Cardiovascular autonomic and peripheral sensory neuropathy in women with obesity.

Introduction: A higher incidence of neural dysfunction in people with obesity has been described. We determined the prevalence of neuropathic lesions in obese women and evaluated their potential association with anthropometric and laboratory parameters. Patients and methods: In our cross-sectional study, we enrolled female patients with obesity and without diabetes before obesity treatment. Voluntary female subjects were controls with a normal body mass index (BMI). Autonomic function was assessed by Ewing's cardiovascular reflex tests, while comprehensive peripheral neuropathic assessments were conducted utilizing the Neurometer®, Tiptherm®, Monofilament®, and Rydel-Seiffer tuning fork tests. Sudomotor function was assessed by the Neuropad®-test. Body composition was examined using the InBody 770. Results: 71 patients (mean ± SD; age: 36.1 ± 8.3 years; BMI: 40.2 ± 8.5 kg/m2) and 36 controls (age: 36.4 ± 13.3 years; BMI: 21.6 ± 2.1 kg/m2) were enrolled. Patients had significantly higher systolic (patients vs. controls; 137.5 ± 16.9 vs. 114.6 ± 14.8 mmHg, p<0.001) and diastolic (83.0 ± 11.7 vs.69.8 ± 11.2 mmHg, p<0.001) blood pressure compared to controls. Among autonomic tests, only the heart rate response to Valsalva maneuver (Valsalva-ratio) revealed significant impairment in patients (1.4 ± 0.2 vs. 1.7 ± 0.4, p<0.001). Neurometer® at the median nerve revealed increased current perception threshold (CPT) values at all stimulating frequencies in patients (CPT at 2000 Hz: 204.6 ± 70.9 vs. 168.1 ± 66.9, p=0.013; 250 Hz: 84.4 ± 38.9 vs. 56.5 ± 34.8, p<0.001; CPT at 5 Hz: 58.5 ± 31.2 vs 36.9 ± 29.1, p<0.001). The Rydel-Seiffer tuning fork test has revealed a significant impairment of vibrational sensing on the lower limb in patients (right hallux: 6.8 ± 0.9 vs. 7.4 ± 0.8, p=0.030; left hallux: 6.9 ± 0.8 vs. 7.3 ± 0.9, p=0.029). The Neuropad® testing showed a significant impairment of sudomotor function in women with obesity. A negative correlation was found in patients between BMI and the 25-hydroxy-D3/D2-vitamin levels (r=-0.41, p=0.00126) and a positive correlation between the BMI and resting systolic blood pressure (r=0.26, p=0.0325). Conclusion: Peripheral sensory neuronal and sudomotor function impairments were detected in female patients with obesity compared to the controls with normal BMI. Cardiovascular autonomic dysfunction was also revealed by the Valsalva-ratio in these patients, suggesting the presence of parasympathetic dysfunction. The negative correlation between BMI and the 25-hydroxy-D3/D2-vitamin highlights the potential deficiency of vitamin D in the population affected by obesity.

Uncommonly Missed Diagnosis of Methylmalonic Acidemia (MMA) in Adults and Usefulness of Testing for MMA in Cases of Seizures/Neuropathy/Weakness/Ataxia.

Methylmalonic acidemia (MMA) is a genetic condition affecting cobalamin metabolism causing elevated serum and urine methylmalonic acid without B12 deficiency. MMA presents with ketoacidotic hyperammonemic coma in newborns and can result in neonatal death or severe neurological disability. Rarely, this diagnosis is missed, or patients do not present until later in life. Presentation of this life-threatening condition is variable in adults. Improvement is rapid with IV cobalamin and a specialized diet. This case is intended to increase clinician's awareness of the late presentation of this disease and the importance of high clinical suspicion and prompt diagnosis. We present a case of a 32-year-old man with seizures, polyneuropathy, ataxia, and memory loss which were unexplained until diagnosis with MMA. We aim to help clinicians understand the variable presentation and diagnostic work-up of MMA to prevent catastrophic missed diagnoses. After an extensive work-up, the patient was found to have methylmalonic acidemia and was promptly treated with high dose vitamin B12 and a specialized diet with low protein including restricted isoleucine, threonine, methionine, and valines as well as a high caloric content. The patient showed significant clinical improvement with this treatment. To our knowledge, this is the first case of MMA presenting with these symptoms in a medically stable adult. The patient was adopted from abroad and therefore, lacked access to normal newborn screenings, further complicating diagnosis. We aim to demonstrate to clinicians the importance of considering this diagnosis in patients in whom symptoms may be suggestive, particularly if they lack access to genetic or metabolic screening.

Adult Refsum Disease in Puerto Rico: A Case Report.

Patients with adult Refsum Disease (ARD) have retinitis pigmentosa and thus nyctalopia, anosmia, sensorineural deafness, polyneuropathy, and ataxia. Upon physical examination, patients with ARD have congenital short metacarpals, metatarsals, and cardiac arrhythmias. Manifestations due to the lack of phytanoyl-CoA hydroxylase in peroxisomes needed for alpha-oxidation of phytanic acid lead patients to accumulate phytanic acid in their body tissues. To our knowledge, no consensus for clinical diagnostic criteria for patients with ARD has been published. Our patient had nyctalopia, retinal findings, and visual field results compatible with retinitis pigmentosa. Additionally, the patient had decreased macular thickness and volume in both eyes, the findings being worse in the left eye. The patient had undergone hand surgery due to chronic pain in both hands, as well as his fourth and fifth metatarsal bones were shortened. Interestingly, audiology evaluation showed mild hearing loss in the right ear and mild to moderate hearing loss in the left ear. Inheritance patterns in patients with ARD have been described. Physical examination, phytanic acid evaluation, and genetic studies may all help reach an ARD diagnosis. This is the first report of adult Refsum disease in Puerto Rico.

Peripheral sensory neuropathy is associated with circulating angiopoietins in type 2 diabetes patients in Ghana.

Objective: Peripheral sensory neuropathy (PSN) is a common complication of type 2 diabetes (T2DM) that can lead to frequent ulcerations, lower extremities, and reduced quality of life. Imbalance in the circulating levels of angiogenic growth factors, notably, angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) may be among the underlying mechanisms of PSN in T2DM patients. We studied the association between PSN and angiogenic growth factors, Ang-1, Ang-2 and VEGF in T2DM patients in Ghana. Methods: In a case-control study design, PSN was evaluated in 160 patients with T2DM and 108 nondiabetic controls using vibration perception threshold (VPT) and diabetic neurological examination (DNE). The definition of PSN was abnormal VPT (≥25 mV) or the presence of neuropathic symptoms on examination (DNE score > 3). In addition, fasting venous blood samples were collected to measure circulating levels of Ang-1, Ang-2 and VEGF. Results: Compared to non-diabetic controls, patients with T2DM had a higher prevalence of PSN using abnormal VPT (20.6 % vs 2.8 %, p < 0.001) or neuropathic symptoms (35.6 % vs 3.7 %, p < 0.001). Compared to nondiabetic controls, patients with T2DM had increased levels of Ang-2 [597 (274 - 1005) vs 838 (473 - 1241) ng/ml, p = 0.018] and VEGF [48.4 (17.4 - 110.1) vs 72.2 (28 - 201.8), p = 0.025] and decreased Ang-1 levels [41.1 (30 - 57.3) vs 36.1 (24.7 - 42.1) ng/ml, p = 0.01]. In regression analyses, an increase in Ang-1 levels was associated with decreased odds, while an increase in Ang-2 levels was associated with increased odds, of abnormal VPT and neuropathic symptoms in T2DM patients. Conclusion: In our study population, PSN was associated with reduced plasma levels of Ang-1 and increased plasma levels of Ang-2 in patients with T2DM. Therefore, an imbalance of angiopoietins may be associated with PSN in T2DM.

Predictive Factors for Lower Limb Amputation in Type 2 Diabetics.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a major public health problem. Foot-related complications are common in diabetic patients. The aim of this study is to identify predictive factors for lower limb amputation (LLA) in order to better identify this at-risk population. METHODS: This was a cross-sectional study involving 134 patients who were hospitalised for the management of T2DM complicated by diabetic foot, in the department of endocrinology and diabetology. We included patients with T2DM whose diabetes was diagnosed 10 years ago or more, and who had a diabetic foot problem. Statistical differences between predictors of amputations were tested using: t-tests for numerical variables and chi-square tests for categorical variables. Significant variables were analysed by logistic regression to determine significant predictors. RESULTS: The mean duration of diabetes was 17±7 years. We found that 70% of patients with LLA were older than 50 years (p<10-3). The prevalence of LLA was higher (p=0.015) in patients with diabetes for more than 20 years. We noted that 58% of patients who underwent LLA were hypertensive (p<10-3). The majority of patients with LLA (58%) had abnormal micro-albuminuria (p<10-3). We found that 70% (n=12) of patients with LLA had low-density protein cholesterol levels above the target value (p<10-3). Diabetic foot grade ≥4 (4 or 5) according to Wagner's classification, was present in 24% of amputee patients. Based on a 95% confidence interval level, the independent significant predictive factors for LLA in our patients were: T2DM for more than 20 years, hypertension and diabetic foot grade ≥4. CONCLUSIONS: After multivariate analysis, the significant independent predictive factors associated with LLA were: T2DM for more than 20 years, hypertension, and diabetic foot grade ≥4. Early management of diabetic foot problems is therefore recommended to avoid amputations.

Small Fiber Neuropathy Associated With the Moderna SARS-CoV-2 Vaccine.

Efforts of controlling viral transmission began soon after the first cases of coronavirus disease 2019 (COVID-19) infections were identified. Initial efforts were related to contact precautions, hand hygiene, and mask-wearing; however, it was soon evident that a robust global immunization drive was the most effective way to curb disease transmission. In the United States, the first doses of COVID-19 vaccines were rolled out soon after the FDA granted emergency use authorization for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. What this also meant was that many of the routine phases that any new drug or vaccine goes through before being released publicly were bypassed. Over the past two years, various side effects and reactions have been seen after COVID-19 vaccine administration, the most common being local injection site events (e.g., pain, redness, swelling) and systemic effects (e.g., fatigue, headaches, myalgias). We report the case of a 64-year-old female who developed bilateral lower extremity numbness and tingling within weeks of receiving the third dose of Moderna SARS-CoV-2 vaccine. The patient underwent extensive testing to ascertain the diagnosis. She had negative autonomic testing and normal nerve conduction study/electromyography (EMG), which did not reveal large fiber neuropathy. Eventually, the patient underwent a skin biopsy, which revealed small fiber neuropathy. This case report highlights the importance of keeping a broad differential for rare side effects, such as small fiber neuropathy, that are currently being seen and reported in the literature.

Neuropathy in Human Immunodeficiency Virus: A Review of the Underlying Pathogenesis and Treatment.

This article explores the various causes of the human immunodeficiency virus (HIV), and its associated neuropathy, including the effects of HIV on the nervous system and the long-standing therapy that is often provided to patients with HIV. Several studies regarding the neurotoxic effects of combined antiretroviral therapy (cART) and HIV were reviewed and various hypotheses were discussed. Furthermore, we present the nature of HIV-sensory neuropathy (HIV-SN) among different demographic populations and their subsequent risk factors predisposing them to this condition. It was observed that the incidence of the disease increases in increased survival of the patients as well as in males. Finally, the current approach to HIV-SN and its overlapping features with other causes of peripheral neuropathy have been discussed which demonstrates that a clinical examination is the most important clue for a healthcare professional to suspect the disease. Our main aim was to study the current perspectives and guidelines for diagnosing and managing a patient with HIV-SN to reduce disease prevalence and bring about a more aware frame of mind when following up with an HIV patient.

Nanoparticle albumin-bound paclitaxel is superior to liposomal paclitaxel in the neoadjuvant treatment of breast cancer.

Aim: The present study aimed to retrospectively compare the efficacy and safety between liposomal paclitaxel (Lps-P) and nanoparticle albumin-bound paclitaxel (Nab-P) in neoadjuvant systemic treatment (NST) of breast cancer. Materials & methods: Two hundred thirty-five patients who were diagnosed with invasive breast cancer and then received dose-dense NST with epirubicin and cyclophosphamide followed by paclitaxel were enrolled. Results: Nab-P has an advantage in improving the total and axillary-only pathologic complete response rate over Lps-P. Although Nab-P can cause a higher incidence and severity of peripheral sensory neuropathy (PSN), most symptoms are temporary and reversible. In the Lps-P group, the proportion of patients with residual irreversible PSN is larger. Conclusion: Nab-P might be superior to Lps-P in NST of breast cancer.

Neoadjuvant systemic treatment (NST) is recommended for many patients with breast cancer before they undergo surgery to remove the cancer. This study retrospectively compared the efficacy and safety of two potential NST drugs, liposomal paclitaxel (Lps-P) and nanoparticle albumin-bound paclitaxel (Nab-P). Two hundred thirty-five patients participated in the study. These patients had been diagnosed with invasive breast cancer and were recommended NST with paclitaxel before surgery. The results showed that more participants who received Nab-P had no signs of cancer in their tissue samples from their breasts and armpit lymph nodes than participants who received Lps-P. Although Nab-P can cause a higher incidence and severity of peripheral sensory neuropathy (PSN), most symptoms are temporary and reversible. In conclusion, Nab-P might be superior to Lps-P for NST.

Systemic Manifestation of Miliary Tuberculosis in Patient With Advanced Diabetic Retinopathy Presenting With Electrolyte Imbalance, Seizures, and Adrenal Insufficiency.

Extra-pulmonary manifestations of tuberculosis can have diverse presentations depending on the affected organs. In this case report, we describe a case of a 50-year-old man of South Asian origin who presented with acute adrenal crisis on a background of undiagnosed miliary tuberculosis. Imaging after repeated episodes of adrenal crisis and seizures revealed bilaterally enlarged adrenals and cerebral tuberculomas, suggesting adrenal and central nervous system involvement. CT chest, abdomen and pelvis showed apical lung nodules and tree-in-bud appearance suggestive of tuberculosis. Due to high endogenous levels of adrenocorticotropic hormone and a flat response after a short synacthen test, a diagnosis of primary adrenal insufficiency secondary to tuberculosis infection was made. He remains well on anti-tuberculous chemotherapy, corticosteroids, and anti-epileptic medication. This case report exemplifies the unusual but life-threatening presentations of extra-pulmonary tuberculosis that may become increasingly common with immunosuppression because of the human immunodeficiency virus global epidemic and immunosuppressant therapies; therefore, a low index of suspicion is needed in these cases.

Peripheral and Autonomic Neuropathy Status of Young Patients With Type 1 Diabetes Mellitus at the Time of Transition From Pediatric Care to Adult-Oriented Diabetes Care.

Introduction: The prevalence of neuropathic lesions in young patients with type 1 diabetes mellitus (T1DM) at the time of transition from pediatric care to adult-oriented diabetes care is poorly studied. A comparative study with healthy volunteers to assess the possible neuropathic condition of this special population and to identify the potential early screening needs has not been performed yet. The results may provide important feedback to pediatric diabetes care and a remarkable baseline reference point for further follow up in adult diabetes care. Patients and Methods: Twenty-nine young patients with T1DM [age: 22.4 ± 2.9 years; HbA1c: 8.5 ± 2.1%, diabetes duration: 12.2 ± 5.8 years; (mean ± SD)] and 30 healthy volunteers (age: 21.5 ± 1.6 years; HbA1c: 5.3 ± 0.3%) were involved in the study. Autonomic function was assessed by standard cardiovascular reflex tests. Complex peripheral neuropathic testing was performed by Neurometer®, Neuropad®-test, Tiptherm®, Monofilament®, and Rydel-Seiffer tuning fork tests. Results: T1DM patients had significantly higher diastolic blood pressure than controls (80 ± 9 vs. 74 ± 8 mmHg, p < 0.01), but there was no significant difference in systolic blood pressure (127 ± 26 vs. 121 ± 13 mmHg). Cardiovascular reflex tests had not revealed any significant differences between the T1DM patients and controls. No significant differences with Neurometer®, Neuropad®-test, and Monofilament® were detected between the two groups. The vibrational sensing on the radius on both sides was significantly impaired in the T1DM group compared to the controls with Rydel-Seiffer tuning fork test (right: 7.5 ± 1.0 vs. 7.9 ± 0.3; left: 7.5 ± 0.9 vs. 7.9 ± 0.3, p < 0.05). The Tiptherm®-test also identified a significant impairment in T1DM patients (11 sensing failures vs. 1, p < 0.001). In addition, the neuropathic complaints were significantly more frequently present in the T1DM patient group than in the controls (9 vs. 0, p < 0.01). Conclusion: In this young T1DM population, cardiovascular autonomic neuropathy and cardiac morphological alterations could not be found. However, Rydel-Seiffer tuning fork and Tiptherm®-tests revealed peripheral sensory neurological impairments in young T1DM patients at the time of their transition to adult diabetes care.

Multicenter phase II clinical study of the efficiency and safety of capecitabine plus intermittent oxaliplatin with bevacizumab as first-line therapy in patients with metastatic colorectal cancer (VOICE trial).

PURPOSE: The aim of this phase II study was to evaluate the efficacy and safety of combination therapy with five-cycle CAPOX (capecitabine plus oxaliplatin) plus bevacizumab, followed by five-cycle maintenance therapy with capecitabine plus bevacizumab and reintroduction of CAPOX plus bevacizumab for five cycles, with a preplanned intermittent oxaliplatin strategy in metastatic colorectal cancer (mCRC). METHODS: Patients with untreated mCRC were administered CAPOX (130 mg/m2 oxaliplatin on day 1, 2000 mg/m2/day capecitabine on days 1-14, every 21 days) + bevacizumab (7.5 mg/kg) every 3 weeks for five cycles, maintenance treatment without oxaliplatin for five cycles, and CAPOX + bevacizumab reintroduction for five cycles or upon tumor progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the time to treatment failure (TTF), overall survival, response rate (RR), and safety. RESULTS: Forty-seven patients who fulfilled the inclusion criteria were enrolled in the evaluation of efficacy and safety. Median PFS was 14.1 months (95% confidence interval [CI], 8.6-19.5), and median TTF was 12.3 months (95% CI, 10.3-14.3). The objective RRs were 51.1% (24/47) during induction therapy, 58.3% (21/36) during maintenance therapy, and 63.6% (14/22) during reintroduction therapy. The frequency of patients with neutropenia, diarrhea, peripheral sensory neuropathy, venous thromboembolism, or grade ≥ 3 allergic reactions was 2.1%. CONCLUSION: CAPOX plus bevacizumab therapy with a preplanned intermittent oxaliplatin strategy consisting of brief five-cycle induction therapy, five-cycle maintenance therapy with capecitabine plus bevacizumab, and five-cycle reintroduction therapy consisting of CAPOX plus bevacizumab is safe and effective for mCRC patients. TRIAL REGISTRATION: UMIN ID: 000,005,732, date of registration: June 7, 2011.  https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000006695.

Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Relative Risk of Peripheral Neuropathy With Ado-Trastuzumab Emtansine (T-DM1) Compared to Taxane-Based Regimens in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Cancers: A Systematic Review and Meta-Analysis.

Background Peripheral neuropathy (PN), especially peripheral sensory neuropathy (PSN), is significant toxicity of taxanes, the most used class of microtubule inhibitors for human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Ado-trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate, consisting of trastuzumab and a microtubule inhibitor DM1, which has been approved for HER2-positive breast cancer. T-DM1 has also been found to cause significant PN, including PSN. Methods We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of PN and PSN associated with T-DM1 as compared to taxanes. A total of 1,857 patients were included in the analysis. The Cochran-Mantel-Haenszel method and the random-effects model were used to calculate the pooled risk ratio (RR) with a 95% confidence interval (CI) for all-grade and grade ≥3 PN and PSN.  Results The relative risks of all-grade PN and all-grade PSN were lower with T-DM1 compared to taxanes. The pooled RR of all-grade PN was 0.59, 95% CI: 0.39-0.89, P = 0.01, and the pooled RR of all-grade PSN was 0.58, 95% CI: 0.46-0.74, P < 0.0001. Conclusions Our meta-analysis demonstrated that T-DM1 is associated with a relatively lower risk of all-grade PN and PSN than the taxane-based regimens for HER2-positive cancers. It could be an area of consideration in selecting therapy for HER2-positive breast cancer patients at high risk of developing or having pre-existing PN and PSN.

Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer.

BACKGROUND AND AIM: The optimal standard second-line chemotherapy for metastatic pancreatic cancer (MPC) remains unclear. Here, we evaluated the efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with oral fluoropyrimidine S-1 as a second-line chemotherapy in patients with MPC. METHODS: We retrospectively reviewed 76 consecutive patients with metastatic pancreatic adenocarcinoma who underwent mFOLFIRINOX or S-1 treatment as a second-line chemotherapy after gemcitabine plus nab-paclitaxel (GnP) failure at our department between December 2014 and February 2019. RESULTS: Patients who underwent mFOLFIRINOX treatment exhibited significantly better objective response rates (ORRs) and progression-free survival (PFS) than S-1 (ORR, 20.0% vs 0%, P = 0.003; PFS, 3.7 vs 2.1 months, P = 0.010). Although baseline patient characteristics of age, performance status, and serum albumin levels differed significantly between the two groups, mFOLFIRINOX was identified as an independent factor of favorable PFS on multivariate analyses. Grade 3-4 neutropenia and peripheral sensory neuropathy occurred more frequently in the mFOLFIRINOX group. The median overall survival from the initiation of second-line chemotherapy was not significantly longer in the mFOLFIRINOX group than in the S1 group (8.5 vs 5.8 months, respectively; P = 0.213); however, the 8-month survival rate was significantly higher in the mFOLFIRINOX group (56.0% vs 27.5%, respectively; P = 0.030). CONCLUSIONS: mFOLFIRINOX as a second-line regimen contributed to favorable treatment outcomes, but induced more frequent adverse events than S-1. On multivariate analyses, mFOLFIRINOX was identified as an independent factor with favorable PFS, suggesting that mFOLFIRINOX could be a promising treatment option for patients with GnP failure.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Peripheral neuropathy and headache in cancer patients treated with immunotherapy and immuno-oncology combinations: the MOUSEION-02 study.

INTRODUCTION: Treatment-related neurotoxicity is a common side effect in cancer patients. However, few data are available regarding the risk of several neurotoxicities in patients treated with immune checkpoint inhibitors. AREAS COVERED: The MOUSEION-02 study is an up-to-date meta-analysis aimed at assessing the risk of peripheral neuropathy, peripheral sensory neuropathy, and headache in cancer patients receiving immunotherapy and immuno-oncology combinations. Patients receiving immunotherapy (as monotherapy or in combination with other anticancer agents) showed lower risk of all-grade peripheral neuropathy (RR, 0.50; 95% CI, 0.35-0.70) and all-grade peripheral sensory neuropathy (RR, 0.49; 95% CI, 0.30-0.79). Similarly, in patients treated with immune checkpoint inhibitor monotherapy, we observed lower risk of all-grade peripheral neuropathy (RR, 0.05; 95% CI, 0.03-0.10) and all-grade peripheral sensory neuropathy (RR, 0.11; 95% CI, 0.05-0.23). No differences were observed in terms of all-grade headache. EXPERT OPINION: Although the results of this meta-analysis should be interpreted with caution due to several issues, our study draws attention to immunotherapy-related neurotoxicity with the aim of maximizing clinical outcomes of cancer patients experiencing these not uncommon, and yet poorly studied, adverse events.

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study).

BACKGROUND: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer. PATIENTS AND METHODS: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS). RESULTS: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66). CONCLUSION: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN. TRIAL IDENTIFIER: UMIN000012535.

Is nab-paclitaxel better than conventional taxanes as neoadjuvant therapy for breast cancer? A meta-analysis.

OBJECTIVE: This study compared the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with conventional taxanes as neoadjuvant chemotherapy for breast cancer. METHODS: We searched the literature using PubMed, the Cochrane Library, and Web of Science from their inception to December 15, 2019 based on predetermined inclusion and exclusion criteria. The relevant studies compared pathologic complete response (pCR) and adverse event rates. RESULTS: The meta-analysis included five studies and 2335 patients. Compared with conventional taxanes, neoadjuvant chemotherapy with nab-paclitaxel was associated with a higher pCR rate (odds ratio [OR] = 1.39, 95% confidence interval [CI] = 1.16-1.67), especially among patients with triple-negative breast cancer or Ki67 indices of >20%. Pooled outcomes also revealed better event-free survival in the nab-paclitaxel group (hazard ratio = 0.69, 95% CI = 0.57-0.85). However, all-grade (OR = 2.17, 95% CI = 1.38-3.40) and grade ≥3 peripheral sensory neuropathy (OR = 3.92, 95% CI = 2.44-6.28) were more frequent in the nab-paclitaxel group. CONCLUSIONS: This meta-analysis implied that nab-paclitaxel more effectively improved pCR than conventional taxanes. Nab-paclitaxel may have greater benefits in patients with triple-negative breast cancer. However, additional attention is required for the early diagnosis and management of peripheral sensory neuropathy.

Phase II multi-institutional prospective trial of nab-paclitaxel as second-line chemotherapy for advanced gastric cancer refractory to fluoropyrimidine with modified dose reduction criteria (CCOG1303).

BACKGROUND: The aim of this study was to explore the efficacy and safety of nab-paclitaxel as second-line chemotherapy for advanced gastric cancer with modified dose reduction criteria by which the doses were manipulated earlier. METHODS: Gastric cancer patients who developed progression during the fluoropyrimidine-containing first-line chemotherapy were assigned to receive nab-paclitaxel (260 mg/m2) by triweekly administration. Dose reduction was regulated according to predefined toxicity criteria which included neutropenia less than 1000/mm3 and/or peripheral sensory neuropathy of grade 2 or more. The primary endpoint was progression-free survival. RESULTS: A total of 50 patients were enrolled, 47 of whom were eligible for efficacy analyses. The median number of treatment cycles and relative dose intensity given per patient was four (range 1-25), and 90% (range 60-100). Of total administration throughout the trial of 280 cycles, dose reduction was required in 50 cycles. The median progression-free survival was 3.5 months (95% confidence interval 2.5-4.4) that met the primary endpoint. The median overall survival was 9.0 months (95% confidence interval 6.8-11.8), overall response rate was 16% (95% confidence interval 2-30), and disease control rate was 72% (95% confidence interval 54-90). The median time to treatment failure was 3.5 months (95% confidence interval 2.5-4.4). Adverse events of grade 3 or worse included neutropenia in 49%, and peripheral sensory neuropathy in 11%. Febrile neutropenia occurred only in one patient (2%). CONCLUSION: The modified dose reduction criteria for triweekly administration of nab-paclitaxel resulted in decreased incidence of severe peripheral sensory neuropathy without decline in efficacy.

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation.

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.