Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.

Targeting TBK1 to overcome resistance to cancer immunotherapy.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

Genome mining leads to the identification of a stable and promiscuous Baeyer-Villiger monooxygenase from a thermophilic microorganism.

Baeyer-Villiger monooxygenases (BVMOs) are NAD(P)H-dependent flavoproteins that convert ketones to esters and lactones. While these enzymes offer an appealing alternative to traditional Baeyer-Villiger oxidations, these proteins tend to be either too unstable or exhibit too narrow of a substrate scope for implementation as industrial biocatalysts. Here, sequence similarity networks were used to search for novel BVMOs that are both stable and promiscuous. Our genome mining led to the identification of an enzyme from Chloroflexota bacterium (strain G233) dubbed ssnBVMO that exhibits i) the highest melting temperature of any naturally sourced BVMO (62.5 ºC), ii) a remarkable kinetic stability across a wide range of conditions, similar to those of PAMO and PockeMO, iii) optimal catalysis at 50 °C, and iv) a broad substrate scope that includes linear aliphatic, aromatic, and sterically bulky ketones. Subsequent quantitative assays using propiophenone demonstrated >95% conversion. Several fusions were also constructed that linked ssnBVMO to a thermostable phosphite dehydrogenase. These fusions can recycle NADPH and catalyze oxidations with sub-stoichiometric quantities of this expensive cofactor. Characterization of these fusions permitted identification of PTDH-L1-ssnBVMO as the most promising protein that could have utility as a seed sequence for enzyme engineering campaigns aiming to develop biocatalysts for Baeyer-Villiger oxidations.

The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Utility of ChatGPT for Automated Creation of Patient Education Handouts: An Application in Neuro-Ophthalmology.

BACKGROUND: Patient education in ophthalmology poses a challenge for physicians because of time and resource limitations. ChatGPT (OpenAI, San Francisco) may assist with automating production of patient handouts on common neuro-ophthalmic diseases. METHODS: We queried ChatGPT-3.5 to generate 51 patient education handouts across 17 conditions. We devised the "Quality of Generated Language Outputs for Patients" (QGLOP) tool to assess handouts on the domains of accuracy/comprehensiveness, bias, currency, and tone, each scored out of 4 for a total of 16. A fellowship-trained neuro-ophthalmologist scored each passage. Handout readability was assessed using the Simple Measure of Gobbledygook (SMOG), which estimates years of education required to understand a text. RESULTS: The QGLOP scores for accuracy, bias, currency, and tone were found to be 2.43, 3, 3.43, and 3.02 respectively. The mean QGLOP score was 11.9 [95% CI 8.98, 14.8] out of 16 points, indicating a performance of 74.4% [95% CI 56.1%, 92.5%]. The mean SMOG across responses as 10.9 [95% CI 9.36, 12.4] years of education. CONCLUSIONS: The mean QGLOP score suggests that a fellowship-trained ophthalmologist may have at-least a moderate level of satisfaction with the write-up quality conferred by ChatGPT. This still requires a final review and editing before dissemination. Comparatively, the rarer 5% of responses collectively on either extreme would require very mild or extensive revision. Also, the mean SMOG score exceeded the accepted upper limits of grade 8 reading level for health-related patient handouts. In its current iteration, ChatGPT should be used as an efficiency tool to generate an initial draft for the neuro-ophthalmologist, who may then refine the accuracy and readability for a lay readership.

Anatomical determinants of occipitocervical fusion in skull base chordoma resection: a systematic review of the literature with illustrative cases.

OBJECTIVE: Skull base chordomas are rare, locally osseo-destructive lesions that present unique surgical challenges due to their involvement of critical neurovascular and bony structures at the craniovertebral junction (CVJ). Radical cytoreductive surgery improves survival but also carries significant morbidity, including the potential for occipitocervical (OC) destabilization requiring instrumented fusion. The published experience on OC fusion after CVJ chordoma resection is limited, and the anatomical predictors of OC instability in this context remain unclear. METHODS: PubMed and Embase were systematically searched according to the PRISMA guidelines for studies describing skull base chordoma resection and OC fusion. The search strategy was predefined in the authors' PROSPERO protocol (CRD42024496158). RESULTS: The systematic review identified 11 surgical case series describing 209 skull base chordoma patients and 116 (55.5%) who underwent OC instrumented fusion. Most patients underwent lateral approaches (n = 82) for chordoma resection, followed by midline (n = 48) and combined (n = 6) approaches. OC fusion was most often performed as a second-stage procedure (n = 53), followed by single-stage resection and fusion (n = 38). The degree of occipital condyle resection associated with OC fusion was described in 9 studies: total unilateral condylectomy reliably predicted OC fusion regardless of surgical approach. After lateral transcranial approaches, 4 studies cited at least 50%-70% unilateral condylectomy as necessitating OC fusion. After midline approaches-most frequently the endoscopic endonasal approach (EEA)-at least 75% unilateral condylectomy (or 50% bilateral condylectomy) led to OC fusion. Additionally, resection of the medial atlantoaxial joint elements (the C1 anterior arch and tip of the dens), usually via EEA, reliably necessitated OC fusion. Two illustrative cases are subsequently presented, further exemplifying how the extent of CVJ bony elements removed via EEA to achieve complete chordoma resection predicts the need for OC fusion. CONCLUSIONS: Unilateral total condylectomy, 50% bilateral condylectomy, and resection of the medial atlantoaxial joint elements were the most frequently described independent predictors of OC fusion in skull base chordoma resection. Additionally, consistent with the occipital condyle harboring a significantly thicker joint capsule at its posterolateral aspect, an anterior midline approach seems to tolerate a greater degree of condylar resection (75%) than a lateral transcranial approach (50%-70%) prior to generating OC instability.

The Effect of Anticoagulant and Antiplatelet Medications on Wide-Awake Hand Surgery: An Analysis of 2,162 Cases.

PURPOSE: The purpose of the study was to determine if perioperative prescription anticoagulant (AC) or antiplatelet (AP) medication use increases the rate of revision surgeries or complications following wide-awake hand surgery performed under local anesthesia. METHODS: All patients who underwent outpatient wide-awake hand surgery under local anesthesia without a tourniquet by two fellowship-trained orthopedic hand surgeons at a single academic practice over a 3-year period were included. Prescription history was reviewed to determine if any prescriptions were filled for an AC/AP drug within 90 days of surgery. All cases requiring revision were identified. Office notes were reviewed to determine postoperative complications and/or postoperative antibiotics prescribed for infection concerns. The number of revisions, complications, and postoperative antibiotic prescriptions were compared between patients who did, and did not, use perioperative AC/AP drugs. RESULTS: A total of 2,162 wide-awake local anesthesia surgeries were included, and there were 128 cases (5.9%) with perioperative AC/AP use. Of the 2,162 cases, 19 cases required revision surgery (18 without AC/AP use and one with AC/AP use). Postoperative wound complications occurred in 42 patients (38 without AC/AP use and four with AC/AP use). Of the wound complications, four were related to postoperative bleeding, one case of incisional bleeding, and three cases of incisional hematomas (three without AC/AP use and one with AC/AP use). None of these patients required additional intervention; their incisional bleeding or hematoma was resolved by their subsequent office visit. Sixty-five patients received postoperative antibiotics for infection concerns (59 without AC/AP use and six with AC/AP use). CONCLUSIONS: Prescription AC/AP medication use in the perioperative period for wide-awake hand surgery performed under local anesthesia was not associated with an increased risk for revision surgery or postoperative wound complications. This study demonstrates the safety of continuing patients' prescribed AC/AP medications during wide-awake hand surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis IV.

Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways.

It has become necessary to accept the clinical reality of therapeutic agents targeting the cancer-associated immune system. In recent decades, several investigations have highlighted the role of inflammation in cancer development. It has now been recognized that inflammatory cells secrete mediators, including enzymes, chemokines, and cytokines. These secreted substances produce an inflammatory microenvironment that is critically involved in cancer growth. Inflammation may enhance genomic instability leading to DNA damage, activation of oncogenes, or compromised tumor suppressor activity, all of which may promote various phases of carcinogenesis. Conventional cancer treatment includes surgery, radiation, and chemotherapy. However, treatment failure occurs because current strategies are unable to achieve complete local control due to metastasis. Nanoparticles (NPs) are a broad spectrum of drug carriers typically below the size of 100 nm, targeting tumor sites while reducing off-target consequences. More importantly, NPs can stimulate innate and adaptive immune systems in the tumor microenvironment (TME); hence, they induce a cancer-fighting immune response. Strikingly, targeting cancer cells with NPs helps eliminate drug resistance and tumor recurrence, as well as prevents inflammation. Throughout this review, we provide recent data on the role of inflammation in cancer and explore nano-therapeutic initiatives to target significant mediators, for example, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins (ILs) associated with cancer-related inflammation, to escort the immunomodulators to cancer cells and associated systemic compartments. We also highlight the necessity of better identifying inflammatory pathways in cancer pathophysiology to develop effective treatment plans.

Autophagy and Herpesvirus: A collaboration Contributing to Alzheimer's Disease.

Since the 1960s viral pathogenesis researchers have considered herpesviruses as an underlying factor for Alzheimer's disease (AD). We reported molecular interactions between herpes simplex virus type 1 (HSV-1) and the amyloid precursor protein (APP), the parent of amyloid plaques pathognomonic for AD (Sapute-Krishnan et al., 2003 and 2006; Chen et al., 2011, Bearer and Wu, 2019). Furthermore, others report biochemical interactions between HSV-1 and autophagy. Using several brain banks for specimens of four brain regions in post-mortems of individuals with and without cognitive impairment prior to death. Readhead et al. 2018 found molecular-genetic evidence linking activity of 6 different human herpesviruses to AD, including HSV-1, HSV-2, HHN6, HHN7, VZV and CMV to AD. Of these, HHN6, a common virus causing a minor childhood illness thought to be a nuisance, emerged as most significant. Using a quantitative trait loci approach, a network of candidate AD-associated genes were found that correlated with viral load and activity. These ontology networks did not specifically consider autophagy genes. Our hypothesis is that viral replication and egress highjacks cellular membrane systems and thereby alters autophagic function. Those individuals carrying genetic variations that protect against this dynamic will be less vulnerable to cognitive impairment despite viral load, or viral load will be diminished. Here we first prepared lists of autophagy genes (ATG), including 180 we uniquely identified through machine learning, as well as lists from publications (Mitzushima, 2019) and websites (Autophagy Gene List, Tanpaku.org). We applied software developed by Readhead et al. 2018, available through Synapse.com, to expression and sequence data from post-mortem brains obtained from publications and public sites hosted by Alzheimer's Center brain banks. We first determined ATG expression levels correlating with either non-AD (<1 plaque per section, Braak<3, and no dementia, or pre-clinical AD, defined as Braak III-IV with no cognitive impairment. Virtually all ATG were down-regulated in pre-clinical compared to non-AD controls. Next we searched the list of quantitative trait loci (QTL) that correlated with increased viral load and activity for ATG genes from 300+ brains in the Nun's Study brain bank (ROSMAP) and the Mount Sinai Brain Bank (MSBB). Lastly, we correlated those ATG-associated QTL with expression levels of these genes in control and preclinical AD (Liang et al. 2007, 2008 and 2010). We found that decreased ATG expression due to single nucleotide polymorphisms correlate with viral load and AD. This study suggests autophagy is a novel mechanism linking herpesvirus to AD, which may aid in finding new diagnostic and therapeutic targets. Since HHV6 is a common infection of childhood, infecting nearly 100% of humans, identifying genetic vulnerabilities to persistence and progression will be critically important for prevention of adult AD.

Postoperative stereotactic radiosurgery for intracranial solitary fibrous tumors: systematic review and pooled quantitative analysis.

BACKGROUND: Intracranial solitary fibrous tumors (SFTs), formerly hemangiopericytomas (HPCs), are rare, aggressive dural-based mesenchymal tumors. While adjuvant radiation therapy has been suggested to improve local tumor control (LTC), especially after subtotal resection, the role of postoperative stereotactic radiosurgery (SRS) and the optimal SRS dosing strategy remain poorly defined. METHODS: PubMed, EMBASE, and Web of Science were systematically searched according to PRISMA guidelines for studies describing postoperative SRS for intracranial SFTs. The search strategy was defined in the authors' PROSPERO protocol (CRD42023454258). RESULTS: 15 studies were included describing 293 patients harboring 476 intracranial residual or recurrent SFTs treated with postoperative SRS. At a mean follow-up of 21-77 months, LTC rate after SRS was 46.4-93% with a mean margin SRS dose of 13.5-21.7 Gy, mean maximum dose of 27-39.6 Gy, and mean isodose at the 42.5-77% line. In pooled analysis of individual tumor outcomes, 18.7% of SFTs demonstrated a complete SRS response, 31.7% had a partial response, 18.9% remained stable (overall LTC rate of 69.3%), and 30.7% progressed. When studies were stratified by margin dose, a mean margin dose > 15 Gy showed an improvement in LTC rate (74.7% versus 65.7%). CONCLUSIONS: SRS is a safe and effective treatment for intracranial SFTs. In the setting of measurable disease, our pooled data suggests a potential dose response of improving LTC with increasing SRS margin dose. Our improved understanding of the aggressive biology of SFTs and the tolerated adjuvant SRS parameters supports potentially earlier use of SRS in the postoperative treatment paradigm for intracranial SFTs.

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases.

LRRK2 serine/threonine kinase is associated with inherited Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective for LRRK2 phosphorylated Rabs, and closely related PPM1J exhibits no activity towards substrates such as Rab8a phosphorylated at Thr72 (pThr72). Here, we have identified the molecular determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a structurally conserved phosphatase fold that strikingly has evolved a 110-residue flap domain adjacent to the active site. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays, crosslinking and 3-D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimaera with the PPM1H flap domain dephosphorylates pThr72 of Rab8a both in vitro and in cellular assays. Therefore, PPM1H has acquired a Rab-specific interaction domain within a conserved phosphatase fold.

In Vitro Comparison of Local Nasal Vaccine Delivery and Correlation with Device Spray Performance.

PURPOSE: This study is the first vaccine candidate in vitro investigation with a focus on finding a correlation between the spray characteristics and the delivery efficiency of the local deposition in the nasal airways of infants under 24 months using various intranasal devices. METHODS: In vitro tests were developed to measure the spray characteristics of four intranasal delivery devices and how they regionally deliver a candidate vaccine formulation matrix in five nasal airway replicas (3 to 24 months). The correlation between the spray performance, geometric parameters, and delivery efficiency were assessed. RESULTS: All four devices performed consistently in terms of spray characteristics and were capable of delivering a high percentage of the candidate vaccine to the target areas, with a minimum delivery efficiency of 80%. Moreover, the delivery efficiency was affected by either the spray droplet size distribution or the distance between the nozzle tip and the internal nasal valve. Correlations between the spray performance and the in vitro local dose deposition were established. CONCLUSION: The infant nasal model tests can be complementary to device spray performance evaluation. In the absence of in vivo correlations, they can also facilitate the process of new product development by estimating delivery a priori.

Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro.

BACKGROUND: Harmaline is a ß-carboline alkaloid that can be extracted from the seeds of Peganum harmala. Harmaline has been shown to exhibit a potent cytotoxic effect against tumor cells. In this study, the anti-glioblastoma activity of harmaline was investigated in vitro. METHODS AND RESULTS: Cell viability, apoptosis, and cell cycle arrest were assessed in U-87 cells treated with harmaline at different doses. Reactive oxygen species (ROS) generation and the mRNA expression of apoptosis-associated genes were assessed. The anti-metastatic effect of harmaline on U-87 cells was evaluated by gelatin zymography assay where matrix metalloproteinase [MMP]-2/-9 enzymatic activity was measured, and the scratch assay was used to assess migratory responses. Flow cytometry demonstrated that harmaline could suppress the proliferation and induce sub-G1 cell cycle arrest and apoptotic cell death in glioblastoma cells. Harmaline treatment was also associated with an upregulation of the cell cycle-related genes, p21 and p53, and pro-apoptotic Bax, as well as the induction of ROS. The zymography assay indicated that the essential steps of metastasis were potently suppressed by harmaline through inhibiting the expression of MMP-2 and - 9. In addition, the migration of U-87 cells was significantly reduced after harmaline treatment. CONCLUSION: Our data suggest a basis for further research of harmaline which has potential cytotoxic activities in glioblastoma cells; inducing cell cycle arrest and apoptosis, repression of migration, possibly invasion, and metastasis.

Urolithin B inhibits proliferation and migration and promotes apoptosis and necrosis by inducing G2/M arrest and targeting MMP-2/-9 expression in osteosarcoma cells.

Osteosarcoma (OS) is the most prevalent primary bone cancer, with a high morbidity and mortality rate. Over the past decades, therapeutic approaches have not considerably improved patients' survival rates, and further research is required to find efficient treatments for OS. Data from several studies have shown that urolithin B (UB), the intestinal metabolite of polyphenolic ellagitannins, is emerging as a new class of anticancer compounds, yet its effect on OS cancer cells remains elusive. Herein, we investigated UB's antimetastatic, antiproliferative, and apoptotic effects on the MG-63 OS cell line. Cell viability assay, annexin V/propidium iodide staining, cell cycle arrest analysis, determination of the gene expression of MMP-2, MMP-9, Bax, Bcl-2, and p53 messenger RNA (mRNA), evaluation of reactive oxygen species (ROS) generation and migration, and MMP-2 and MMP-9 protein expression assessments were performed. UB caused late apoptosis, necrosis, G2/M arrest, and ROS generation in MG-63 cells. It increased the mRNA expression of the p53 tumor suppressor and Bax proapoptotic genes. UB also inhibited the migration and metastatic behavior of MG-63 OS cells by downregulating mRNA and MMP-2 and MMP-9 protein expression. In general, although further in vivo investigations are warranted, the current results showed that UB might be utilized as a potential novel natural compound for OS therapy due to its nontoxic, antiproliferative, and antimetastatic nature.

Anterior-posterior diameter is a key driver of resectability and complications for pituitary adenomas with suprasellar extension in endoscopic transsphenoidal surgery.

BACKGROUND: As endoscopic transsphenoidal approaches are more routinely selected for progressively larger pituitary adenomas with parasellar extension, understanding potential anatomical factors that limit resection and contribute to complications is becoming increasingly important for tailoring a surgical approach. This study aimed to reevaluate existing predictive tools for resectability in pituitary adenomas specifically with suprasellar extension, and furthermore identify any additional measurable features that may be more useful in preoperative planning. METHODS: A single-center retrospective chart review of adult patients who underwent endoscopic transsphenoidal surgery for pituitary adenomas with suprasellar extension from 2015 to 2020 was performed. Preoperative MRIs were systematically assessed to assign a Knosp classification, a Zurich Pituitary Score (ZPS), and for dimensional measurements of the suprasellar aspect of the lesions. Univariate comparisons and multivariate regression models were employed to assess the influence of these factors on extent of resection and postoperative complications. RESULTS: Of the 96 patients with suprasellar pituitary adenomas who underwent endoscopic transsphenoidal surgery, 74 patients (77%) had a gross total resection (GTR). Neither Knosp grade nor ZPS score, even when dichotomized, demonstrated an association with GTR (Knosp 3A-4 versus Knosp 0-2, p = 0.069; ZPS III-IV versus ZPS I-II, p = 0.079). Multivariate regression analysis identified suprasellar anterior-posterior tumor diameter (SSAP) as the only significant predictor of extent of resection in this cohort (OR 0.951, 95% CI 0.905-1.000, p = 0.048*). A higher SSAP also had the strongest association with intraoperative CSF leaks (p = 0.0012*) and an increased overall rate of postoperative complications (p = 0.002*). Further analysis of the regression model for GTR suggested an optimal cut point value for SSAP of 23.7 mm, above which predictability for failing to achieve GTR carried a sensitivity of 89% and a specificity of 41%. CONCLUSIONS: This study is unique in its examination of endoscopic transsphenoidal surgical outcomes for pituitary adenomas with suprasellar extension. Our findings suggest that previously established grading systems based on lateral extension into the cavernous sinus lose their predictive value in lesions with suprasellar extension and, more specifically, with increasing suprasellar anterior-posterior diameter.

Long-term outcomes of surgical clipping of saccular middle cerebral artery aneurysms: a consecutive series of 92 patients.

Despite advances in endovascular treatment, microsurgical clipping of middle cerebral artery (MCA) aneurysms remains appropriate. We review the high occlusion rate and treatment durability seen with surgical clipping of MCA aneurysms. We retrospectively reviewed patients who underwent microsurgical clipping of saccular MCA aneurysms by a single surgeon. Outcomes included aneurysm occlusion rate and durability, modified Rankin scale (mRS), and postoperative neurological morbidities. Ninety-two patients with 92 saccular MCA aneurysms were included, 50% of which were ruptured aneurysms. The mean follow-up period was 59 months. Complete aneurysm occlusion was achieved in all except one patient (99%) with near-complete occlusion. MCA aneurysm clipping was durable, with only one patient (1%) requiring retreatment after 4 years due to regrowth. Of the cohort, 79.3% achieved mRS 0-2 at last follow-up, including all with unruptured aneurysms. Poor outcome at discharge was associated with age > 65 (p = .03), postoperative neurological morbidities (p = .006), and aneurysm rupture (p < .001). Older age remained the single correlate for poor long-term outcome (p = .04). For ruptured aneurysms, predictors of poor long-term outcome included hemiparesis on presentation (p = .017), clinical vasospasm requiring treatment (p = .026), and infarction related to vasospasm (p = .041). Older age (p = .046) and complex anatomy (p = .036) were predictors of new postoperative neurological morbidities in the unruptured group. MCA aneurysm clipping is safe, durable, and should be considered first-line treatment for patients with saccular MCA aneurysms, especially in centers with abundant surgical experience.

Maculopathies Referred to Neuro-Ophthalmology Clinic as Optic Neuropathies: A Case Series.

BACKGROUND: The clinical features of maculopathies and optic neuropathies often overlap: Both present with decreased visual acuity and variable loss of color vision; thus, maculopathy can be misdiagnosed as optic neuropathy, leading to patient harm. We aimed to determine what findings and/or tests were most helpful in differentiating between optic neuropathy and maculopathy. METHODS: A retrospective chart review of consecutive patients over 4.5 years who were referred to neuro-ophthalmology clinics with the diagnosis of optic neuropathy but whose final diagnosis was maculopathy. Patient demographics, mode of presentation, clinical profile, complete ophthalmological examination, results of all ancillary testing, and final diagnosis were recorded. RESULTS: A total of 47 patients (27 women) were included. The median age was 55 years (range, 18-85). Most referrals were by ophthalmologists (72.3%) and optometrists (12.8%). The diagnosis of maculopathy was made in 51.1% of patients at the time of first neuro-ophthalmic consultation. Only 6.4% patients (3) had relative afferent pupillary defect. Benign disc anomalies (tilted, myopic, small, or anomalous discs) were present in 34.0%, and 21.3% had pathologic disc changes unrelated or secondary to maculopathy. Macular ocular coherence tomography (OCT) was abnormal in 84.4% (with outer retinal pathology in 42.2% and inner retina pathology in 17.8%). Retinal nerve fiber layer (RNFL) thickness was normal in 82.6% of patients. CONCLUSIONS: Macular OCT is a high-yield test in differentiating between optic neuropathy and maculopathy and should be obtained in patients with suspected optic neuropathies who have normal RNFL thickness. Macular dystrophies, particularly cone dystrophies, unspecified retinal disorders, and macular degeneration were the most common mimics of optic neuropathy. The diagnosis was often present on OCT of the macula. The presence of coexistent benign and pathological disc anomalies may lead to maculopathy being misdiagnosed as optic neuropathy.

Unilateral Pendular Nystagmus in Multiple Sclerosis: A Case Series.

BACKGROUND: Acquired pendular nystagmus is most often seen in patients with demyelinating disease. Although it is often bilateral, rare cases may be monocular. There is paucity of data on the spectrum of clinical presentation, underlying mechanism, and response to treatment in patients with monocular pendular nystagmus. METHODS: Retrospective case series of patients with monocular pendular nystagmus seen in 2 tertiary neuro-ophthalmology clinics between January 2019 and June 2022. All patients underwent a complete neuro-ophthalmological assessment and MRI. RESULTS: We describe 5 patients (3 women) aged 31-49 with monocular pendular nystagmus. All had a diagnosis of multiple sclerosis. Three patients had horizontal and 2 had vertical pendular nystagmus. The Snellen visual acuity in the eye with pendular nystagmus varied from 20/20 to 20/200. Two patients were asymptomatic and 3 suffered visually debilitating oscillopsia. Treatment response was available for 2 patients, both of which responded well to treatment with memantine. The pendular nystagmus was observed in the eye with worse visual acuity in 4 of 5 cases (80%). Three patients had bilateral pontine lesions, and 2 had unilateral pontine lesion ipsilateral to the side of nystagmus. CONCLUSIONS: Monocular pendular nystagmus in adults is seen most often in patients with multiple sclerosis. Asymmetry in brainstem lesions and afferent visual input may be the culprit. Treatment with memantine may result in significant improvement in symptomatic patients.

Inappropriate Indexing of Case Reports to the "Papilledema" Subject Heading: A Systematic Review.

BACKGROUND: Papilledema must be managed distinctly from other causes of optic disc edema (ODE) due to its basis in raised intracranial pressure (ICP). However, evidence indicates that the term "papilledema" is widely misused across specialties to describe ODE without raised ICP. Sources of this misconception remain undiscerned. Because all physicians consult medical databases, our objective was to evaluate whether nonspecific "papilledema" subject heading definitions misleadingly associate articles on other conditions with papilledema proper. METHODS: Systematic review of case reports, prospectively registered on PROSPERO (CRD42022363651). MEDLINE and Embase were searched to July 2022 for any full-length case report indexed to the "papilledema" subject heading. Studies were graded for incorrect indexing, defined as cases lacking evidence for raised ICP. Nonpapilledema diagnoses were assigned to a predefined set of diseases and pathophysiological mechanisms for subsequent comparison. RESULTS: Incorrect indexing occurred in 40.67% of 949 included reports. Embase-derived studies were misindexed significantly less than MEDLINE-derived studies ( P < 0.01). There was also significant heterogeneity in incorrect indexing among specific diseases ( P = 0.0015) and mechanisms ( P = 0.0003). The most commonly misindexed diseases were uveitis (21.24% of errors), optic neuritis (13.47%), and instances with no mention of ODE (13.99%). The most commonly misindexed mechanisms were inflammation (34.97%), other mechanism (e.g., genetic; 25.91%), and ischemia (20.47%). CONCLUSIONS: Database subject headings, especially from MEDLINE, do not adequately distinguish between true papilledema and other causes of ODE. Inflammatory diseases were most often incorrectly indexed among other diseases and mechanisms. Current "papilledema" subject headings should be revised to reduce the probability of misinformation.