Real-world treatment patterns and outcomes of patients with advanced melanoma treated with nivolumab plus relatlimab.

The use of programmed death-1 (PD-1) inhibitors has been a pivotal advancement in treating advanced melanoma, yet their efficacy is limited. The approval of relatlimab (RELA), a lymphocyte activation gene 3 protein (LAG-3) antibody, in combination with nivolumab (NIVO), a PD-1 inhibitor, marked a significant stride toward enhancing treatment efficacy for metastatic and unresectable stage 3 and 4 melanoma. This combination has been shown to synergistically improve antitumor activity and effector T-cell activity in the tumor microenvironment, despite limited data on real-world outcomes. Our retrospective review at a tertiary cancer center of patients with stage 3 and 4 melanoma treated with NIVO-RELA revealed an overall response rate (ORR) of 39%, with notable improvements in median PFS and ORR, especially in first-line treated patients. Our study highlights the superior efficacy of NIVO-RELA over previous reports, demonstrating its significant potential in the treatment landscape of advanced melanoma.

Cranioplasty Outcomes From 500 Consecutive Neuroplastic Surgery Patients.

BACKGROUND: Cranioplasty is critical to cerebral protection and restoring intracranial physiology, yet this procedure is fraught with a high risk of complications. The field of neuroplastic surgery was created to improve skull and scalp reconstruction outcomes in adult neurosurgical patients, with the hypothesis that a multidisciplinary team approach could help decrease complications. OBJECTIVE: To determine outcomes from a cohort of cranioplasty surgeries performed by a neuroplastic surgery team using a consistent surgical technique and approach. METHODS: The authors reviewed 500 consecutive adult neuroplastic surgery cranioplasties that were performed between January 2012 and September 2020. Data were abstracted from a prospectively maintained database. Univariate analysis was performed to determine association between demographic, medical, and surgical factors and odds of revision surgery. RESULTS: Patients were followed for an average of 24 months. Overall, there was a reoperation rate of 15.2% (n = 76), with the most frequent complications being infection (7.8%, n = 39), epidural hematoma (2.2%, n = 11), and wound dehiscence (1.8%, n = 9). New onset seizures occurred in 6 (1.2%) patients.Several variables were associated with increased odds of revision surgery, including lower body mass ratio, 2 or more cranial surgeries, presence of hydrocephalus shunts, scalp tissue defects, large-sized skull defect, and autologous bone flaps. importantly, implants with embedded neurotechnology were not associated with increased odds of reoperation. CONCLUSIONS: These results allow for comparison of multiple factors that impact risk of complications after cranioplasty and lay the foundation for development of a cranioplasty risk stratification scheme. Further research in neuroplastic surgery is warranted to examine how designated centers concentrating on adult neuro-cranial reconstruction and multidisciplinary collaboration may lead to improved cranioplasty outcomes and decreased risks of complications in neurosurgical patients.

Prurigo nodularis: Pathogenesis and management.

Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.

Translucent Customized Cranial Implants Made of Clear Polymethylmethacrylate: An Early Outcome Analysis of 55 Consecutive Cranioplasty Cases.

BACKGROUND: Large skull reconstruction, with the use of customized cranial implants, restores cerebral protection, physiologic homeostasis, and one's preoperative appearance. Cranial implants may be composed of either bone or a myriad of alloplastic biomaterials. Recently, patient-specific cranial implants have been fabricated using clear polymethylmethacrylate (PMMA), a visually transparent and sonolucent variant of standard opaque PMMA. Given the new enhanced diagnostic and therapeutic applications of clear PMMA, we present here a study evaluating all outcomes and complications in a consecutive patient series. METHODS: A single-surgeon, retrospective, 3-year study was conducted on all consecutive patients undergoing large cranioplasty with clear PMMA implants (2016-2019). Patients who received clear PMMA implants with embedded neurotechnologies were excluded due to confounding variables. All outcomes were analyzed in detail and compared with previous studies utilizing similar alloplastic implant materials. RESULTS: Fifty-five patients underwent cranioplasty with customized clear PMMA implants. Twenty-one (38%) were performed using a single-stage cranioplasty method (ie, craniectomy and cranioplasty performed during the same operation utilizing a prefabricated, oversized design and labor-intense, manual modification), whereas the remaining 34 (62%) underwent a standard, 2-stage reconstruction (craniectomy with a delayed surgery for cranioplasty and minimal-to-no implant modification necessary). The mean cranial defect size was 101.8 cm. The mean follow-up time was 9 months (range, 1.5-39). Major complications requiring additional surgery occurred in 7 patients (13%) consisting of 2 (4%) cerebrospinal fluid leaks, 2 (4%) epidural hematomas, and 3 (4%) infections. In addition, 3 patients developed self-limiting or nonoperative complications including 2 (4%) with new onset seizures and 1 (2%) with delayed scalp healing. CONCLUSIONS: This is the first reported consecutive case series of cranioplasty reconstruction using customized clear PMMA implants, demonstrating excellent results with regard to ease of use, safety, and complication rates well below published rates when compared with other alloplastic materials. Clear PMMA also provides additional benefits, such as visual transparency and sonolucency, which is material specific and unavailable with autologous bone. Although these early results are promising, further studies with multicenter investigations are well justified to evaluate long-term outcomes.

Bilateral Versus Unilateral Cranialization in the Management of a Breached Frontal Sinus.

BACKGROUND: Frontal sinus breach during craniotomy may occur inadvertently or intentionally. Management of a breached frontal sinus is controversial as numerous operative techniques have been described. Frontal sinus breach may result in life-threatening complications, require additional surgeries, and increase the risk for long-term infectious sequelae. A literature review found a paucity of neurosurgical reports examining breached frontal sinus management or specific analyses of unilateral versus bilateral frontal sinus cranialization. OBJECTIVE: A frontal sinus cranialization technique employed for patients involving frontal sinus breach and analyze outcomes managed with bilateral versus unilateral cranialization was presented in this study. METHODS: A retrospective review of outcomes was performed using our Institutional Review Board-approved surgical case database between September 2012 and September 2018. RESULTS: Thirty-three frontal sinus cranializations following frontal sinus breach were identified. Average follow-up time was 25 months. A statistically significant difference in postoperative infections was observed in patients with a history of previous cranial surgery who underwent unilateral compared to bilateral frontal sinus cranialization. CONCLUSION: These results suggest surgeons performing craniotomy or consulted intraoperatively for suspected frontal sinus breach should have a high suspicion for breached frontal sinus and a low threshold for frontal sinus cranialization. Furthermore, when performing frontal sinus cranialization, surgeons should consider performing bilateral, instead of unilateral, cranialization in patients with a history of previous craniotomy as bilateral cranialization was shown to decrease the risk of postoperative infection.

Risk of Complications in Primary Versus Revision-Type Cranioplasty.

INTRODUCTION: Cranioplasty (CP) is a multifaceted procedure in a heterogenous patient population, with a high risk for complication. However, no previous large-scale studies have compared outcomes in primary (ie, first attempt) CP versus revision CP (ie, following previous attempts). The authors, therefore, analyzed long-term outcomes of 506 consecutive primary and revision CPs, performed by a single surgeon. METHODS: All CPs performed between 2012 and 2019 were analyzed under IRB protocol approval. Surgeries were categorized as either primary (no previous CP; n = 279) or revision CP (at least one previous CP; n = 227). Complications were defined as either major or minor. Subgroup analyses investigated whether or not CP complication risk directly correlated with the number of previous neuro-cranial surgeries and/or CP attempts. RESULTS: The primary CP group experienced a major complication rate of 9% (26/279). In comparison, the revision CP group demonstrated a major complication rate of 32% (73/227). For the revision CP group, the rate of major complications rose with each additional surgery, from 4% (1 prior surgery) to 17% (2 prior surgeries) to 39% (3-4 prior surgeries) to 47% (≥5 prior surgeries). CONCLUSION: In a review of 506 consecutive cases, patients undergoing revision CP had a 3-fold increase in incidence of major complications, as compared to those undergoing primary CP. These results provide critical insight into overall CP risk stratification and may guide preoperative risk-benefit discussions. Furthermore, these findings may support a center-of-excellence care model, particularly for those patients with a history of previous neuro-cranial surgeries and/or CP attempts.

Transcranioplasty Ultrasound Through a Sonolucent Cranial Implant Made of Polymethyl Methacrylate: Phantom Study Comparing Ultrasound, Computed Tomography, and Magnetic Resonance Imaging.

BACKGROUND: Current methods of transcranial diagnostic ultrasound imaging are limited by the skull's acoustic properties. Craniotomy, craniectomy, and cranioplasty procedures present opportunities to circumvent these limitations by substituting autologous bone with synthetic cranial implants composed of sonolucent biomaterials. OBJECTIVE: This study examined the potential to image the brain using transcranioplasty ultrasound (TCU) through a sonolucent cranial implant. MATERIALS AND METHODS: A validated adult brain phantom was imaged using computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound without an implant. Next, for experimental comparison, TCU was performed through a sonolucent implant composed of clear polymethyl methacrylate. RESULTS: All imaging modalities successfully revealed elements of the brain phantom, including the bilateral ventricular system, the falx cerebri, and a deep hyperdense mass representing a brain tumor or hematoma. In addition, ultrasound images were captured which closely resembled axial images obtained with both CT and MRI. CONCLUSION: The results obtained in this first-ever, preclinical, phantom study suggest TCU is now a viable immediate and long-term diagnostic imaging modality deserving of further clinical investigation.

Sonolucent Cranial Implants: Cadaveric Study and Clinical Findings Supporting Diagnostic and Therapeutic Transcranioplasty Ultrasound.

BACKGROUND: Previously, sonographic evaluation of the intracranial contents was limited to intraoperative use following bone flap removal, with placement of the probe directly on the cortical surface or through a transsulcal tubular retractor. Cranioplasty with sonolucent implants may represent a postoperative window into the brain by allowing ultrasound to serve as a novel bedside imaging modality. The potential sonolucency of various commonly used cranial implant types was examined in this study. METHODS: A 3-phase study was comprised of cadaveric evaluation of transcranioplasty ultrasound (TCU) with cranioplasty implants of varying materials, intraoperative TCU during right-sided cranioplasty with clear implant made of poly-methyl-methacrylate (PMMA), and bedside TCU on postoperative day 5 after cranioplasty. RESULTS: The TCU through clear PMMA, polyether-ether-ketone, and opaque PMMA cranial implants revealed implant sonoluceny, in contrast to autologous bone and porous-polyethylene. Intraoperative ultrasound via the clear PMMA implant in a single patient revealed recognizable ventricular anatomy. Furthermore, postoperative bedside ultrasound in the same patient revealed comparable ventricular anatomy and a small epidural fluid collection corresponding to that visualized on an axial computed tomography scan. CONCLUSION: Sonolucent cranial implants, such as those made of clear PMMA, hold great promise for enhanced diagnostic and therapeutic applications previously limited by cranial bone. Furthermore, as functional cranial implants are manufactured with implantable devices housed within clear PMMA, the possibility of utilizing ultrasound for real-time surveillance of intracranial pathology becomes much more feasible.

Full-Thickness Skin Grafting for Local Defect Coverage Following Scalp Adjacent Tissue Transfer in the Setting of Cranioplasty.

INTRODUCTION: Numerous techniques have been described to overcome scalp deficiency and high-tension closure at time of cranioplasty. However, there is an existing controversy, over when and if a free flap is needed during complex skull reconstruction (ie, cranioplasty). As such the authors present here our experience using full-thickness skin grafts (FTSGs) to cover local defects following scalp adjacent tissue transfer in the setting of cranioplasty. METHODS: By way of an institutional review board-approved database, the authors identified patients treated over a 3-year period spanning January 2015 to December 2017, who underwent scalp reconstruction using the technique presented here. Patient demographics, clinical characteristics, technical details, outcomes, and long-term follow up were statistically analyzed for the purpose of this study. RESULTS: Thirty-three patients, who underwent combined cranioplasty and scalp reconstruction using an FTSG for local donor site coverage, were identified. Twenty-five (75%) patients were considered to have "high complexity" scalp defects prior to reconstruction. Of them, 12 patients (36%) were large-sized and 20 (60%) medium-sized; 21 (64%) grafts were inset over vascularized muscle or pericranium while the remaining grafts were placed over bare calvarial bone. In total, the authors found 94% (31/33) success for all FTSGs in this cohort. Two of the skin grafts failed due to unsuccessful take. Owing to the high rate of success in this series, none of the patient's risk factors were found to correlate with graft failure. In addition, the success rate did not differ whether the graft was placed over bone verses over vascularized muscle/pericranium. CONCLUSION: In contrary to previous studies that have reported inconsistent success with full-thickness skin grafting in this setting, the authors present a simple technique with consistent results-as compared to other more complex reconstructive methods-even in the setting of highly complex scalp reconstruction and simultaneous cranioplasty.

Improving Postoperative Nasal Airway Patency in Le Fort-Based, Maxillofacial Trauma Patients Via a Modified Nasal Packing Technique.

INTRODUCTION: Combined mid-face and nasal apparatus trauma injuries pose a significant challenge to airway patency (AW), in the immediate postoperative setting following fracture reduction. As such, the authors describe a modified technique with the goal of maintaining a patent nasal AW, while at the same time, minimizing nasopharyngeal bleeding and nasal AW edema-which can complicate patients requiring intermaxillary fixation (IMF) in the setting of pan-facial trauma. METHODS: A modified technique was devised to assist the reconstruction surgeon in avoiding the risks associated with tracheostomy placement. In an effort to avoid surgical AW complications and improve nasal AW patency in the setting of concurrent IMF and nasal trauma, the authors developed a 2-stage technique drawing upon knowledge from the literature and the authors' own experiences. TECHNIQUE: Following safe extubation, the authors insert open lumen nasal splints in both the nostrils, and suture them together to the nasal septum. If additional inner nasal support is required, polyvinyl alcohol nonabsorbable nasal packing dressing is covered with antibiotic ointment, and then placed within the nasal cavity lateral to the open lumen splints-as a way to further bolster the internal valve and mid-vault anatomy. DISCUSSION: Given the fact that traditional nasal packing with merocele/gauze dressing in concomitant to IMF reduced patients ability to ventilate, the authors felt that a modified technique should be applied. The authors' preferred materials in such patients are open lumen splint, which provides nasal AW patency along with some septum support accompanied by merocele dressing. The authors feel that by applying this technique they achieve dual objectives by supporting the traumatized nose and maintaining nasal AW patency.

Adult Cranioplasty Reconstruction With Customized Cranial Implants: Preferred Technique, Timing, and Biomaterials.

INTRODUCTION: Complex cranial defects requiring delayed reconstruction present numerous challenges. Delayed cranioplasties accompany frequent complications approaching an incidence of 35 to 40%. Therefore, the authors sought to collate their experience in hopes of sharing their perspective on several topics including technique, timing, and preferred biomaterials. METHODS: The authors' 5-year consecutive experience over 430 customized cranial implants is described herein. Since its inception in 2012, the authors' team has employed the pericranial-onlay cranioplasty technique instead of the standard epidural approach. Optimal timing for cranioplasty is determined using objective criteria such as scalp healing and parenchymal edema, close collaboration with neuroplastic surgery, conversion from autologous bone to sterile implant in instances of questionable viability/storage, and the first-line use of solid poly(methylmethacrylate) implants for uncomplicated, delayed cases, first-line porous polyethylene (MEDPOR) implants for single-stage cranioplasty, and first-line polyether-ether-ketone implants for cases with short notice. Furthermore, the use of the pterional design algorithm with temporal bulking for all customized implants has helped to correct and/or prevent temporal hollowing deformities. RESULTS: The authors' team has observed a three-fold reduction in reported complications as compared with the existing literature, with a major complication rate of 11%. The multidisciplinary center has provided an optimal stage for synergy and improved outcomes versus standard cranioplasty techniques. CONCLUSION: Secondary cranial reconstruction, or cranioplasty, can be challenging due to numerous reasons. These best practices, developed in collaboration with neuroplastic surgery and neurosurgery, appear to encompass the largest published experience to date. The authors find this approach to be both safe and reliable.

IL-31 Inhibition as a Therapeutic Approach for the Management of Chronic Pruritic Dermatoses.

Chronic pruritus is a debilitating symptom with limited treatment options. Identifying molecular targets underlying chronic pruritic dermatoses is essential for the development of novel, targeted therapies. IL-31 is an important mediator of itch by integrating dermatologic, neural, and immune systems. IL-31 helps induce and maintain chronic pruritus via both indirect stimulation of inflammatory cells and through direct neural sensitization. IL-31 is overexpressed in various chronic pruritic skin conditions, and exogenous IL-31 induces itch and scratching behavior. Studies have demonstrated that IL-31R and IL-31 antagonism significantly reduces itch in patients with atopic dermatitis and prurigo nodularis, two extremely pruritic skin conditions. Emerging evidence, including recent phase II clinical trials of IL-31R antagonists, demonstrates that IL-31 plays an important role in itch signaling. Additional studies are ongoing to evaluate IL-31R and IL-31 antagonism as treatments of chronic pruritus.

Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of Th2 and Th17 pathways in both lesional versus non-lesional and lesional versus control (p < 0.01), while Th1 and Th22 upregulation were observed in lesional versus control (p < 0.05). Evidence for a broad immune signature also was supported by upregulated Th1 and Th22 pathways, and clinically may represent greater severity of AD in AA. Furthermore, population-level analysis of data from TriNetX, a global federated health research network, revealed that AA AD patients had higher values for CRP, ferritin, and blood eosinophils compared to age-, sex-, and race-matched controls as well as white AD patients, suggesting broad systemic inflammation. Therefore, AA AD patients may feature broader immune activation than previously thought and may derive benefit from systemic immunomodulating therapies that modulate key drivers of multiple immune pathways.

Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization.

Prurigo nodularis (PN) is an understudied, chronic inflammatory skin disease that disproportionately affects African Americans and presents with intensely pruritic nodules of unknown etiology. To better characterize the immune dysregulation in PN, PBMCs and skin biopsies were obtained from patients with PN and healthy subjects (majority African American) matched by age, race, and sex. Flow cytometric analysis of functional T-cell response comparing patients with PN with healthy subjects identified increased γδT cells (CD3+CD4-CD8-γδTCR+) and Vδ2+ γδT enrichment. Activated T cells demonstrated uniquely increased IL-22 cytokine expression in patients with PN compared with healthy controls. CD4+ and CD8+ T cells were identified as the source of increased circulating IL-22. Consistent with these findings, RNA sequencing of lesional PN skin compared with nonlesional PN skin and biopsy site‒matched control skin demonstrated robust upregulation of T helper (Th) 22‒related genes and signaling networks implicated in impaired epidermal differentiation. Th22‒related cytokine upregulation remained significant, with stratifications by race and biopsy site. Importantly, the expression of the IL-22 receptors IL22RA1 and IL22RA2 was significantly elevated in lesional PN skin. These results indicate that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22/IL-22 profile. PN may benefit from immunomodulatory therapies directed at Th22‒mediated inflammation.