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Objective: Oxaliplatin is a platinum-group chemotherapeutic agent commonly used in the treatment of colorectal cancer. In addition to hematological and gastrointestinal side effects, laryngopharyngeal dysesthesia associated with cold is reported as a rare side effect. In this article, seven cases with pharyngolaryngeal dysesthesia were presented and the diagnosis and treatment planning were reviewed in the light of literature findings., Material and Methods: Patient records of cancer patients with laryngopharyngeal dysesthesia were retrospectively analyzed between 2020 and 2023. Demographic characteristics, presenting complaints, vital signs, physical examination, and laboratory tests of the patients diagnosed with laryngopharyngeal dysesthesia were recorded., Results: Seven patients who had gastrointestinal malignancy and oxaliplatin chemotherapy were diagnosed with laryngopharyngeal dysesthesia. The symptoms most commonly developed due to cold weather. The symptoms of three patients had developed while receiving treatment, while four patients were admitted to emergency service after oxaliplatin infusion. The physical examinations revealed no pathological findings of the allergic reaction at presentation or during follow-up skin. Patients were monitored and nasal oxygen therapy was administered. A 5 mg intravenous infusion was given for anxiety symptoms in three patients. Patients were discharged after 4 hours of follow-up with resolution of all symptoms., Conclusion: Laryngopharyngeal dysesthesia should be kept in mind in patients treated with oxaliplatin and presenting with shortness of breath and a feeling of suffocation after cold exposure., Competing Interests: Declaration of Conflicting InterestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The recreational use of nitrous oxide (N2O) has increased in recent years with a noticeable surge in the incidence of nitrous oxide-related myeloneuropathy., Objectives: To raise awareness of increasing myeloneuropathy due to recreational nitrous oxide misuse in Israel., Methods: We conducted a case series documenting the clinical and investigative features of eight patients presenting with nitrous oxide-induced myeloneuropathy who were admitted to our departments., Results: Paresthesia was the chief complaint in all patients, with sensory gait ataxia being a common feature, which was often accompanied by Romberg's sign and mild lower limb weakness. Vitamin B12 levels were below the normal range in seven patients, accompanied by elevated homocysteine and methylmalonic acid levels. Magnetic resonance imaging scans revealed hyperintense signals in the dorsal columns of the cervical spine. All patients improved following vitamin B12 injections., Conclusions: Enhancing awareness, prompting the use of appropriate investigations, and advocating for timely treatment are needed to overcome the risks associated with nitrous oxide misuse.

Objective: This analysis of the first-line cohort of LASER201 study evaluated the efficacy and safety of lazertinib 240 mg as a frontline therapy for epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)., Methods: A total of 43 patients, with EGFR mutation-positive (Exon19Del, n = 24; L858R, n = 18; G719X, n = 1) locally advanced or metastatic NSCLC who had not previously received EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, received once-daily lazertinib 240 mg. EGFR mutation status was confirmed by local or central testing. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review. Secondary efficacy endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), tumor shrinkage, and overall survival (OS)., Results: At the primary data cut-off (DCO; January 8, 2021), the ORR was 70 % (95 % confidence interval [CI]: 56.0-83.5), DCR was 86 % (95 % CI: 75.7-96.4) and the median DoR was 23.5 (95 % CI: 12.5-not reached) months. The median PFS was 24.6 (95 % CI: 12.2-30.2) months. At the final DCO (March 30, 2023), the median OS was not estimable and the median follow-up duration for OS was 55.2 [95 % CI: 22.8-55.7] months. OS rates at 36 months and 54 months were 66 % (95 % CI: 47.5-79.3 %) and 55 % (95 % CI: 36.6-70.7 %), respectively. The most commonly reported TEAEs were rash (54 %), diarrhea (47 %), pruritus (35 %), and paresthesia (35 %). No drug-related rash or pruritus TEAEs of grade 3 or higher were reported. Diarrhea and paresthesia of grade 3 or higher were reported in 3 (7 %) and 1 (2 %) patients, respectively., Conclusion: This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Byoung Chul Cho has received research funding from MOGAM Institute, LG Chem, Oscotec Inc., Interpark Bio Convergence Corp, GI Innovation, GI Cell, Abion, Abbvie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Eli Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, BridgeBio Therapeutics, Yuhan Corporation, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center and Vertical Bio AG. He has received consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono Pharmaceutical, Onegene Biotechnology, Yuhan Corporation, Pfizer, Eli Lilly, GI Cell, Guardant Health, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint Medicines, RandBio, and Hanmi. He receives royalty from Champions Oncology, Crown Bioscience, Imagen and serves on the advisory board of Kanaph Therapeutics Inc., BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, and Oscotech Inc, J INTS BIO, Therapex, Gilead, Amgen. He was an invited speaker for ASCO, AstraZeneca, Guardant Health, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer. He is on the board of directors for J INTS BIO. He is an employee of Yonsei University Health System and the founder of the DAAN Biotherapeutics. He owns stocks of TheraCanVac Inc., Gencurix Inc., BridgeBio Therapeutics, Kanaph Therapeutics Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp., and J INTS BIO. Ji-Youn Han reports research funding from Pfizer, Takeda, ONO, Roche; consulting fees from AstraZeneca, Janssen, Amgen, Oncobix, Merck, Novartis, Abion, Takeda, J INTS BIO and honoraria for lectures from AstraZeneca, Janssen, Takeda, Merck, Yuhan Corporation, Novartis and Pfizer and payment for expert testimony from AstraZeneca He participated in Data Safety Monitoring Board for AstraZeneca, Janssen, J INTS BIO. Ki Hyeong Lee reports grants from Merck Serono. He has received consulting fees from MSD, Pfizer, Eli Lilly, Yuhan Corporation, AstraZeneca, BMS. Yun-Gyoo Lee reports honoraria for lectures from AstraZeneca, MSD, Lilly, Boehringer Ingelheim and Yuhan. He participated in Data Safety Monitoring Board or Advisory Board for BeiGene, Dakeda, Guardant Health, Yuhan, Ono and Novartis. Dong-Wan Kim reports research funding to his institution from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, BMS, BridgeBio Therapeutics, Chong Keun Dang, Daiichi-Sankyo, GSK, Hanmi, InnoN, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan Corporation, and honoraria from the Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society, Asian Thoracic Oncology Research Group. He reports travel support for attending meetings for the International Association for the Study of Lung Cancer, Asian Thoracic Oncology Research Group, Taiwan Lung Cancer Society. He provides medical writing assistance to Amgen, AstraZeneca, Boehringer-Ingelheim, BridgeBio Therapeutics, BMS, Chong Keun Dang, Daiichi-Sankyo, GSK, Pfizer, MSD, Merck, Merus, Novartis, Roche, Takeda, Yuhan Corporation. He participated in advisory boards for Amgen, AstraZeneca, BMS/Ono Pharmaceutical, Daiichi-Sankyo, GSK, Janssen, Meck, MSD, Pfizer, SK Biopharm, Takeda. He is on the Board of Directors for Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, and Korean Society of Medical Oncology. He is a scientific advisor for Health Insurance Review and Assessment Service, Republic of Korea. Eun Kyung Cho reports participation in data safety monitoring meeting for Yuhan Corporation for this clinical trial and received study drugs for conducting this clinical trial from Yuhan Corporation. Young Joo Min reports research funding from AstraZeneca, MSD, Merck, Ono Pharmaceutical, Yuhan Corporation, Amgen, Roche and honoraria from AstraZeneca, MSD, Merck, and Ono Pharmaceutical. Na Mi Lee, Jangyoung Wang, and Hyejoo Park are employees of Yuhan Corporation. Myung-Ju Ahn received consulting fees and research funding from AstraZeneca, Eli Lilly, MSD, Merck, Ono Pharmaceutical, Takeda, Yuhan Corporation, Amgen, Novartis, Roche, Alpha-Pharmaceuticals, and honoraria from AstraZeneca, Eli Lilly, MSD, Merck, Ono Pharmaceutical, Takeda, Yuhan Corporation, Amgen, Novartis and Roche. All other authors have no relevant relationships to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Subacute combined degeneration (SCD) is an acquired neurologic complication from prolonged vitamin B12 deficiency. As a result of dorsal and lateral spinal cord column degeneration, patients present with a range of neurological symptoms, including paresthesias, ataxia, and muscle weakness. Without prompt treatment, irreversible nerve damage occurs. Here we present a young man who developed progressive ascending paresthesias and lower extremity weakness after escalated nitrous oxide use. This case highlights the importance of considering SCD from nitrous oxide toxicity when patients present with progressive ataxia, paresthesia, and lower extremity weakness.

Background: Most oncologic patients receiving chemotherapy suffer from neuropathy, which not only severely affects quality of life but also may lead to chemotherapy dose reductions or even discontinuation of cancer therapy. Still, it is difficult to sufficiently control these symptoms with the currently available pharmacological treatments. High tone therapy was reported to be an effective option for neuropathies due to different etiologies. However, to date, there are no studies on high tone therapy in patients with chemotherapy-induced peripheral neuropathy., Methods: This randomized, double-blind, and placebo-controlled two-center study was conducted at the Departments of Physical and Rehabilitation Medicine at the Clinics Donaustadt and Ottakring, Vienna, Austria. Patients with histologically verified colorectal carcinoma treated with a platin derivate and neuropathic symptoms were invited to participate. High tone therapy took place in a home-based setting using the HiToP 191 PNP ® or placebo device for three weeks. Neuropathic symptoms and quality of life were assessed via questionnaires. After the follow-up examination, an opt-in was offered to the patients in the placebo group in terms of an open-label treatment with a verum HiToP PNP ® device. In addition, patients with chemotherapy-induced peripheral neuropathy due to various malignant diseases were treated in an open-label setting reflecting a clinical application observation. These patients are reported as a separate group., Results: In the verum group, there was a significant reduction of paresthesias and mental stress due to paresthesias from baseline until end of therapy, compared to placebo. These findings were observed in the opt-in subgroup, as well. In the open-label clinical application observation group, intensity and mental stress due to paresthesia, pain, cramps, and intensity of tightness/pressure were significantly lower at the end of therapy, compared to baseline., Conclusions: Home-based high tone therapy brought about a significant alleviation in paresthesias and mental stress due to paresthesias in the verum but not the placebo group. In the clinical application observation, a significant alleviation in several further neuropathic symptoms was seen., Trial Registration: This study was registered at clinicaltrials.gov (NCT06048471, 03/02/2020)., (© 2024. The Author(s).)

Introduction: Oxaliplatin is a platinum containing alkylating agent commonly used in the management of colorectal cancers. The most common dose-limiting toxicity of oxaliplatin is peripheral neuropathy, which can be severe enough to cause treatment discontinuation. We present a case of dysarthria and laryngopharyngeal dysesthesia (LPD) that developed during the first dose of oxaliplatin, which showed dose-dependent reduction in severity in subsequent cycles., Case Report: A 52-year-old female patient with adenocarcinoma of rectum (pT4N2M0) was prescribed oxaliplatin (130 mg/m 2 ) and capecitabine(2000mg/m 2 ). She developed heaviness in the tongue, slurred speech, jaw pain, perioral paresthesia within 30 min after the end of 3 h infusion of oxaliplatin in the first cycle. The symptoms subsided without any sequelae in two days. However, in the subsequent cycles as the dose of the oxaliplatin was reduced, similar symptoms reappeared but were of reduced in severity. No dysesthesia symptoms were observed in the 4th cycle when the oxaliplatin was administered at 85 mg/m 2 ., Management and Outcome: As and when the patient developed symptoms - slurred speech, jaw pain during the first three cycles, she was managed with inj. Hydrocortisone (100 mg i.v.) and one ampoule of pheniramine (45 mg i.v.)., Discussion: Occurrence of laryngopharyngeal dysesthesia due to oxaliplatin does not warrant drug withdrawal, dose titration can be helpful, thereby preventing the drug withdrawal for the patient management.

Background: This is an updated version of the Cochrane Review published in 2015. Epilepsy is a chronic neurological disorder, characterised by recurring, unprovoked seizures. Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with drug-resistant epilepsy. VNS consists of chronic, intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator., Objectives: To evaluate the efficacy and tolerability of VNS when used as add-on treatment for people with drug-resistant focal epilepsy., Search Methods: For this update, we searched the Cochrane Register of Studies (CRS), and MEDLINE Ovid on 3 March 2022. We imposed no language restrictions. CRS Web includes randomised or quasi-randomised controlled trials from the Specialised Registers of Cochrane Review Groups, including Epilepsy, CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform., Selection Criteria: We considered parallel or cross-over, randomised, double-blind, controlled trials of VNS as add-on treatment, which compared high- and low-level stimulation (including three different stimulation paradigms: rapid, mild, and slow duty-cycle), and VNS stimulation versus no stimulation, or a different intervention. We considered adults or children with drug-resistant focal seizures who were either not eligible for surgery, or who had failed surgery., Data Collection and Analysis: We followed standard Cochrane methods, assessing the following outcomes: 1. 50% or greater reduction in seizure frequency 2. Treatment withdrawal (any reason) 3. Adverse effects 4. Quality of life (QoL) 5. Cognition 6. Mood, Main Results: We did not identify any new studies for this update, therefore, the conclusions are unchanged. We included the five randomised controlled trials (RCT) from the last update, with a total of 439 participants. The baseline phase ranged from 4 to 12 weeks, and double-blind treatment phases from 12 to 20 weeks. We rated two studies at an overall low risk of bias, and three at an overall unclear risk of bias, due to lack of reported information about study design. Effective blinding of studies of VNS is difficult, due to the frequency of stimulation-related side effects, such as voice alteration. The risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.73 (95% confidence interval (CI) 1.13 to 2.64; 4 RCTs, 373 participants; moderate-certainty evidence), showing that high frequency VNS was over one and a half times more effective than low frequency VNS. The RR for treatment withdrawal was 2.56 (95% CI 0.51 to 12.71; 4 RCTs, 375 participants; low-certainty evidence). Results for the top five reported adverse events were: hoarseness RR 2.17 (99% CI 1.49 to 3.17; 3 RCTs, 330 participants; moderate-certainty evidence); cough RR 1.09 (99% CI 0.74 to 1.62; 3 RCTs, 334 participants; moderate-certainty evidence); dyspnoea RR 2.45 (99% CI 1.07 to 5.60; 3 RCTs, 312 participants; low-certainty evidence); pain RR 1.01 (99% CI 0.60 to 1.68; 2 RCTs; 312 participants; moderate-certainty evidence); paraesthesia 0.78 (99% CI 0.39 to 1.53; 2 RCTs, 312 participants; moderate-certainty evidence). Results from two studies (312 participants) showed that a small number of favourable QOL effects were associated with VNS stimulation, but results were inconclusive between high- and low-level stimulation groups. One study (198 participants) found inconclusive results between high- and low-level stimulation for cognition on all measures used. One study (114 participants) found the majority of participants showed an improvement in mood on the Montgomery-Åsberg Depression Rating Scale compared to baseline, but results between high- and low-level stimulation were inconclusive. We found no important heterogeneity between studies for any of the outcomes., Authors' Conclusions: VNS for focal seizures appears to be an effective and well-tolerated treatment. Results of the overall efficacy analysis show that high-level stimulation reduced the frequency of seizures better than low-level stimulation. There were very few withdrawals, which suggests that VNS is well tolerated. Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnoea, pain, paraesthesia, nausea, and headache, with hoarseness and dyspnoea more likely to occur with high-level stimulation than low-level stimulation. However, the evidence for these outcomes is limited, and of moderate to low certainty. Further high-quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug-resistant focal seizures., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Several neurologic complications have been reported in close temporal association with both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and following vaccination against SARS-CoV-2. Specifically, several cases of Guillain-Barré syndrome (GBS) have been reported in temporal relationship with COVID-19 vaccination, with two small case series describing a specific phenotype with bifacial weakness and paresthesia in the limbs., Methods: We retrospectively collected patients who developed a new-onset neuromuscular disorder in the first 6 weeks after receiving a COVID-19 vaccine (either first or second dose). The patients were collected from one tertiary care centre and one secondary care centre from February to July 2021., Results: We report eight patients who developed phenotypically diverse neuromuscular disorders in the weeks following COVID-19 vaccination, with a presumed immune-mediated etiology. In our case series, we report three patients with classical GBS, one patient with bifacial weakness with paresthesia variant of GBS, two patients with subacute-onset chronic inflammatory demyelinating polyneuropathy (CIDP), one patient with brachial plexopathy and one patient with subacute axonal sensorimotor polyneuropathy., Conclusions: New-onset neuromuscular disorders with onset in the weeks after COVID-19 vaccination can include diverse phenotypes. A causal relationship between these disorders and the vaccine cannot be proven at present, and further epidemiological studies are needed to further investigate this association., (© 2022. The Author(s).)

Aim: The aim of this systematic review is to accumulate the available evidence on management approaches as well as factors resulting in the development of paresthesia due to sealer extrusion., Materials and Methods: A literature search was conducted in MEDLINE, EMBASE, and Web of Science and Cochrane Central Register of Controlled Trials up to March 2022, accompanied by a manual search of journals, textbooks, and grey literature. Inclusion criteria were studies on adult patients experiencing paresthesia related to sealer extrusion. The quality of included studies was appraised using a custom set of criteria., Results: A total of 102 publications were identified, and 9 of them fulfilled the inclusion criteria. All of the included studies were case reports describing a total of 10 patients. The predetermined data were independently extracted and evaluated by four reviewers., Conclusion: Because of the low amount and quality of available evidence, conclusions on the factors resulting in paresthesia due to sealer extrusion cannot be drawn. The management approach remains empirical. The need for prospective studies is highlighted. The future case reports in endodontics ought to be reported in a uniform and methodological way., Clinical Significance: Paresthesia as a result of endodontic sealer extrusion is an alarming complication of endodontic treatment that general dentists need to be aware of. Although worrying, for both clinician and patient, it is a manageable complication and early diagnosis is important; thus, dentists need to be educated on this topic.

Introduction: Vortioxetine, a multimodal serotonergic drug, is widely used as treatment for major depressive disorder. Although on the market since late 2013, the data of the relative safety of vortioxetine, especially compared to selective serotonin reuptake inhibitors, are still scarce., Objective: The aim of this study was to explore the adverse event reporting pattern of vortioxetine through a cluster analysis. Furthermore, to compare the adverse event reporting pattern for vortioxetine with that of the selective serotonin reuptake inhibitors., Methods: Individual case safety reports for vortioxetine in VigiBase up to 1 November, 2019 were subjected to consensus clustering, to identify and describe natural groupings of reports based on their reported adverse events. A vigiPoint exploratory analysis compared vortioxetine to the selective serotonin reuptake inhibitors in terms of relative frequencies for a wide range of covariates, including patient sex and age, reported drugs and adverse events, and reporting country. Important differences were identified using odds ratios with adaptive statistical shrinkage., Results: Thirty-six clusters containing at least five reports were identified and analysed. The two largest clusters included 48% of the vortioxetine reports and appeared to represent gastrointestinal adverse events and hypersensitivity adverse events. Other distinct clusters were related to, respectively, fatigue, aggression/suicidality, convulsion, medication errors, arthralgia/myalgia, increased weight, paraesthesia and anticholinergic effects. Some of these clusters are not labelled for vortioxetine, such as arthralgia/myalgia and paraesthesia, but are known adverse events for selective serotonin reuptake inhibitors. A vigiPoint analysis revealed a higher proportion of reports from consumers and non-health professionals for vortioxetine as well as higher relative reporting rates of gastrointestinal symptoms, pruritus and mood-related symptoms, consistent with the cluster analysis., Conclusions: A pattern of co-reported adverse events that is consistent with labelled adverse events for vortioxetine and the safety profile for selective serotonin reuptake inhibitors in general was revealed. Clusters of unlabelled adverse events were identified that reflect clinical entities that might represent signals of previously unknown adverse events. More extensive analyses of spontaneous reports may help to further understand the reporting pattern of adverse events., (© 2022. The Author(s).)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Osteoarthritis (OA) is the most common joint disease and leading cause of pain and disability in the elderly population. Most guidelines recommend the use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids for the non-operative treatment of OA. Monoclonal nerve growth factor (NGF) antibodies are new drugs with the potential to provide pain relief and functional improvement in OA. We compared the efficacy (pain reduction and functional improvement), and safety of monoclonal NGF antibodies with NSAIDs and opioids in the treatment of OA with a Bayesian network meta-analysis., Results: 38 articles, comprising 41 trials and 20489 patients with OA were included. Overall from the network meta-analysis, anti-NGFs were the most effective drugs for pain relief (Standardized Mean Difference or SMD compared with placebo 4.25, 95% CI 2.87 to 5.63, Surface Under the Cumulative RAnking curve or SUCRA=93.7%) and for functional improvement (SMD 4.90, 95% CI 3.46 to 6.33, SUCRA=98.3%). Although anti-NGFs were associated with higher risk of peripheral sensation abnormality (paresthesia and pruritus), they were not associated with higher risk of other AEs (headaches and nausea) or with higher withdrawal rates related to AEs., Conclusions: Monoclonal NGF antibodies provide significantly greater pain relief and functional improvement in OA compared to NSAIDs and opioids. Monoclonal NGF antibodies are not associated with severe AEs. More studies are needed to confirm these findings., Methods: PubMed, CNKI, Web of Science, Scopus, Embase and Cochrane Library databases were searched for relevant studies (OA treated with anti-NGFs, opioids, selective COX-2 inhibitors or NSAIDs) published between January 1999 to January 2020. Bayesian network and conventional meta-analyses were conducted. Pain relief, functional improvement and AEs were assessed.

Purpose: This study aims to (1) examine the prevalence of painful versus non-painful chemotherapy-induced peripheral neuropathy (CIPN) among long-term colorectal cancer (CRC) survivors, (2) identify sociodemographic, clinical, and psychological factors associated with painful and non-painful CIPN, and (3) examine the associations of painful CIPN with health-related quality of life (HRQoL) in comparison with non-painful CIPN, i.e., numbness/tingling., Methods: All CRC survivors diagnosed between 2000 and 2009 as registered by the population-based Netherlands Cancer Registry (Eindhoven region) were eligible for participation. Chemotherapy-treated survivors (n = 477) completed questions on CIPN (EORTC QLQ-CIPN20) and HRQoL (EORTC QLQ-C30)., Results: Painful CIPN was reported by 9% (n = 45) of survivors and non-painful CIPN was reported by 22% (n = 103). Time since diagnosis was related to painful CIPN, and time since diagnosis, a higher disease stage, osteoarthritis, and more anxiety symptoms were related to non-painful CIPN. Finally, survivors with painful CIPN reported a worse global quality of life and worse physical, role, cognitive, and social functioning compared to survivors with non-painful CIPN and those without any sensory CIPN. No differences were found between survivors with non-painful CIPN and those without sensory CIPN., Conclusions: It seems that painful CIPN must be distinguished from non-painful CIPN, as only painful CIPN was related to a worse HRQoL. Future research is needed to examine whether painful CIPN must be distinguished from non-painful CIPN regarding predictors, mechanisms, and treatment.

Palmar plantar erythrodysesthesia (PPE) is a commonly reported skin toxicity of chemotherapeutic agents that significantly affects patients' quality of life. PPE is described as inflammation, swelling, and even cracks and ulcers in the skin of palms and soles of the feet. Conventional treatment includes topical creams, analgesics, or corticosteroids. However, serious cases are not responding to these medications. PPE has been reported to cause drug cessation or dose reduction if not properly treated. Sildenafil citrate (SC) has a well-documented activity in wound healing through improving blood supply to the affected area. However, SC has poor physicochemical properties limiting its transdermal permeation and deposition. This research endeavored to elaborate novel vesicular system with natural components, phospholipids and oleic acid, loaded with sildenafil citrate for topical management of PPE. Sildenafil-loaded oleosomes were prepared using modified ethanol injection method. Optimized oleosomes had nanometric particle size (157.6 nm), negative zeta potential (- 85.2 mv), and high entrapment efficiency (95.56%). Ex vivo studies on human skin revealed that oleosomes displayed 2.3-folds higher permeation and 4.5-folds more deposition through the human skin compared to drug suspension. Results endorsed SC oleosomes as suitable topical treatment of PPE providing ameliorated sildenafil permeability in addition to acting as a reservoir for gradual release of the drug. Graphical abstract.

Purpose: The incidence and time of onset of acute chemotherapy-induced peripheral neuropathy (ACIPN) caused by oxaliplatin remain unclarified. Hence, we investigated the prevalence, onset time, and location of ACIPN symptoms in patients with colorectal cancer (CRC) receiving oxaliplatin without cold stimulation., Methods: The study cohort comprised patients receiving oxaliplatin for CRC at our hospital between April 2017 and August 2018. Patients were instructed not to touch and/or drink cold things and were monitored for ACIPN symptoms in the hospital for 24 h after chemotherapy. ACIPN symptoms that appeared > 24 h after chemotherapy were recorded at the next visit. Symptom appearance time was defined as the duration from the administration of chemotherapy until the appearance of paresthesia classified as grade 1 using the Common Terminology Criteria for Adverse Events., Results: Forty-five patients received chemotherapy, comprising 23 men and 22 women, aged 67 years (29-88 years). The location of ACIPN was the fingers in 55.6% of cases, pharynx in 26.7%, perioral region in 24.4%, and feet in 6.7%. The average duration from oxaliplatin administration to symptom development was 182 min (range 62-443 min) for the fingers, 291 min (176-432 min) for the pharynx, 311 min (127-494 min) for the perioral region, and 297 min (234-355 min) for the feet. Pharyngeal symptoms were more common in patients older than 65 years than in those younger than 65 years., Conclusions: The incidence and time of the onset of ACIPN caused by oxaliplatin varies between the body and regions.

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely hyposalivation, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, reactive keratosis, dysesthesia, osteonecrosis, infection, angioedema, and malignancy., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up., Methods: This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient's Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study., Results: From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE -0.62±0.18, p=0.0006), WOMAC Physical Function (-0.71±0.17, p<0.0001) and PGA-OA (-0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%-7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo., Conclusion: Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups., Trial Registration Number: NCT02709486., Competing Interests: Competing interests: FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, outside the submitted work. FJB reports grants and personal fees from Pfizer, and grants from AbbVie, UCB, Bristol-Meyers Squibb, Roche, Servier, Bioiberica, Sanofi, Grunenthal, GlaxoSmithKline, Lilly, Janssen, Regeneron, Amgen and TRB Chemedica, outside the submitted work. AG reports personal fees from Merck Serono, Pfizer, TissueGene, Roche, Galapagos, AstraZeneca, personal fees from Boston Imaging Core Lab, LLC, outside the submitted work. KM reports personal fees from Merck, Pfizer, Lilly, Ayumi, Mundi Pharma, Janssen, Nippon Zok, outside the submitted work. LV reports personal fees and other from Eli Lilly and Company, outside the submitted work. TY reports personal fees and other from Pfizer outside the submitted work. RJ reports personal fees and other from Pfizer outside the submitted work. WC reports personal fees and other from Pfizer outside the submitted work. MTB reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). CRW reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). KMV reports personal fees and other from Pfizer outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC-ND. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the effectiveness and tolerability of brivaracetam (BRV) in a refractory epilepsy population in an outpatient clinical setting., Methods: Retrospective medical information system review and self-report questionnaire for all patients treated with BRV until the end of 2017., Results: Thirty-eight patients were included, 73.7% female and mean age 36.2. The mean number of antiepileptic drugs (AEDs) for previous use was 8.9, and for current use was 2.5. Mean seizure frequency in the last 3 months was 12 per month. At 3, 6, 12, and 15 months, the 50% responder rates were 36.1%, 32%, 41.2%, and 45.5%, respectively. Patients took BRV for a median duration of 8.25 months, ranging from 7 days to 60 months. Retention rate was 75.0%, 72.0%, 59.2%, and 47.9% at 3, 6, 12, and 15 months, respectively. Overall, the main reasons for discontinuation were adverse events (AEs) (52.3%), lack of efficacy (35.3%), or both (11.8%). The rate of total AEs was 60.5% according to medical records and 85.7% according to questionnaire, including mostly tiredness, psychiatric, and memory complaints. Psychiatric side effects occurred in 31.6% according to medical records and 47.4% according to questionnaire results, which is higher than previously reported and persisted throughout the study period., Conclusions: BRV appears to be a useful and safe add-on treatment, even in a very refractory group of patients. In this real-life clinical setting, psychiatric AEs were found at a higher rate than previously published.

Objectives: Melatonin is an endogenous hormone, which regulates circadian rhythms and promotes sleep. In recent years, several randomised controlled trials examining the prophylactic use of melatonin to prevent delirium were published with conflicting findings. The primary aim of this review was to determine the effect of melatonin on the incidence of delirium in hospitalised patients., Data Sources: MEDLINE, EMBASE and CENTRAL were systematically searched from their inception until December 2018., Review Methods: All randomised clinical trials were included., Results: Sixteen trials (1634 patients) were included in this meta-analysis. Incidence of delirium was not significantly lower in patients who received melatonin, with an odd ratio, OR (95%Cl) of 0.55 (0.24-1.26); ρ = 0.16, certainty of evidence = low, trial sequential analysis = inconclusive. However, patients who randomised to melatonin had a significantly shorter length of stay in intensive care units, with a mean difference, MD (95%CI) of -1.84 days (-2.46, -1.21); ρ < 0.001. No differences were demonstrated in the need for physical restraints (OR 95%Cl 0.65; 0.31-1.37; ρ = 0.26) and the requirement of sedative agents (OR 95%Cl 0.86; 0.48-1.55; ρ = 0.62)., Conclusions: In summary, the results of this meta-analysis of sixteen trials neither support nor oppose the use of melatonin in the prevention of delirium of hospitalised patients. We identified high heterogeneity across all the included trials and low certainty of evidence with potential type II error. Future multi-centre, adequately powered randomised controlled trials are warranted to provide more certainty on the use of melatonin for the prevention of delirium., Prospero: CRD42019123546., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: In recent years, there has been a sharp increase in the number of patients with neurological disorders associated with recreational use of nitrous oxide (N 2 O) in China. Here, we summarize the clinical characteristics of patients with neurological disorders associated with N 2 O abuse diagnosed in our Hospital. Further, we conducted a literature search on recent cases reported in mainland China to improve the awareness of the outbreak of neurological disorders associated with N 2 O abuse., Methods: We retrospectively collected data of patients diagnosed with neurological disorders associated with recreational use of N 2 O in Shengjing Hospital of China Medical University from January 2018 to June 2019, and performed a literature search using the "nitrous oxide" and "neurological disorder" as keywords in the Chinese literature databases of WANFANG and CNKI and the English literature databases of Pubmed and Web of Science RESULTS: We enrolled 43 patients (average age: 21.9 ± 3.3 years). The main clinical manifestations were weakness and paresthesia in the four extremities and unsteady gait. Further, most patients showed significantly lower levels of serum vitamin B12 (169.4 ± 79.1 pg/mL) and increased homocysteine levels (78.1 ± 32.2 μmol/L). MRI of the spinal cord showed longitudinal high T2 signal lesions in the dorsal spinal cord in some patients. Moreover, electromyography showed sensory and motor nerve axonal damage combined with demyelination, which was relatively more severe in the lower limbs. There was rapid improvement of the symptoms after treatment with intramuscular injections of vitamin B12 and the overall prognosis was good. The literature search indicated that the number of published papers and related patients showed a rapid annual increase since the first Chinese case reported in 2016 CONCLUSION: Recreational use of N 2 O is an emerging public health problem in China that needs prompt action from the society and government. Early diagnosis and treatment allow a good overall prognosis.

Background: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting., Methods: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment., Findings: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related., Interpretation: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories., Funding: Bristol-Myers Squibb and ONO Pharmaceutical., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

There is ongoing debate about the best neo-adjuvant strategy for localised resectable oesophageal cancer, however chemotherapy is often employed. Both oesophageal cancer and cisplatin carry an increased risk of thrombosis. Here, we look at an unusual finding in a previously fit woman who presented following neo-adjuvant chemotherapy for resectable oesophageal cancer with increasing difficulty in walking and lower limb paraesthesia. This case looks particularly at the diagnostic challenge and concerns raised in a patient undergoing radical treatment as well as the challenge of complications secondary to treatment with chemotherapy. Willingness to reassess and revisit is a vital part of the diagnostic process. Vascular complications of a disease can be notorious to diagnose and, as in this case can mimic arguably more logical diagnoses. Cancer care provides the unique challenge of investigating unusual presentations related both to disease and treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

A 69-year-old man with a medical history of hypertension and diabetes presented with altered mental status once he returned from a 14-day Alaskan cruise. An extensive workup for stroke was negative. His physical examination was normal without any focal motor deficits, but he had developed memory loss and paresthesia. He admitted to eating a lot of fish when he was in Alaska. The whole-blood mercury level was found to be elevated. He was managed conservatively and his symptoms resolved completely in a few days. This led to a diagnosis of organic mercury toxicity., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT)., Material and Methods: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17)., Results: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy., Conclusions: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Aim of the Study: The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting., Patients and Methods: Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%., Results: Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively., Conclusion: Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step., Trial Registration: Clinicaltrials.gov, NCT01674309., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real-life use conditions. A simple roll-on formulation containing an extremely rare isotope of aluminum ( 26 Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26 Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26 Al citrate was administered intravenously (i.v.) to estimate fraction absorbed (F abs ) following topical delivery. In blood samples after i.v. administration, 26 Al was readily detected (mean area under the curve (AUC) = 1,273 ± 466 hours×fg/mL). Conversely, all blood samples following topical application were below the lower limit of quantitation (LLOQ; 0.12 fg/mL), except two samples (0.13 and 0.14 fg/mL); a maximal AUC was based on LLOQs. The aluminum was above the LLOQ (61 ag/mL) in 31% of urine samples. From the urinary excretion data, a conservative estimated range for dermal F abs of 0.002-0.06% was calculated, with a mean estimate of 0.0094%., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

In cases of criminal thallium poisoning, forensic investigation is required to identify the amount and time of thallium exposure. Usually, blood and urine thallium levels are respectively used as biomarkers. Additionally, hair has the unique potential to reveal retrospective information. Although several studies have attempted to clarify how thallium is distributed in hair after thallium poisoning, none have evaluated the time course of changing thallium distribution. We investigated changes in the distribution of thallium in hair at different time points after exposure in five criminal thallotoxicosis patients. Scalp hair samples were collected twice, at 2.6 and 4.2-4.5months after an exposure incident by police. Results of our segmented analysis, a considerable amount of thallium was detected in almost all hair sample segments. The thallium exposure date estimated from both hair sample collections matched the actual exposure date. We found that determination of thallium amounts in hair samples divided into consecutive segments provides valuable information about exposure period even if a considerable time passes after exposure. Moreover, when estimating the amount of thallium exposure from a scalp hair sample, it is necessary to pay sufficient attention to individual differences in its decrease from hair., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Endodontic therapy is a routinely practised clinical procedure with few reported complications but, as a bleaching agent, inadvertent spillage of sodium hypochlorite beyond the root canal system may result in extensive soft tissue or nerve damage, and even airway compromise. Although very rare, complications arising from hypochlorite extrusion beyond the root apex are described. NaOCl causes oxidation of protein and lipid membrane and causes necrosis, hemolysis and dermal ulcerations (2-4). Neurological complication are very rare. Paraesthesia and anaesthesia may affect the mental, inferior dental and infra-orbital branches of the trigeminal nerve and normal sensation may take many months to  completely resolve (6, 7). Nerve damage (the buccal branch) was described in 2005 by Witton et al. (8) and patients exhibited a loss of the naso-labial groove and a down turning of the angle of the mouth and the motor function was regained after several months. We present a case in which the extrusion of NaOCl solution during endodontic therapy led to important destructive effects on soft tissues and nerves. The arisen medico legal issues are discussed.

Objective: Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity., Methods: Questionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination)., Results: The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m 2 with a half-life of about 10d., Conclusions: Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study., Significance: Nerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity., (Copyright © 2017 International Federation of Clinical Neurophysiology. All rights reserved.)

Introduction: Topiramate is a well-known anticonvulsant drug with a broad spectrum of actions. It has been proposed in the treatment of several types of epileptic seizures both in monotherapy and in add-on. Its usage has been extended to other disorders including migraine, essential tremor, obesity, alcohol and drug addiction. The most frequent side-effects of topiramate include dizziness, somnolence, insomnia, and ataxia. Paraesthesia, metabolic acidosis, kidney stones, hypohidrosis, cognitive impairment and eye symptoms have also been reported., Case Report: We report on a girl affected by epileptic seizures treated with levetiracetam for five years. Due to worsening of the seizures, the dosage of this drug was increased and afterwards lowdosage topiramate was initiated. After 12 days from the introduction of topiramate, the girl began to present neurologic signs including limbs rigidity, pain, incoordination and flexed fingers. Gradual withdrawn of the topiramate resulted in progressive resolution of the symptomatology. This clinical episode could represent a probable topiramate-related side effect (Naranjo score 5), never reported before in this form., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis., Objective: The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations., Methods: Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires., Results: The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells., Limitations: The study was small and drug treatment was for a short duration (4 weeks)., Conclusion: This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.

Background: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas., Methods: In 28 healthy volunteers, capsaicin (100 μg/0.1 mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10 mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10 cm). Contralateral injection of 0.1 mL isotonic saline served as a control., Results: Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p < 0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0 ± 2.6 cm 10 min in normal skin to 10.3 ± 1.8 cm 10 min in allodynic skin (p < 0.01) for cowhage and -56% from 20.0 ± 3.5 cm 10 min in normal skin to 8.8 ± 2.3 cm 10 min allodynic skin (p < 0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli., Conclusions: Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain., Significance: This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients., (© 2017 European Pain Federation - EFIC®.)

Background: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions., Objectives: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search., Selection Criteria: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI., Data Collection and Analysis: We used standard methodological procedures as expected by Cochrane., Main Results: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I 2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I 2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I 2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality., Authors' Conclusions: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

Hydroxychloroquine is an oral antimalarial medication commonly used off-label for a variety of rheumatological conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and dermatomyositis. We present a case of a 64-year-old woman who presented with acute onset headache, bilateral tinnitus, and left-sided facial numbness and tingling in the setting of accidentally overdosing on hydroxychloroquine. By the next morning, the patient began to experience worsening in the tingling sensation and it eventually spread to her left arm, thigh and distal extremities. The patient also complained of new onset blurring of her peripheral vision and feeling 'off balance.' Despite a complete neurological and ophthalmological work-up with unremarkable imaging and blood work, the patient has had no improvement in her tinnitus, left-sided paresthesias, visual disturbance or ataxia. This is a unique case of hydroxychloroquine overdose resulting in permanent neurotoxic vestibulopathy., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Which medication, if any, to use to prevent the headache of pediatric migraine has not been established., Methods: We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment., Results: A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt., Conclusions: There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).

Intrathecal catheter devices using a catheter-over-needle design and softer flexible material have been introduced to clinical practice with the aim of reducing some of the complications such as postdural puncture headaches and paresthesias seen with previous versions of intrathecal catheters. We present a case series of 5 cesarean deliveries using the Wiley Spinal intrathecal system (Epimed, Johnstown, New York), which was recently approved by the US Food and Drug Administration. The intrathecal catheter system consists of a flexible 23-gauge intrathecal cannula over a 27-gauge pencil-point spinal needle. The placement of the intrathecal catheter was successful in all 5 cases; however, paresthesias in 3 cases and postdural puncture headaches in 2 cases complicated the placement and use of the device. Although the unique catheter-over-needle design facilitates the use of smaller-gauge spinal needles for dural puncture and larger-gauge catheters for medication administration, this case series using the Wiley Spinal suggests that paresthesias and postdural puncture headaches may still limit its widespread utilization. Future studies are needed to determine the true incidence of complications and to determine the role of continuous spinal anesthesia in the obstetric population.

We analyzed adverse events in a clinical phase I trial to assess dose-dependent metabolic effects of St. John's wort co-administered with rifampicin in 12 healthy volunteers. Within 3-6 days after increasing the St. John's wort dose from 300 to 600 mg TID, five of six female participants developed ambient temperature-dependent allodynia and paresthesia in sun-exposed areas (back of the hands and perioral and nasal area). Aggravation of symptoms resulted in persistence of paresthesia and phototoxic erythrodermia. None of the male participants showed any of these effects. Gender, duration of treatment, dose, and solar exposure seem to be extrinsic and host factors facilitating St. John's wort-induced neuropathy. The risk to develop this adverse effect is almost exclusively present in women.

Purpose: Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data., Methods: This study was a narrative review of the literature and unpublished data., Findings: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations., Implications: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)