in all. Five patients were initially thought to have immune-mediated sensory neuronopathy and received immunotherapy. Skin biopsies showed a near complete and non-length-dependent loss of intraepidermal nerve fibers. Moreover, nerve biopsy findings suggested a prominent involvement of small myelinated and unmyelinated fibers. The burden of CANVAS extends far beyond cerebellar ataxia and vestibular manifestations. Indeed, our study shows that a chronic cough and neuropathic pain may represent a major source of impairment in these patients and should not be overlooked to allow an early diagnosis and prevent unnecessary immunotherapy.

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) induces numerous symptoms affecting patient quality of life, leading to decreased doses or even to cessation of anticancer therapy. Previous studies have reported that a widely used drug, ramipril, improves neuroprotection in several rodent models of peripheral neuropathy. The protective role of the angiotensin II type 2 receptor (AT2) in the central and peripheral nervous systems is well-established. Here, we evaluate the effects of ramipril in the prevention of PIPN and the involvement of AT2 in this effect. Paclitaxel was administered in wild type or AT2-deficient mice on alternate days for 8 days, at a cumulative dose of 8 mg/kg (2 mg/kg per injection). Ramipril, PD123319 (an AT2 antagonist), or a combination of both were administered one day before PTX administration, and daily for the next twenty days. PTX-administered mice developed mechanical allodynia and showed a loss of sensory nerve fibers. Ramipril prevented the functional and morphological alterations in PTX mice. The preventive effect of ramipril against tactile allodynia was completely absent in AT2-deficient mice and was counteracted by PD123319 administration in wild type mice. Our work highlights the potential of ramipril as a novel preventive treatment for PIPN, and points to the involvement of AT2 in the neuroprotective role of ramipril in PIPN.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and dose-limiting adverse side effect of treatment. CIPN affects the oncological prognosis of patients, as well as their quality of life. To date, no specific pharmacological therapy has demonstrated effectiveness in preventing CIPN. Accumulating preclinical evidence suggests that renin-angiotensin system (RAS) inhibitors may have neuroprotective effects. One hundred and twenty patients were included in this observational study and were followed from the beginning of their neurotoxic chemotherapy schedule until their final assessment, at least one month after its cessation. The National Cancer Institute’s common toxicity criteria 4.0 (NCI-CTC 4.0) were used to grade the severity of adverse events. Follow-ups also included electrochemical skin conductance and scales for pain, quality of life and disability. Among patients receiving a platinum-based regimen, the mean grade of sensory neuropathy (NCI-CTC 4.0) was significantly lower in the RAS inhibitor group after the end of their anticancer treatment schedule. Because of the observational design of the study, patients in the RAS inhibitor group cumulated comorbidities at risk of developing CIPN. Randomized controlled trials in platinum-based regimens would be worth conducting in the future to confirm the neuroprotective potential of RAS inhibitors during chemotherapy.

The occurrence of neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting effect of many commonly-used anticancer agents. Polyvalent human immunoglobulins (hIg), used in the treatment of several peripheral neuropathies, may alleviate neuropathic pain. The aim of this project was to investigate the preventive effect of hIg in two mouse models of CIPN, induced by vincristine (VCR, 100 µg/kg/d) and oxaliplatin (OXP, 6 mg/kg/3d). Human Ig were administered one day before the first injection of chemotherapy. The onset of CIPN and effects of hIg were assessed via functional tests and morphological analyses of sensory nerves. To evaluate the effect of hIg on chemotherapy cytotoxicity, viability assays were performed using hIg (0 to 12 mg/mL) combined with anticancer agents on human cancer cell lines. The preventive treatment with hIg alleviated tactile hypersensitivity and nerve injuries induced by VCR. It also alleviated tactile/cold hypersensitivities and nerve injuries induced by OXP. Treatment with hIg did not affect the cytotoxicity of either chemotherapy. Furthermore, in combination with VCR, hIg potentiated chemo-induced cell death. In conclusion, hIg is a promising therapy to prevent the onset of CIPN and potentiate chemotherapy effect on cancer, reinforcing the interest in hIg in the management of CIPN.

Methionine dependence represents a well-known metabolic vulnerability in cancer. Despite promising preclinical results, methionine restriction is impaired by the presence of methionine-independent cancer cells. After confirming both inter- and intra-tumoral heterogeneity in methionine dependence, we demonstrate that "methionine-independent" cells are rather "methionine self-sufficient," relying on the vitamin B12 (B12)-dependent methionine synthase (MTR) to sustain growth without exogenous methionine, which renders them highly vulnerable to B12 deprivation. Dual methionine and B12 deprivation produced synergistic cytotoxicity, inhibiting proliferation and inducing apoptosis across multiple cancer types and primary tumor cells, while sparing fibroblasts. This synergy persisted under moderate nutrient restriction, supporting translational potential. Moreover, dual therapy prevented the adaptive metabolic shift seen with methionine deprivation alone, avoiding rebound proliferation and resistance. In vivo, a methionine-restricted diet plus a synthesized B12 antagonist significantly suppressed growth of methionine-independent pancreatic xenografts without hematologic toxicity. These findings uncover a selective, synergistic anticancer strategy targeting methionine self-sufficiency.