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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. 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. 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. 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. Bristol-Myers Squibb and ONO Pharmaceutical.

Orthognathic surgery involves invasive and major surgical procedures commonly used to correct maxillofacial deformities. Bilateral sagittal split ramus osteotomy (BSSO) is often used to treat dentofacial anomalies related to the mandible, but it can result in various complications, the most common of which is inferior alveolar nerve damage. Nerve damage–induced paresthesia of the lower lip significantly affects patient comfort. Medical treatments such as steroids and vitamin B, low-level laser therapy (LLLT), and platelet-rich fibrin (PRF) can be used as supportive therapies for nerve regeneration after damage. This study aimed to investigate the effectiveness of two different types of lasers in treating lower lip paresthesia after BSSO. This clinical trial was a controlled, single-center, prospective, single-blind, randomized study. Thirty patients were included in the study and randomly assigned to three groups: Group I (laser GRR, n = 10) received transcutaneous and transmucosal GRR laser treatment, Group II (Epic10 laser, n = 10) received transmucosal and transcutaneous Epic10 laser treatment, and Group III (vitamin B, n = 10) received B-complex vitamin tablets orally once a day. Two-point and brush tests were performed six times at specific intervals, and a visual analog scale was used to evaluate pain and sensitivity. Both vitamin B and laser therapies accelerated nerve regeneration. The contribution of the laser groups to the healing rate was better than that of the vitamin B group. Although there was no statistically significant difference between the two laser groups, clinical observations indicated better results in the GRR laser group.

BACKGROUND:Pain relief with spinal cord stimulation (SCS) has focused historically on paresthesias overlapping chronically painful areas. A higher level evidence supports the use of SCS in treating leg pain than supports back pain, as it is difficult to achieve adequate paresthesia coverage, and then pain relief, in the low back region. In comparison, 10-kHz high-frequency (HF10 therapy) SCS therapy does not rely on intraoperative paresthesia mapping and remains paresthesia-free during therapy. OBJECTIVE:To compare long-term results of HF10 therapy and traditional low-frequency SCS. METHODS:A pragmatic randomized, controlled, pivotal trial with 24-month follow-up was conducted across 11 comprehensive pain treatment centers. Subjects had Visual Analog Scale scores of ≥5.0/10.0 cm for both back and leg pain, and were assigned randomly (1:1) to receive HF10 therapy or low-frequency SCS. The primary end point was a responder rate, defined as ≥50% back pain reduction from baseline at 3 months with a secondary end point at 12 months (previously reported). In this article, 24-month secondary results are presented. Non-inferiority was first assessed, and if demonstrated the results were tested for superiority. RESULTS:In the study, 198 subjects were randomized (101 HF10 therapy, 97 traditional SCS). One hundred seventy-one subjects (90 HF10 therapy, 81 traditional SCS) successfully completed a short-term trial and were implanted. Subjects averaged 54.9 ± 12.9 years old, 13.6 ± 11.3 years since diagnosis, 86.6% had back surgery, 88.3% were taking opioid analgesics. At 3 months, 84.5% of implanted HF10 therapy subjects were responders for back pain and 83.1% for leg pain, and 43.8% of traditional SCS subjects were responders for back pain and 55.5% for leg pain (P < .001 for both back and leg pain comparisons, non-inferiority and superiority). At 24 months, more subjects were responders to HF10 therapy than traditional SCS (back pain76.5% vs 49.3%; 27.2% difference, 95% CI, 10.1%-41.8%; P < .001 for non-inferiority and superiority; leg pain72.9% vs 49.3%; 23.6% difference, 95% CI, 5.9%-38.6%; P < .001 for non-inferiority and P = .003 for superiority). Also at 24 months, back pain decreased to a greater degree with HF10 therapy (66.9% ± 31.8%) than traditional SCS (41.1% ± 36.8%, P < .001 for non-inferiority and superiority). Leg pain also decreased to a greater degree with HF10 therapy (65.1% ± 36.0%) than traditional SCS (46.0% ± 40.4%, P < .001 for non-inferiority and P = .002 for superiority). CONCLUSION:This study demonstrates long-term superiority of HF10 therapy compared with traditional SCS in treating both back and leg pain. The advantages of HF10 therapy are anticipated to impact the management of chronic pain patients substantially. ABBREVIATIONS:IPG, implantable pulse generatorMCID, minimal clinically important differencePI, permanent implantODI, Oswestry Disability IndexSCS, spinal cord stimulationVAS, Visual Analog Scale

In childhood and adolescent migraine, amitriptyline and topiramate were no better than placebo and not significantly different from each other in achieving a 50% or greater reduction in days with headache. The trial was stopped early for futility. More than 6 million children and adolescents in the United States have migraines. 1 – 3 The majority continue to have headaches into adulthood, taking a toll on the U.S. economy of approximately $36 billion and resulting in substantial effects on quality of life. 4 – 7 Pediatric clinical practice guidelines for migraine treatment are consensus based rather than evidence based, 8 , 9 with no Food and Drug Administration (FDA)–approved migraine prevention medication for children younger than 12 years of age. The Childhood and Adolescent Migraine Prevention (CHAMP) trial tested the effects of amitriptyline and topiramate in comparison with each other and with placebo in . . .

Background: Transforaminal and interlaminar epidural steroid injections are commonly used interventional pain management procedures in the treatment of radicular low back pain. Even though several studies have shown that transforaminal injections provide enhanced short-term outcomes in patients with radicular and low back pain, they have also been associated with a higher incidence of unintentional intravascular injection and often dire consequences than have interlaminar injections. Objectives: We compared 2 different approaches, midline and lateral parasagittal, of lumbar interlaminar epidural steroid injection (LESI) in patients with unilateral lumbosacral radiculopathic pain. We also tested the role of concordant pressure paresthesia occurring during LESI as a prognostic factor in determining the efficacy of LESI. Study Design: Prospective, randomized, blinded study. Setting: Pain management center, part of a teaching-community hospital in a major metropolitan US city. Methods: After Institutional Review Board approval, 106 patients undergoing LESI for radicular low back pain were randomly assigned to one of 2 groups (53 patients each) based on approach: midline interlaminar (MIL) and lateral parasagittal interlaminar (PIL). Patients were asked to grade any pressure paresthesia as occurring ipsilaterally or contralaterally to their “usual and customary pain,” or in a distribution atypical of their daily pain. Other variables such as: the Oswestry Disability Index questionnaire, pain scores at rest and during movement, use of pain medications, etc. were recorded 20 minutes before the procedure, and on days 1, 7, 14, 21, 28, 60, 120, 180 and 365 after the injection. Results: Results of this study showed statistically and clinically significant pain relief in patients undergoing LESI by both the MIL and PIL approaches. Patients receiving LESI using the lateral parasagittal approach had statistically and clinically longer pain relief then patients receiving LESI via a midline approach. They also had slightly better quality of life scores and improvement in everyday functionality; they also used less pain medications than patients receiving LESI using a midline approach. Furthermore, patients in the PIL group described significantly higher rates of concordant moderate-to-severe pressure paresthesia in the distributions of their “usual and customary pain” compared to the MIL group. In addition, patients who had concordant pressure paresthesia and no discordant pressure paresthesia (i.e., “opposite side or atypical”) during interventional treatment had better and longer pain relief after LESI. Two patients from each group required discectomy surgery in the one-year observation period. Limitations: The major limitation of this study is that we did not include a transforaminal epidural steroid injection group, since that is one of the approaches still commonly used in contemporary pain practices for the treatment of low back pain with unilateral radicular pain. Conclusions: This study showed that the lateral parasagittal interlaminar approach was more effective than the midline interlaminar approach in targeting low back pain with unilateral radicular pain secondary to degenerative lumbar disc disease. It also showed that pressure paresthesia occurring ipsilaterally during an LESI correlates with pain relief and may therefore be used as a prognostic factor. Key words: lumbar epidural steroid injection, interlaminar injection, low back pain, unilateral radicular pain, midline interlaminar approach, lateral parasagittal interlaminar approach, pressure paresthesia, quality of life, everyday functionality

In Canada, anesthesia/paresthesia were the most frequently reported adverse events following immunization (AEFI) against SARS-CoV-2. This study aims to describe the frequency and characteristics of anesthesia/paresthesia cases temporally associated with a first or second dose of COVID-19 vaccines administered in Quebec, Canada. Cases were extracted among AEFI reports submitted to the passive surveillance system. Sociodemographic, vaccination and AEFI information were obtained from the immunization registry. Signs, symptoms and anatomical location were manually extracted from clinical narratives. From December 13, 2020 to December 31, 2022, 15.2 million doses of vaccines were administered in Quebec. By July 1, 2022, 1024 cases of anesthesia/paresthesia following COVID-19 vaccination had been reported. The global reporting rate was 7.7 per 100,000 doses administered. Rates were higher with the first than the second dose (11.4 vs. 3.8 per 100,000 doses), and higher with ChAdOx1 than with mRNA vaccines Comirnaty™ (BNT-162b2, Pfizer BioNTech) or Spikevax™ (mRNA-1273, Moderna) (28.7 vs. 6.1 and 7.9, respectively). Rates were 3- to 4-times higher in women, with the highest rate ratios among those 18–49 years of age. Median time to onset was 24 h (IQR: 3–96). Paresthesia, hypoesthesia/anesthesia (83 %) were more common than dysesthesias (13 %). Symptoms were reported mostly in upper limbs (62 %), but also frequently in lower limbs (47 %) or the face (42 %). Most reported mild (41 %) or moderate (48 %) symptoms, with a median duration of 5 days (IQR: 2–15), although symptoms lasting 1–5 months (12 %) or over 6 months (1 %) were also reported. Symptoms of anesthesia/paresthesia are commonly reported following the administration of several vaccines, including those against COVID-19. In most instances, symptoms occur shortly after vaccination, have a limited impact on daily activities, and resolve spontaneously within a month of onset. A small proportion of cases report sensory and/or motor symptom of longer duration, which remain undiagnosed following neurological investigations. Despite being a common occurrence, post-vaccination sensory disturbances remain a poorly understood phenomenon that warrants further study.

PurposeTo investigate prevalence and risk factors associated with self-reported chronic pain, and other symptoms related to breast cancer or its treatment among breast cancer survivors (BCS).MethodsA cross-sectional study of a random sample of 410 female BCS, members of “Leumit” healthcare fund, diagnosed with primary nonmetastatic invasive breast cancer in the years 2002–2012. The study questionnaire included questions on health-related quality of life, pain symptoms, and was completed by all women contacted.ResultsA total of 305 BCS (74%), with a median of 7.4 years since diagnosis reported chronic pain, of whom 84% had moderate pain, and 97% experienced pain at least 1–3 days/week. Other symptoms were paresthesia (63%), allodynia (48%), and phantom sensations (15%). Report of pain symptoms, alone or combined, was significantly associated with poorer quality of life. In multivariable analyses, chronic pain was positively associated with mastectomy compared to breast-conserving surgery [Odds ratio (OR), 3.54; 95% confidence interval (CI) 1.46–8.59; P = 0.005], radiotherapy compared to non-radiotherapy (OR 2.96; 95% CI 1.43–6.12; P = 0.003), breast cancer stage at diagnosis—regional versus localized (OR 3.63; 95% CI 2.00–6.57; P < 0.001), and inversely with age (OR per one-year increment, 0.96; 95% CI 0.94–0.99; P = 0.002), and with time since diagnosis (OR per one-year increment, 0.82; 95% CI 0.75–0.90; P < 0.001).ConclusionsWith the increasing incidence of detected breast cancer and the improvements in treatment and consequently survival, knowledge about prevalence, and factors related to treatment late effects of chronic pain is highly relevant for potential prevention or management without negatively impacting quality of life.

ObjectiveTanezumab, 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.MethodsThis 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.ResultsFrom 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.ConclusionTanezumab 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 numberNCT02709486.

Modeling studies show that increased expression of nerve growth factor is associated with increased pain. This study tested the safety and efficacy of the monoclonal antibody tanezumab — which targets nerve growth factor — for the treatment of knee pain in patients with osteoarthritis. Nerve growth factor is a neurotrophin that regulates the structure and function of responsive sensory neurons, including small-diameter nociceptive afferents. There has been increasing recognition of the potential role of nerve growth factor in pain modulation through nociceptor sensitization. 1 – 7 In animals and humans, exogenous nerve growth factor increases pain either locally or systemically, depending on the dose and the route of administration. 8 , 9 Increased expression of nerve growth factor is found in inflamed tissues from patients with conditions such as arthritis, pancreatitis, and prostatitis. 10 – 12 Levels of nerve growth factor are also elevated in animal models of inflammatory pain, . . .