Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Bladder dysfunction in adolescents with type 1 diabetes.

BACKGROUND: It is increasingly significant that adults with diabetes experience lower urinary tract symptoms, however, there has been limited research in younger individuals with type 1 diabetes. OBJECTIVE: To investigate bladder function using non-invasive urodynamics as a potential indicator of autonomic neuropathy in adolescents with type 1 diabetes. This involved examining the association between urinary flow disturbances, reported symptoms, and results from other autonomic tests. STUDY DESIGN: Cross-sectional study enrolling 49 adolescents with type 1 diabetes and 18 control subjects. All participants underwent uroflowmetry and ultrasound scanning, completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire, and were instructed to record their morning urine volume and voiding frequencies and report them back. Cardiovascular reflex tests (CARTs) and the quantitative sudomotor axon reflex test (QSART) were performed. RESULTS: The main results are shown in the Summary figure. DISCUSSION: In this study, urological abnormalities were not significantly more frequent in adolescents with diabetes, however, urological issues were observed. This is supported by previous findings of Szabo et al. who found that adolescents with type 1 diabetes had reduced flow acceleration and time to maximum flow compared to control subjects. In our study, we observed cases with reduced acceleration and prolonged uroflow curves, possibly indicating detrusor underactivity. People with diabetes had a higher risk of nocturia than healthy controls, which our results supported. Some adolescents reported urination twice per night. Based on these findings, it is considered beneficial to ask about urological symptoms annually to determine if more examinations (frequency-volume charts and uroflowmetry) are necessary and/or if any opportunities for treatment optimization exist. However, uroflowmetry has limitations, as bladder filling and emptying is a complex process involving multiple pathways and neurological centers, making it difficult to standardize and evaluate. Another limitation of this study was that our control group was smaller and consisted of fewer males than females, which could affect the results due to differences in anatomy and physiology in the lower urinary tract system. CONCLUSION: In conclusion, adolescents with type 1 diabetes, as well as healthy adolescents, frequently experience urological symptoms. Although urological abnormalities were not significantly more frequent in adolescents with diabetes in this study, the focus on nocturia and risk for bladder dysfunction seems relevant, even in adolescents without any other tests indicating autonomic dysfunction.

Development and Progression of Polyneuropathy Over 5 Years in Patients With Type 2 Diabetes.

BACKGROUND AND OBJECTIVES: There is a need for knowledge regarding the natural course of diabetic polyneuropathy (DPN), a complication in type 2 diabetes (T2D). The aim of this study was to examine the development of DPN over time. METHODS: Patients with newly diagnosed T2D, recruited from a national cohort, and controls without diabetes of similar age and sex, underwent sensory phenotyping in 2016-2018. The Toronto consensus criteria were used to classify patients into possible, probable, and confirmed DPN. For this 5-year, observational, follow-up, cohort study, all participants were invited to a reexamination combining bedside sensory examination, quantitative sensory testing (QST), nerve conduction studies (NCSs), and skin biopsies measuring intraepidermal nerve fiber density (IENFD) in order to compare phenotypic and diagnostic changes over time. RESULTS: Of the baseline 389 patients and 97 controls, 184 patients (median [interquartile range] diabetes duration 5.9 [4.1-7.4] years, mean hemoglobin A1c [HbA1c] 51 ± 11 mmol/mol at baseline) and 43 controls completed follow-up (46.9%). Confirmed DPN was present in 35.8% and 50.3%, probable DPN in 27.2% and 14.6%, possible DPN in 17.2% and 16.6%, and no DPN in 15.2% and 17.9% at baseline and follow-up, respectively. The estimated prevalence (95% CI) of confirmed DPN was 33.5% (24.9-42.1) compared with 22.7% (17.5-28.0) at baseline. During the follow-up period, 43.9% of patients with probable DPN developed confirmed DPN. Progression of neuropathy occurred in 16.5% and 24.7% and regression in 5.9% and 18.6% of patients based on NCS and IENFD, respectively. Progression based on NCS and/or IENFD was associated with higher baseline waist circumference and triglycerides, and regression with lower baseline HbA1c. Patients with at least probable DPN at baseline but neither patients without DPN nor controls developed increased spread of hyposensitivity, more hyposensitivity on QST and lower NCS z-scores at follow-up, and worsening of nerve parameters at follow-up correlated with higher baseline triglycerides. DISCUSSION: In patients with well-regulated T2D, the proportion of patients with confirmed DPN increased over 5 years driven by progression from probable DPN. A large proportion of patients progressed, and a smaller proportion regressed on nerve parameters. Higher triglycerides correlated with this progression and may constitute a risk factor.

Assessment of neuropathy subtypes in type 1 diabetes.

INTRODUCTION: Diabetic polyneuropathy (DPN), a common complication of diabetes, can manifest as small, large, or mixed fiber neuropathy (SFN, LFN, and MFN, respectively), depending on the type of fibers involved. Despite evidence indicating small fiber involvement prior to large fiber involvement in type 1 diabetes mellitus (T1DM)-associated DPN, no evidence has been produced to determine the more prevalent subtype. We aim to determine the more prevalent type of nerve fiber damage-SFN, LFN, and MFN-in T1DM-associated DPN, both with and without pain. RESEARCH DESIGN AND METHODS: In this cross-sectional study, participants (n=216) were divided into controls; T1DM; T1DM with non-painful DPN (NP-DPN); and T1DM with painful DPN (P-DPN). DPN was further subgrouped based on neuropathy severity. The more prevalent type of fiber damage was determined applying small and large fiber-specific tests and three diagnostic models: model 1 (≥1 abnormal test); model 2 (≥2 abnormal tests); and model 3 (≥3 abnormal tests). RESULTS: MFN showed the highest prevalence in T1DM-associated DPN. No differences in neuropathy subtype were found between NP-DPN and P-DPN. DPN, with prevalent SFN plateaus between models 2 and 3. All models showed increased prevalence of MFN according to DPN severity. Model 3 showed increased DPN with prevalent LFN in early neuropathy. DPN with prevalent SFN demonstrated a similar, but non-significant pattern. CONCLUSIONS: DPN primarily manifests as MFN in T1DM, with no differentiation between NP-DPN and P-DPN. Additionally, we propose model 2 as an initial criterion for diagnosing DPN with a more prevalent SFN subtype in T1DM. Lastly, the study suggests that in mild stages of DPN, one type of nerve fiber (either small or large) is more susceptible to damage.