Tumor Necrosis Factor and Interleukin Modulators for Pathologic Pain States: A Narrative Review.

Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future.

Anesthesia Liability Related to Pre-existing Conditions.

In 1985, the American Society of Anesthesiologists initiated a quality improvement closed claims analysis project for anesthetic injury to elevate patient safety. To date, there have been a total of 8954 documented claims, describing injuries contracted under sedation, regional anesthesia, or failure to attend to a patient's post-operative needs. The Closed Claims database reveals that the most highly documented health care complications were a loss of life at 2%, nerve injuries at 2%, and damage to the brain at 9%. The highest documented cases of damage from anesthesia involved regional-block-related events at 20%, followed by respiratory-related adverse effects at 17%, cardiovascular-related events at 13%, together with apparatus-linked events at 10%. Injury may result from several causes. First, multiple techniques and interventions are used during surgery, and all have potential adverse effects. Additionally, many patients scheduled for surgery have extensive past medical histories and medical comorbidities, thereby increasing their baseline risk for injury. From the Closed Claims database, improved evaluation of clinical-related implications linked to injuries within the handling of airway, sedation, non-operational room locales, obstetric anesthesia, along with chronic pain management. In summary, anesthesia departments should review outcomes of their patients on a routine basis. Assessing factors when an adverse outcome occurs may allow for changes in techniques or other anesthesia considerations to help lessen or prevent future complications.

Testosterone replacement therapy: clinical considerations.

INTRODUCTION: As an increasingly popular therapeutic option, testosterone replacement therapy (TRT) has gained significant notoriety for its health benefits in indicated populations, such as those suffering from hypogonadism. AREAS COVERED: Benefits such as improved libido, muscle mass, cognition, and quality of life have led to widened public interest in testosterone as a health supplement. No therapy exists without side effects; testosterone replacement therapy has been associated with side effects such as an increased risk of polycythemia, benign prostate hypertrophy (BPH), prostate cancer, gynecomastia, testicular atrophy, and infertility. Testosterone replacement therapy is often accompanied by several prophylactic co-therapies aimed at reducing the prevalence of these side effects. Literature searches for sections on the clinical benefits and risks associated with TRT were performed to include clinical trials, meta-analyses, and systematic reviews from the last 10 years. EXPERT OPINION: Data from clinical studies over the last decade suggest that the benefits of this therapy outweigh the risks and result in overall increased quality of life and remission of symptoms related to hypogonadism. With this in mind, the authors of this review suggest that carefully designed clinical trials are warranted for the investigation of TRT in symptomatic age-related hypogonadism.

Infigratinib for the Treatment of Metastatic or Locally Advanced Cholangiocarcinoma With Known FGFR2 Gene Fusions or Rearrangements.

Cholangiocarcinoma (CCA) is an aggressive and diverse malignancy with a poor prognosis. Related to a typical indolent course of progression, most cases of CCA are metastatic or locally advanced at the time of presentation. For patients with nonresectable tumors or metastatic disease, the mainstay of treatment is comprehensive with combination chemotherapy. The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. However, many locally advanced and progressive CCA cases are refractory to first-line management. Within the past few years, the increase in the incidence of metastatic CCA and its poor prognosis has brought to light the need for novel therapeutic approaches to treatment. With advancements in next-generation genome sequencing, multiple molecular pathways have been identified in the pathogenesis of CCA and have shown great potential as alternative treatments in cases of CCA refractory to surgical resection. FGFR2 fusions or rearrangements have been identified in 10-16% of all intrahepatic CCA and are thought to serve as a pathway of resistance for a number of nonresectable and refractory cases of cholangiocarcinoma. A novel therapeutic agent that has been discussed is infigratinib, a selective, ATP-competitive inhibitor of fibroblast growth factor receptor 2 (FGFR2). In a phase 1 trial, infigratinib showed a safe profile and showed remarkable clinical efficacy in advanced CCA with FGFR2 fusions or rearrangements in phase II trials. As of May 2021, the Food and Drug Administration (FDA) approved infigratinib for CCA largely based on tumor response and duration of response. As of 2021, infigratinib, futibatinib, and pemigatinib, similar novel selective FGFR inhibitors, have been approved by the FDA for the treatment of locally advanced or metastatic CCA harboring FGFR2 gene mutations. The present investigation reviews the development of infigratinib in particular and its clinical efficacy compared to other available treatment options for cholangiocarcinoma. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as molecular-directed therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.

Topical Cocaine Hydrochloride Nasal Solution: Anesthetic and Surgical Considerations.

Adequate surgical view during various types of nasal procedures is essential for surgical operations to be performed in a safe, efficient, and successful manner. Minimizing bleeding during surgery is an important way of increasing visualization that is commonly achieved by using a vasoconstrictive agent to control intraoperative hemorrhage. Many otolaryngologists choose to employ topical cocaine to minimize bleeding during surgery owing to its vasoconstrictive properties, while simultaneously benefitting from its dual local anesthetic effects. The relative benefit of topical cocaine for otolaryngologic procedures when compared to other topical analgesics and vasoconstrictors remains a topic of discussion due to the multiple potential cardiac and central nervous system side effects associated with cocaine administration. Furthermore, there is not a scientifically backed maximal safe dose published; instead, most of the guidelines for intranasal cocaine use are based on untested clinical practice. Despite this, the short latency, adequate duration of action, and inherent vasoconstrictive and decongestive capabilities make cocaine a valuable anesthetic agent for use in clinical procedures. As the relative benefit of using topical cocaine compared to the use of other vasoconstrictors and analgesics for nasal procedures remains undetermined in the current literature, this leaves the need for a comprehensive review of research that explores the risks and benefits of using topical cocaine in nasal procedures based on clinical trials that compare intranasal cocaine with various other analgesics and vasoconstrictors.

A 4-Month Whole-Systems Ayurvedic Medicine Nutrition and Lifestyle Intervention Is Feasible and Acceptable for Breast Cancer Survivors: Results of a Single-Arm Pilot Clinical Trial.

PURPOSE: Ongoing symptoms and impairments in quality of life (QOL) among breast cancer survivors remain a significant problem. We tested the feasibility and acceptability of a manualized Ayurvedic nutrition and lifestyle intervention for breast cancer survivors. METHODS: Eligible participants had Stage I-III breast cancer, underwent treatment within the past year that included chemotherapy, and were without active disease. The 4-month individualized Ayurvedic intervention included counseling on nutrition, lifestyle, yoga, and marma (like acupressure) during 8 one-on-one visits with an Ayurvedic practitioner. Feasibility and acceptability were the primary outcomes. QOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ C30]) and symptoms-sleep disturbance (General Sleep Disturbance Scale [GSDS]), fatigue (Lee Fatigue Scale [LFS]), depressive symptoms (Center for Epidemiological Studies-Depression Scale [CES-D]), anxiety (Spielberger State-Trait Anxiety Inventory [STAI-S, STAI-T]), and stress (Perceived Stress Scale [PSS])-were measured prior to, at midpoint, and at the end of the 4-month intervention. Effect sizes (Cohen's d) were calculated along with paired t tests comparing baseline to end of month 4 time points. Mixed effects models were used for repeated measures analyses. RESULTS: Participants (n = 32) had a mean age of 48 years (SD = 10). Retention at the end of the intervention was 84%. Among those who completed the intervention (n = 27), adherence was high (99.5% of visits with practitioners attended). Large improvements were seen in QLQ-C30 emotional functioning (d = 0.84, P < 0.001), QLQ-C30 cognitive functioning (d = 0.86, P < 0.001), GSDS (d = -1.23, P < 0.001), and CES-D (d = -1.21, P < 0.001). Moderate improvements were seen in QLQ-C30 global health (d = 0.65, p = 0.003), LFS (d = -0.68, P = 0.002), and PSS (d = -0.75, P < 0.001). No adverse events were observed due to the intervention. CONCLUSION: This 4-month Ayurvedic whole-systems multimodal nutrition and lifestyle intervention was feasible and acceptable for breast cancer survivors. Promise of clinical benefit was seen in terms of improvements in symptoms and QOL that warrants further investigation.