Lazertinib as a frontline treatment in patients with EGFR-mutated advanced non-small cell lung cancer: Long-term follow-up results from LASER201.

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.

Leprosy with type 1 reaction in a patient from Ontario, Canada without recent travel misdiagnosed as vasculitic neuropathy: a case report.

BACKGROUND: Leprosy is rare within non-endemic countries such as Canada, where cases are almost exclusively imported from endemic regions, often presenting after an incubation period of as many as 20 years. Due to its rarity and prolonged incubation period, diagnosis is often delayed, which may result in neurologic impairment prior to the initiation of treatment. In this report we describe a case that is novel in its incubation period, which is the longest reported to-date and may have contributed to diagnostic delay. The case also uniquely demonstrates the challenges of distinguishing leprosy reactions from new rheumatologic manifestations in a patient with established autoimmune disease. CASE PRESENTATION: We describe an 84-year-old male patient with rheumatoid arthritis on methotrexate and hydroxychloroquine, with no travel history outside Canada for 56 years, who presented in 2019 with new-onset paresthesias and rash. His paresthesias persisted despite a short course of prednisone, and his rash recurred after initial improvement. He underwent skin biopsy in May 2021, which eventually led to the diagnosis of leprosy. He was diagnosed with type 1 reaction and was started on rifampin, dapsone, clofazimine and prednisone, with which his rash resolved but his neurologic impairment remained. CONCLUSION: This case report serves to highlight the potential for leprosy to present after markedly prolonged incubation periods. This is especially relevant in non-endemic countries that is home to an aging demographic of individuals who migrated decades ago from endemic countries. The importance of this concept is emphasized by the persistent neurologic impairment suffered by our case due to untreated type 1 reaction. We also demonstrate the necessity of skin biopsy in distinguishing this diagnosis from other autoimmune mimics in a patient with known autoimmune disease.

5-fluorouacil in the treatment of odontogenic keratocysts-incidence of recurrence and inferior alveolar nerve paresthesia: a systematic review.

PURPOSE: To evaluate the recurrence rate of odontogenic keratocyst (OKC) after treatment with 5-fluoracil as an adjunctive therapy and to evaluate, as well, the efficacy of this medication in reducing the incidence of inferior alveolar nerve paresthesia associated with other chemotherapeutic agents. MATERIAL AND METHODS: The research question (developed according to the patient/population, intervention, comparison, and outcomes [PICO] method) addressed was "Does the use of 5-fluorouracil as an adjunctive therapy in the treatment of OKC reduce both the recurrence rate and the incidence of inferior alveolar nerve paresthesia as compared with other chemotherapeutic agents?" A systematic review was performed by searching 4 databases: PubMed, EBSCO, Portal Evidencia, and Cochrane Reviews. Each search was conducted twice. Two independent reviewers evaluated the data. For each database, a search strategy was developed that included the following generic terms: Fluorouracil, 5-Fluorouracil, or liquid nitrogen and odontogenic cyst or odontogenic keratocyst. Three filters were applied to the searches, as well, consisting of the terms clinical trials, English papers, and Spanish papers. RESULTS: Of the 74 papers retrieved. The titles and abstracts of the selected papers were reviewed to determine whether those papers were relevant to our research question; only 3 papers were selected for this systematic review: 2 retrospective cohort studies and 1 clinical trial. Assessments risk bias and the quality of evidence were performed. CONCLUSIONS: The risk of bias and quality of evidence in this systematic review are moderate due to the study's design, although the clinical results were excellent with respect to the reduction of both OKC recurrence and paresthesia associated with this kind of cyst.

'White Cord Syndrome': A Rare Catastrophic Complication Following Anterior Cervical Discectomy and Fusion.

Background: 'White-cord syndrome' is an extremely rare entity following decompression of cervical cord in which post-operative reperfusion injury results in worsening of patient's neurology and MRI reveals signal changes in spinal cord in absence of cord compression. We wish to report a case of 'white-cord syndrome' following a 'routine' ACDF. Case Description: A 39-year-old woman with paresthesias and spastic quadriparesis was found to have C5-C6 PIVD on MRI. ACDF was performed at C5-C6, after which worsening of quadriparesis was noted, for which intravenous high-dose steroids were started. An urgent MRI was done, which revealed findings of white-cord syndrome, without compression on underlying cord. With conservative management, her ASIA grade improved from C to D and the features of white-cord syndrome disappeared on follow-up imaging. Conclusion: It is important for surgeons and patients to be aware of this rare but potentially catastrophic entity as this needs to be discussed while taking consent for surgery.

Dose dependent slurred speech and laryngopharyngeal dysesthesia due to oxaliplatin.

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/m2) and capecitabine(2000mg/m2). 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/m2. 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.

Multiple neurological manifestations in a patient with systemic lupus erythematosus and anti-NXP2-positive myositis: A case report.

RATIONALE: Systemic lupus erythematosus (SLE) is a complex autoimmune inflammatory disease that frequently affects various organs. Neuropsychiatric manifestations in SLE patients, known as neuropsychiatric SLE, are clinically common. However, the principal manifestation of cranial neuropathy in patients with SLE and comorbidities is relatively rare. PATIENT CONCERNS: In this report, we describe a 51-year-old Chinese woman who was admitted with a chief complaint of chronic-onset facial paresthesia, dysphagia, and choking cough when drinking water, accompanied by slurred speech, salivation, and limb weakness. The blood autoantibody test results showed that many SLE-associated antibodies were positive. Meanwhile, anti-nuclear matrix protein 2 (NXP2) antibody was strongly positive in the idiopathic inflammatory myopathy (IIM) spectrum test from the serum. Muscle biopsy indicated inflammatory infiltration of the muscle fiber stroma. DIAGNOSES: Taking into account the clinical manifestations and laboratory tests of the present case, the diagnosis of SLE and probable IIM was established. INTERVENTIONS: Corticosteroids and additional gamma globulin were administered and the clinical symptoms were relieved during the treatment process. OUTCOMES: Unfortunately, the patient experienced sudden cardiac and respiratory arrest. Multiple system dysfunctions exacerbated disease progression, but in the present case, we speculated that myocardial damage resulting from SLE could explain why she suddenly died. LESSONS: To our knowledge, multiple neurological manifestations in patients with SLE and anti-NXP2-positive myositis are rare. Note that SLE is still a life-threatening disease that causes multiple system dysfunctions, which requires increasing attention.

Oleosomes Encapsulating Sildenafil Citrate as Potential Topical Nanotherapy for Palmar Plantar Erythrodysesthesia with High Ex vivo Permeation and Deposition.

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.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

Acute Myeloid Leukemia Presenting with Numb Chin Syndrome: A Case Report and Review of Literature.

BACKGROUND Numb chin syndrome is a rare and under diagnosed neuropathy of the inferior alveolar branch of the trigeminal nerve usually causing a lower lip and chin anesthesia or paresthesia. The syndrome is commonly associated with broad-spectrum malignant and non-malignant conditions. CASE REPORT Here we report a case of a 30-year-old male who presented with numb chin syndrome in the form of jaw pain, paresthesia, and hypoesthesia of the mental area as the presenting symptoms of acute of myeloid leukemia with t(8;21) treated with (3+7) protocol (3 days anthracycline+7 days cytarabine). The pain and paresthesia improved but hypothesia persisted. CONCLUSIONS Acute myeloid leukemia is one of the most serious causes of numb chin syndrome which should not be overlooked.

[Acute sensory neuropathy associated with Hodgkin's lymphoma: a case study].

The case of a 17-year-old man with Hodgkin's lymphoma who presented with paraneoplastic sensory neuropathy is presented. The patient visited our hospital because of acute progression of dysesthesiae in the bilateral face and extremities. He also developed an ataxic gait due to decreased deep sensation. Post-contrast T1-weighted MRI showed enhancement of both trigeminal nerves and the cauda equina. Cerebrospinal fluid examination was unremarkable. Intravenous immunoglobulin therapy and subsequent steroid pulse therapy did not improve his symptoms. Laboratory data showed an elevated serum soluble interleukin-2 receptor level. His chest X-ray and CT showed enlarged lymph nodes in the mediastinum, and the histopathologic examination of a lymph node biopsy specimen showed classical Hodgkin's lymphoma. He was treated with chemotherapy. His symptoms of neuropathy improved promptly while the lymphoma was being successfully treated, and he was able to walk with a cane. The present case was characterized by paraneoplastic sensory neuropathy as the initial clinical feature in association with Hodgkin's lymphoma. It is necessary to consider a paraneoplastic neurological syndrome even in a young patient with acute/subacute sensory neuropathy. Paraneoplastic sensory neuropathy associated with Hodgkin's lymphoma could be expected to improve with oncotherapy, and examination of the malignancy and early treatment are important.

Treatment of Notalgia Paresthetica with Bee Venom and Capsaicin: A Pilot Study with 20 Patients.

Notalgia paresthetica (NP) is a common clinical disorder characterized by hyperpigmentation, pruritus, paresthesia, and/or pain, located on the back. There is no effective treatment for patients with NP. We investigated the efficacy of a product containing bee venom (0.04%) and capsaicin (0.025%) for treating NP. Twenty patients (10 men and 10 women) with NP were included in this open-label pilot study. A biopsy was performed for each patient to exclude other dermatologic diseases. The patients were asked to apply the product to the pruritic areas once daily for 2 weeks. No other product was used during the study. The Visual Analogue Scale (VAS) score was used to evaluate the efficacy of the product. VAS scores before and after treatment were statistically different ( p = 0.005). The pretreatment median of VAS score was 8 (7-10) (8.20 ± 1.03), while the median after treatment was 3 (1-7) (3.40 ± 1.71). The product containing bee venom and capsaicin is effective in treating NP. A double-blind and placebo-controlled study has been planned and initiated with a greater sample size.

Comparison of Two ß-Alanine Dosing Protocols on Muscle Carnosine Elevations.

OBJECTIVE: ß-alanine (BA) is a nonproteogenic amino acid that combines with histidine to form carnosine. The amount taken orally in individual doses, however, is limited due to symptoms of paresthesia that are associated with higher doses. The use of a sustained-release formulation has been reported to reduce the symptoms of paresthesia, suggesting that a greater daily dose may be possible. The purpose of the present study was to determine whether increasing the daily dose of BA can result in a similar increase in muscle carnosine in a reduced time. METHODS: Eighteen men and twelve women were randomized into either a placebo (PLC), 6-g BA (6G), or 12-g BA (12G) groups. PLC and 6G were supplemented for 4 weeks, while 12G was supplemented for 2 weeks. A resting blood draw and muscle biopsy were obtained prior to (PRE) and following (POST) supplementation. Plasma and muscle metabolites were measured by high-performance liquid chromatography. The loss in peak torque (ΔPT) was calculated from maximal isometric contractions before and after 250 isokinetic kicks at 180°·sec-1 PRE and POST. RESULTS: Both 12G (p = 0.026) and 6G (p = 0.004) increased muscle carnosine compared to PLC. Plasma histidine was decreased from PRE to POST in 12G compared to PLC (p = 0.002) and 6G (p = 0.001), but no group x time interaction (p = 0.662) was observed for muscle histidine. No differences were observed for any hematological measure (e.g., complete blood counts) or in symptoms of paresthesia among the groups. Although no interaction was noted in ΔPT, a trend (p = 0.073) was observed. CONCLUSION: Results of this investigation indicate that a BA supplementation protocol of 12 g/d-1, using a sustained-release formulation, can accelerate the increase in carnosine content in skeletal muscle while attenuating paresthesia.

Safety and tolerability of topical clonazepam solution for management of oral dysesthesia.

OBJECTIVES: The aim of the study was to determine the absolute and relative safety of treatment with 2 concentrations of topical clonazepam solution (0.1 mg/mL, 0.5 mg/mL) for management of oral dysesthesia. STUDY DESIGN: The study was a retrospective chart review of patients diagnosed with oral dysesthesia and managed with topical clonazepam solution (swish and spit) between 2008 and 2015. The relative safety of the 2 concentrations was evaluated in terms of occurrence of adverse drug reactions (ADRs) and occurrence of change to treatment plan secondary to ADRs. RESULTS: For the study, 162 patients were included-84 patients in the 0.1 mg/mL cohort and 78 in the 0.5 mg/mL cohort, who were evaluated for a median follow-up period of 6 weeks. Thirty-eight (23%) patients developed ADRs. The most frequently reported ADR was sedation (62% of ADRs), followed by altered mental status and dizziness (7% each). Dose adjustments were required in 9 patients (6%) and treatment discontinuation in 13 (8%). ADRs were more frequently reported in the 0.5 mg/mL cohort, but no significant difference was found in terms of occurrence of ADRs, change to treatment plan secondary to ADRs, or types of ADRs (P > .05). CONCLUSIONS: Treatment with topical clonazepam solution in either 0.5 mg/mL or 0.1 mg/mL concentration appears to be safe and well-tolerated. Future prospective studies are needed to confirm this finding.

Pruritic hyperpigmented patch on back.

The location of the pruritic area on this patient's back and the darkened patch that followed helped us to identify the cause of her chronic discomfort.

Neurocutaneous disease: Neurocutaneous dysesthesias.

Dysesthesia is a generic term for a cutaneous symptom--such as pruritus, burning, tingling, stinging, anesthesia, hypoesthesia, tickling, crawling, cold sensation, or even pain--without a primary cutaneous condition in a well-defined location that is often caused by nerve trauma, impingement, or irritation. There are multiple types of dysesthesias depending on the body location and the nerves involved. While location, exact symptoms, and etiologies might vary, the underlying theme is that these conditions are of neurologic origin and have dermatologic consequences. For many of these conditions, the symptoms are localized to the skin, and patients frequently present to the dermatologist; it is important for dermatologists to be knowledgeable about these symptoms and their underlying causes. In part II of this continuing medical education review, the primary diagnoses associated with underlying cutaneous dysesthesias will be explored, including scalp dysesthesia, trigeminal trophic syndrome, meralgia paresthetica, notalgia paresthetica, and brachioradial pruritus. The typical demographics in terms of symptoms, location, and patient populations will be discussed in addition to the specific etiologies, workups, and possible treatment options.

[Sensory neuronopathy. Its recognition and early treatment]. / Neuronopatía sensitiva. Su reconocimiento y tratamiento temprano.

Sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system diseases, frequently associated with dysinmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory proyections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. We retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100%). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and perioral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjögren's syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other. Eight patients were treated with immunotherapy, high dose intravenous methylprednisolone and/or intravenous immunoglobulin; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The present work shows the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment.