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1.
Orthop J Sports Med ; 12(7): 23259671241257622, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39100217

RESUMO

Background: Injuries in professional baseball players have become exceedingly common. Efforts to mitigate injury risk have focused on the kinetic chain, shoulder motion, and so forth. It is unclear whether grip strength is related to injury risk in professional baseball pitchers. Purpose/Hypothesis: The purpose of this study was to determine if grip strength was a risk factor for injury. It was hypothesized that pitchers with weaker grip strength would have a higher likelihood of sustaining a shoulder or elbow injury compared with pitchers with stronger grip strength. Study Design: Case-control study; Level of evidence, 3. Methods: All professional pitchers from a single Major League Baseball organization were included. Dominant and nondominant grip strength were measured after each pitching outing throughout the 2022 season. Injuries over the course of the season were recorded, and data were compared between pitchers who sustained a shoulder or elbow injury and those who did not. Results: Overall, 213 pitchers were included, of whom 53 (24.9%) sustained a shoulder or elbow injury during the season. The mean grip strength for all pitchers was 144.0 ± 20.8 lb (65.3 ± 9.4 kg). The mean dominant-arm grip strength was 142.6 ± 20.8 lb (64.7 ± 9.4 kg) for pitchers who did not sustain a shoulder or elbow injury and 148.2 ± 20.9 lb (67.2 ± 9.5 kg) for pitchers who did sustain an injury, with no significant group difference in grip strength (P > .05). Furthermore, there were no significant differences in change in grip strength over the course of the season between the groups. Conclusion: There was no significant difference in mean grip strength or change in grip strength over the course of a single season between professional baseball pitchers who sustained a shoulder or elbow injury and those who did not.

2.
Orthop J Sports Med ; 12(7): 23259671241256983, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39100215

RESUMO

Background: Disruption of the medial patellofemoral ligament (MPFL) may lead to recurrent lateral patellar dislocation and patellofemoral chondral injury. Despite significant previous work investigating numerous performance parameters, the optimal graft choice for MPFL reconstruction for patellar instability remains unclear. Purpose: To compare functional outcomes scores, subjective recurrent instability, and revision rates between autograft and allograft in MPFL reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent MPFL reconstruction with autograft between 2013 and 2018 were identified. A 2:1 comparison group of patients who underwent MPFL reconstruction with allograft was matched by sex, age (±3 years), and body mass index (BMI) (±3 kg/m2). Patient characteristics, preoperative radiograph measurements, and intraoperative data were compared between the groups, as were patient-reported outcome measures, including International Knee Documentation Committee (IKDC) score, Lysholm score, Single Assessment Numerical Evaluation (SANE), and visual analog scale (VAS) for pain. Subjective recurrent instability and revision rate were also compared between groups. Results: The autograft group was composed of 30 patients (13 male, 17 female) with a mean age of 24.4 years and mean BMI of 25.0 kg/m2, and the allograft group was composed of 60 matched patients (25 male, 35 female) with a mean age of 24.1 years and mean BMI of 25.1 kg/m2. The autograft and allograft groups reported similar IKDC scores (73.0 vs 73.7; P = .678), Lysholm scores (77.5 vs 80.7; P = .514), SANE (72.0 vs 75.8; P = .236), and VAS pain (30.7 vs 26.6; P = .482), as well as similar rates of postoperative patellar subluxations (20.0% vs 19.3%; P = .867) and dislocations (10.0% vs 15.0%; P = .805). Conclusion: Both allograft and autograft were found to be viable options for MPFL reconstruction. There were no significant group differences in failure rates, patient-reported outcomes, pain, or complications between autograft and allograft MPFL reconstruction in this series.

3.
Physiol Rep ; 12(15): e16176, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39118319

RESUMO

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 µg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 µg/kg, 60 µg/kg, 90 µg/kg, and 120 µg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 µg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 µg/kg and especially at 120 µg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.


Assuntos
Implantes Absorvíveis , Fentanila , Naltrexona , Antagonistas de Entorpecentes , Insuficiência Respiratória , Cães , Animais , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Masculino , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/prevenção & controle , Projetos Piloto , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Preparações de Ação Retardada
5.
Reg Anesth Pain Med ; 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39019502

RESUMO

BACKGROUND: There is potential for adverse events from corticosteroid injections, including increase in blood glucose, decrease in bone mineral density and suppression of the hypothalamic-pituitary axis. Published studies note that doses lower than those commonly injected provide similar benefit. METHODS: Development of the practice guideline was approved by the Board of Directors of American Society of Regional Anesthesia and Pain Medicine with several other societies agreeing to participate. The scope of guidelines was agreed on to include safety of the injection technique (landmark-guided, ultrasound or radiology-aided injections); effect of the addition of the corticosteroid on the efficacy of the injectate (local anesthetic or saline); and adverse events related to the injection. Based on preliminary discussions, it was decided to structure the topics into three separate guidelines as follows: (1) sympathetic, peripheral nerve blocks and trigger point injections; (2) joints; and (3) neuraxial, facet, sacroiliac joints and related topics (vaccine and anticoagulants). Experts were assigned topics to perform a comprehensive review of the literature and to draft statements and recommendations, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. The United States Preventive Services Task Force grading of evidence and strength of recommendation was followed. RESULTS: This guideline deals with the use and safety of corticosteroid injections for sympathetic, peripheral nerve blocks and trigger point injections for adult chronic pain conditions. All the statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Board of Directors of the participating societies also approved all the statements and recommendations. The safety of some procedures, including stellate blocks, lower extremity peripheral nerve blocks and some sites of trigger point injections, is improved by imaging guidance. The addition of non-particulate corticosteroid to the local anesthetic is beneficial in cluster headaches but not in other types of headaches. Corticosteroid may provide additional benefit in transverse abdominal plane blocks and ilioinguinal/iliohypogastric nerve blocks in postherniorrhaphy pain but there is no evidence for pudendal nerve blocks. There is minimal benefit for the use of corticosteroids in trigger point injections. CONCLUSIONS: In this practice guideline, we provided recommendations on the use of corticosteroids in sympathetic blocks, peripheral nerve blocks, and trigger point injections to assist clinicians in making informed decisions.

6.
Lancet Reg Health Southeast Asia ; 27: 100437, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39036653

RESUMO

Background: The use of sedation during interventional procedures has continued to rise resulting in increased costs, complications and reduced validity during diagnostic injections, prompting a search for alternatives. Virtual reality (VR) has been shown to reduce pain and anxiety during painful procedures, but no studies have compared it to a control and active comparator for a pain-alleviating procedure. The main objective of this study was to determine whether VR reduces procedure-related pain and other outcomes for epidural steroid injections (ESI). Methods: A randomized controlled trial was conducted in 146 patients undergoing an ESI at 6 hospitals in Thailand and the United States. Patients were allocated to receive immersive VR with local anesthetic, sedation with midazolam and fentanyl plus local anesthetic, or local anesthetic alone. The primary outcome was procedure-related pain recorded on a 0-10 scale. Other immediate-term outcome measures were pain from a standardized subcutaneous skin wheal, procedure-related anxiety, ability to communicate, satisfaction, and time to discharge. Intermediate-term outcome measures at 4 weeks included back and leg pain scores, function, and success defined as a ≥2-point decrease in average leg pain coupled with a score ≥5/7 on a Patient Global Impression of Change scale. Findings: Procedure-related pain scores with both VR (mean 3.7 (SD 2.5)) and sedation (mean 3.2 (SD 3.0)) were lower compared to control (mean 5.2 (SD 3.1); mean differences -1.5 (-2.7, -0.4) and -2.1 (-3.3, -0.9), respectively), but VR and sedation scores did not significantly differ (mean difference 0.5 (-0.6, 1.7)). Among secondary outcomes, communication was decreased in the sedation group (mean 3.7 (SD 0.9)) compared to the VR group (mean 4.1 (SD 0.5); mean difference 0.4 (0.1, 0.6)), but neither VR nor sedation was different than control. The trends favoring sedation and VR over control for procedure-related anxiety and satisfaction were not statistically significant. Post-procedural recovery time was longer for the sedation group compared to both VR and control groups. There were no meaningful intermediate-term differences between groups except that medication reduction was lowest in the control group. Interpretation: VR provides comparable benefit to sedation for procedure-related pain, anxiety and satisfaction, but with fewer side effects, superior communication and a shorter recovery period. Funding: Funded in part by grants from MIRROR, Uniformed Services University of the Health Sciences, U.S. Dept. of Defense, grant # HU00011920011. Equipment was provided by Harvard MedTech, Las Vegas, NV.

7.
BMC Public Health ; 24(1): 1954, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39039466

RESUMO

BACKGROUND: The United States (U.S.) has a growing population of Brazilian immigrant women. However, limited research has explored Pap tests and human papillomavirus (HPV) vaccination among this population. METHODS: Participants completed an online survey between July-August 2020. Bivariate analyses examined associations between healthcare-related variables (e.g., insurance, having a primary care provider) and demographics (e.g., age, education, income, marital status, years living in the U.S., primary language spoken at home) with 1) Pap test recency (within the past 3 years) and 2) HPV vaccination (0 doses vs. 1 + doses). Variables significant at p < 0.10 in bivariate analyses were included in multivariable logistic regression models examining Pap test recency and HPV vaccination. RESULTS: The study found that 83.7% of the sample had a Pap test in the past three years. Women who did not know their household income were less likely to be than women who reported a household income of < $25,000 (adjusted OR [aOR] = 0.34, 95% CI: 0.12, 0.95). Women who had seen a healthcare provider in the past year were more likely to have had a Pap test within the last three years than those who had not seen a provider in the past year ([aOR] = 2.43, 95% CI: 1.32, 4.47). Regarding HPV vaccination, 30.3% of respondents reported receiving one or more doses of the HPV vaccine. The multivariable logic regression models determined that women aged 27 -45 (aOR = 0.35, 95% CI: 0.18, 0.67) were less likely than women aged 18-26 to have been vaccinated against HPV). and that women with a PCP were more likely to be vaccinated than those without a PCP (aOR = 2.47. 95% CI:1.30, 4.59). CONCLUSION: This study found that Brazilian immigrant women in the youngest age groups (21 - 29) for Pap test, 18- 26 for HPV vaccination) had somewhat better rates of Pap screening and HPV vaccination than the general U.S. POPULATION: This study adds new information about cervical cancer prevention and control behaviors among Brazilian immigrant women.


Assuntos
Emigrantes e Imigrantes , Teste de Papanicolaou , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Humanos , Feminino , Adulto , Estudos Transversais , Vacinas contra Papillomavirus/administração & dosagem , Estados Unidos , Brasil , Emigrantes e Imigrantes/estatística & dados numéricos , Teste de Papanicolaou/estatística & dados numéricos , Infecções por Papillomavirus/prevenção & controle , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Neoplasias do Colo do Útero/prevenção & controle , Inquéritos e Questionários , Vacinação/estatística & dados numéricos
8.
Artigo em Inglês | MEDLINE | ID: mdl-39011664

RESUMO

PURPOSE OF REVIEW: To provide an evidence-informed review weighing the pros and cons of particulate vs. nonparticulate steroids for lumbar transforaminal epidural steroid injections (TFESI). RECENT FINDINGS: The relative use of nonparticulate vs. particulate steroids for lumbar TFESI has risen recently in light of catastrophic consequences reported for the latter during cervical TFESI. Among various causes of spinal cord infarct, an exceedingly rare event in the lower lumbar spine, embolization of particulate steroid is among the least likely. Case reports have documented cases of spinal cord infarct during lower lumbar TFESI with both particulate and nonparticulate steroids, with database reviews finding no difference in complication rates. There is some evidence for superiority of particulate over nonparticulate steroids in well-designed studies, which could lead to increase steroid exposure (i.e. more injections) and treatment failure resulting in surgical and/or opioid management when nonparticulate steroids are utilized. SUMMARY: Similar to a paradigm shift in medicine, a personalized approach based on a shared decision model and the consequences of treatment failure, should be utilized in deciding which steroid to utilize. Alternatives to ESI include high-volume injections with nonsteroid solutions, and the use of hypertonic saline, which possesses anti-inflammatory properties and has been shown to be superior to isotonic saline in preliminary clinical studies.

9.
Pancreatology ; 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38969544

RESUMO

BACKGROUND OBJECTIVES: The aim of this study was to determine the role of site-specific metastatic patterns over time and assess factors associated with extended survival in metastatic PDAC. Half of all patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. The site of metastasis plays a crucial role in clinical decision making due to its prognostic value. METHODS: We examined 56,757 stage-IV PDAC patients from the National Cancer Database (2016-2019), categorizing them by metastatic site: multiple, liver, lung, brain, bone, carcinomatosis, or other. The site-specific prognostic value was assessed using log-rank tests while time-varying effects were assessed by Aalen's linear hazards model. Factors associated with extended survival (>3years) were assessed with logistic regression. RESULTS: Median overall survival (mOS) in patients with distant lymph node-only metastases (9.0 months) and lung-only metastases (8.1 months) was significantly longer than in patients with liver-only metastases (4.6 months, p < 0.001). However, after six months, the metastatic site lost prognostic value. Logistic regression identified extended survivors (3.6 %) as more likely to be younger, Hispanic, privately insured, Charlson-index <2, having received chemotherapy, or having undergone primary or distant site surgery (all p < 0.001). CONCLUSION: While synchronous liver metastases are associated with worse outcomes than lung-only and lymph node-only metastases, this predictive value is diminished after six months. Therefore, treatment decisions beyond this time should not primarily depend on the metastatic site. Extended survival is possible in a small subset of patients with favorable tumor biology and good conditional status, who are more likely to undergo aggressive therapies.

10.
Langenbecks Arch Surg ; 409(1): 224, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028426

RESUMO

BACKGROUND: The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS: Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS: Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION: While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.


Assuntos
Carcinoma Ductal Pancreático , Pancreatectomia , Neoplasias Pancreáticas , Pancreaticoduodenectomia , Humanos , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Masculino , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Feminino , Estudos Retrospectivos , Pancreatectomia/métodos , Idoso , Pessoa de Meia-Idade , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/mortalidade , Excisão de Linfonodo , Estudos de Coortes
12.
Joint Bone Spine ; 91(6): 105750, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38857874

RESUMO

Pain is the leading reason people seek orthopedic and rheumatological care. By definition, most pain can be classified as nociceptive, or pain resulting from non-neural tissue injury or potential injury, with between 15% and 50% of individuals suffering from concomitant neuropathic pain or the newest category of pain, nociplastic pain, defined as "pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage, or of a disease or lesion affecting the somatosensory system." Pain classification is important because it affects treatment decisions at all levels of care. Although several instruments can assist with classifying treatment, physician designation is the reference standard. The appropriate treatment of pain should ideally involve multidisciplinary care including physical therapy, psychotherapy and integrative therapies when appropriate, and pharmacotherapy with non-steroidal anti-inflammatory drugs for acute, mechanical pain, membrane stabilizers for neuropathic and nociplastic pain, and serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants for all types of pain. For nonsurgical interventions, there is evidence to support a small effect for epidural steroid injections for an intermediate-term duration, and conflicting evidence for radiofrequency ablation to provide at least 6months of benefit for facet joint pain, knee osteoarthritis, and sacroiliac joint pain. Since pain and disability represent the top reason for elective surgery, it should be reserved for patients who fail conservative interventions. Risk factors for procedural failure are the same as risk factors for conservative treatment failure and include greater disease burden, psychopathology, opioid use, central sensitization and multiple comorbid pain conditions, poorly controlled preoperative and postoperative pain, and secondary gain.

13.
Arch Dermatol Res ; 316(7): 379, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38850290

RESUMO

Hidradenitis suppurativa (HS) is an inflammatory disorder of follicular biology; androgens are believed to be involved in its pathogenesis. Polycystic ovary syndrome (PCOS) is similarly characterized by hyperandrogenism. Previous studies have found a lasting association of HS and PCOS. Socioeconomic status (SES) has been described as a comorbidity for both HS and PCOS that has not been accounted for in prior studies; we sought to investigate this association while adjusting for this. We also analyzed the prevalence of PCOS among HS patients. Using the All of Us database, female HS patients were stratified by PCOS diagnosis and compared by age, race, and ethnicity. Female HS patients were also nearest-neighbor propensity-score matched to controls at a 4:1 ratio, selecting for race, ethnicity, age, ever smoker, alcohol use disorder, obesity, type II diabetes, Medicaid status, and community deprivation index. Univariable and multivariable logistic regression was conducted to estimate the effect of HS on the presence of PCOS. The distribution of race among HS patients with PCOS was significantly different than HS patients without PCOS. A total of 1,022 female HS patients and 4,088 matched female controls were included. Significantly more patients carried a diagnosis of PCOS compared to controls (8.8% versus 4.3%, p < .001). In multivariable logistic regression, PCOS was significantly associated with HS [OR 1.71 (95% CI 1.34-2.17)]. This is the first study investigating the association of HS and PCOS within the All of Us database. We found that females with HS had a 1.34- to 2.17-fold increased odds of having PCOS, which is consistent with previous analyses. However, our analysis, in addition to controlling for common medical co-morbidities found in both HS and PCOS, also accounts for markers of SES at an individual and community level, further strengthening the association of HS with PCOS.


Assuntos
Hidradenite Supurativa , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/epidemiologia , Feminino , Hidradenite Supurativa/epidemiologia , Adulto , Prevalência , Estados Unidos/epidemiologia , Adulto Jovem , Pessoa de Meia-Idade , Comorbidade , Adolescente , Classe Social , Estudos de Casos e Controles
15.
Reg Anesth Pain Med ; 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38942427

RESUMO

BACKGROUND: Peer review represents a cornerstone of the scientific process, yet few studies have evaluated its association with scientific impact. The objective of this study is to assess the association of peer review scores with measures of impact for manuscripts submitted and ultimately published. METHODS: 3173 manuscripts submitted to Regional Anesthesia & Pain Medicine (RAPM) between August 2018 and October 2021 were analyzed, with those containing an abstract included. Articles were categorized by topic, type, acceptance status, author demographics and open-access status. Articles were scored based on means for the initial peer review where each reviewer's recommendation was assigned a number: 5 for 'accept', 3 for 'minor revision', 2 for 'major revision' and 0 for 'reject'. Articles were further classified by whether any reviewers recommended 'reject'. Rejected articles were analyzed to determine whether they were subsequently published in an indexed journal, and their citations were compared with those of accepted articles when the impact factor was <1.4 points lower than RAPM's 5.1 impact factor. The main outcome measure was the number of Clarivate citations within 2 years from publication. Secondary outcome measures were Google Scholar citations within 2 years and Altmetric score. RESULTS: 422 articles met inclusion criteria for analysis. There was no significant correlation between the number of Clarivate 2-year review citations and reviewer rating score (r=0.038, p=0.47), Google Scholar citations (r=0.053, p=0.31) or Altmetric score (p=0.38). There was no significant difference in 2-year Clarivate citations between accepted (median (IQR) 5 (2-10)) and rejected manuscripts published in journals with impact factors >3.7 (median 5 (2-7); p=0.39). Altmetric score was significantly higher for RAPM-published papers compared with RAPM-rejected ones (median 10 (5-17) vs 1 (0-2); p<0.001). CONCLUSIONS: Peer review rating scores were not associated with citations, though the impact of peer review on quality and association with other metrics remains unclear.

18.
Cancer Discov ; 14(7): 1190-1205, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38588399

RESUMO

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias , Inibidores de Proteínas Quinases , Humanos , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Quinases raf/metabolismo , Quinases raf/antagonistas & inibidores , Linhagem Celular Tumoral , Proteínas ras/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo
19.
Pain Pract ; 2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38616347

RESUMO

INTRODUCTION: Persistent Spinal Pain Syndrome (PSPS) refers to chronic axial pain and/or extremity pain. Two subtypes have been defined: PSPS-type 1 is chronic pain without previous spinal surgery and PSPS-type 2 is chronic pain, persisting after spine surgery, and is formerly known as Failed Back Surgery Syndrome (FBSS) or post-laminectomy syndrome. The etiology of PSPS-type 2 can be gleaned using elements from the patient history, physical examination, and additional medical imaging. Origins of persistent pain following spinal surgery may be categorized into an inappropriate procedure (eg a lumbar fusion at an incorrect level or for sacroiliac joint [SIJ] pain); technical failure (eg operation at non-affected levels, retained disk fragment, pseudoarthrosis), biomechanical sequelae of surgery (eg adjacent segment disease or SIJ pain after a fusion to the sacrum, muscle wasting, spinal instability); and complications (eg battered root syndrome, excessive epidural fibrosis, and arachnoiditis), or undetermined. METHODS: The literature on the diagnosis and treatment of PSPS-type 2 was retrieved and summarized. RESULTS: There is low-quality evidence for the efficacy of conservative treatments including exercise, rehabilitation, manipulation, and behavioral therapy, and very limited evidence for the pharmacological treatment of PSPS-type 2. Interventional treatments such as pulsed radiofrequency (PRF) of the dorsal root ganglia, epidural adhesiolysis, and spinal endoscopy (epiduroscopy) might be beneficial in patients with PSPS-type 2. Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic, intractable neuropathic limb pain, and possibly well-selected candidates with axial pain. CONCLUSIONS: The diagnosis of PSPS-type 2 is based on patient history, clinical examination, and medical imaging. Low-quality evidence exists for conservative interventions. Pulsed radiofrequency, adhesiolysis and SCS have a higher level of evidence with a high safety margin and should be considered as interventional treatment options when conservative treatment fails.

20.
Ann Surg ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38606874

RESUMO

OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.

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