Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers Treated With Iterative Hyperthermic Intraperitoneal Chemotherapy.

PURPOSE: High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored. MATERIALS AND METHODS: We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes. RESULTS: Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7-25.3) and the median overall survival was 11.4 months (4.7-42). Mucin-associated genes (MUC16, MUC3A, and MUC5AC) and titin (TTN) had the highest mutation frequencies. Mutational signatures such as single-base substitution 29 and doublet-base substitution 11 were present in >50% of single-base and double-base mutations. Higher PD-L1 coexpression on CD8+ T cells demonstrated a higher PFS both intratumorally (P = .019) and at the margin (P = .025). CONCLUSION: HIPEC-associated mutational signatures were identified in HGAA-PMs. Elevated PD-L1+ cytotoxic T-cell populations after HIPEC had better PFS, offering valuable insights for prognostication in the context of HIPEC treatment.

TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3.

PURPOSE: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC. METHODS: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers). RESULTS: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3. CONCLUSION: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.

GP100 expression is variable in intensity in melanoma.

Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection.

Surgical Outcomes and Utilization of Laparoscopic Versus Robotic Techniques for Elective Colectomy in Asian American and Native Hawaiian-Pacific Islanders (AAPI) Diagnosed With Colon Cancer.

INTRODUCTION: Asian American and Native Hawaiian-Pacific Islanders (AAPI) are the fastest growing racial-ethnic group, with 18.9 million people in 2019, and is predicted to rise to 46 million by 2060. Colorectal cancer (CRC) is the most common cancer in AAPI men and the third most common in women. Treatment techniques like laparoscopic colectomy (LC) emerged as the standard of care for CRC resections; however, new robotic technologies can be advantageous. Few studies have compared clinical outcomes across minimally invasive approaches for AAPI patients with CRC. This study compares utilization and clinical outcomes of LC versus robotic colectomies (RCs) in AAPI patients. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for elective RC and LC in AAPI patients from 2012 to 2020. Outcomes included unplanned conversion to open, operative time, complications, 30-d mortality, and length of stay. Multivariable logistic regression analyses assessed the association between outcomes and the operative approach. RESULTS: Between 2012 and 2020, 83,841 patients underwent elective LC or RC. Four thousand six hundred fifty-eight AAPI patients underwent 3817 (82%) LCs and 841 (18%) RCs. In 2012, all procedures were performed laparoscopically; by 2020, 27% were robotic. Mean operative time was shorter in LC (192 versus 249 min, P < 0.001). On multivariable logistic regression, there was no difference in infection (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.59-1.12), anastomotic leak (OR 0.97, 95% CI 0.59-1.61), or death (OR 0.9, 95% CI 0.31-2.61). Length of stay was shorter for RC (-0.44 d, 95% CI -0.71 to -0.18 d). CONCLUSIONS: Overall, AAPI postoperative outcomes are similar between LC and RC. Future studies that evaluate costs and resource utilization can assist hospitals in determining whether implementing robotic-assisted technologies in their hospitals and communities will be appropriate.

Outcomes Following Implementation of an Electronic Model for Perioperative Hematologic Consultation.

INTRODUCTION: Electronic consultations (e-consults) for periprocedural hematologic questions were introduced at the VA Connecticut Healthcare System in 2011. We sought to explore the relationship between the availability of e-consults, referral patterns, and surgical outcomes. METHODS: A single-center retrospective study of all perioperative hematologic consultations from 2006 to 2018 was conducted. Patient characteristics, indications, and outcomes were analyzed. Primary outcome measures were time from consult to surgery and operative morbidity via Clavien-Dindo classification. Secondary outcomes included consult volume and procedural outcomes of interest. RESULTS: Of 357 consultations, 62% were conducted via e-consults. 68.3% had associated procedural data and constituted the study cohort. Annual consult volume increased from 7 in 2006 to 41 in 2018, a 5.8-fold increase. E-consults comprised 20% of consults in 2011 but had risen to 92.3% in 2018. Time to resolution of e-consults after 2011 improved compared to pre-face-to-face (FTF-pre, P = 0.001) and FTF-post (P = 0.002). Time from consult to surgery remained unchanged. 8.4% had major complications (Clavien-Dindo >2) with readmission or reoperation occurring in 4.0% and 3.7%, respectively. Intraoperative and postoperative transfusions were required in 15.2% and 13.1% of cases, respectively. Hematologic complications (i.e., deep vein thrombosis/pulmonary embolism) occurred in 3.5%. Comparison between FTF and e-consults revealed no significant differences in these outcomes (P > 0.05, all). CONCLUSIONS: E-consults for perioperative hematologic issues were rapidly adopted and addressed more quickly than FTF consultation while time to surgery was unchanged despite increased consult volume. Adoption of the e-consult model was not associated with changes in the assessed operative outcomes.

Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers.

PURPOSE: Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC. METHODS: Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated. RESULTS: In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence. CONCLUSION: This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.

Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma.

PURPOSE: Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in patients with melanoma, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. METHODS: Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. RESULTS: We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions and ulcerated lesions and was associated with shorter survival in primary and metastatic tumors. On multivariable analysis, Breslow thickness, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. CONCLUSION: Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

Educational Review: Clinical Application of Immune Checkpoint Blockade for the Treatment of Melanoma.

In the last decade, immunotherapy has become the cornerstone in the management of patients with melanoma, the foremost cause of skin-cancer-related death in the USA. The emergence of immune checkpoint blockade as a crucial element in current immunotherapy and combination strategies has significantly transformed the treatments of resectable and advanced (unresectable or metastatic) melanoma. This paper reviews the landmark clinical trials that formed the basis of management of melanoma in the perioperative and metastatic setting. Furthermore, we discuss the rationale for the applications of PD-1 blockade and its combination with anti-CTLA-4 and anti-LAG-3. The review also explores new experimental combinations of PD-1 blockade with other immunomodulatory agents, including targeted therapies, anti-TIGIT antibodies, TLR-9 agonists, antiangiogenic agents, and mRNA vaccines.

Melanocortin 1 receptor (MC1R) expression as a marker of progression in melanoma.

Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in melanoma patients, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions, ulcerated lesions, and mucosal melanomas compared to cutaneous melanomas and was associated with shorter survival in primary and metastatic tumors. On multi-variable analysis, Breslow thickness, ulceration, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. In the metastatic melanoma cohort, MC1R expression and mucosal melanomas were independent predictors of inferior overall survival. Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Intrafascicular peripheral nerve stimulation produces fine functional hand movements in primates.

Restoring dexterous hand control is critical for people with paralysis. Approaches based on surface or intramuscular stimulation provide limited finger control, generate insufficient force to recover functional movements, and require numerous electrodes. Here, we show that intrafascicular peripheral electrodes could produce functional grasps and sustained forces in three monkeys. We designed an intrafascicular implantable electrode targeting the motor fibers of the median and radial nerves. Our interface selectively and reliably activated extrinsic and intrinsic hand muscles, generating multiple functional grips, hand opening, and sustained contraction forces for up to 2 months. We extended those results to a behaving monkey with transient hand paralysis and used intracortical signals to control simple stimulation protocols that enabled this animal to perform a functional grasping task. Our findings show that just two intrafascicular electrodes can generate a rich portfolio of dexterous and functional hand movements with important implications for clinical applicability.

Cortical Responses to Vagus Nerve Stimulation Are Modulated by Brain State in Nonhuman Primates.

Vagus nerve stimulation (VNS) has been tested as therapy for several brain disorders and as a means to modulate cortical excitability and brain plasticity. Cortical effects of VNS, manifesting as vagal-evoked potentials (VEPs), are thought to arise from activation of ascending cholinergic and noradrenergic systems. However, it is unknown whether those effects are modulated by brain state at the time of stimulation. In 2 freely behaving macaque monkeys, we delivered short trains of 5 pulses to the left cervical vagus nerve at different frequencies (5-300 Hz) while recording local field potentials (LFPs) from sites in contralateral prefrontal, sensorimotor and parietal cortical areas. Brain states were inferred from spectral components of LFPs and the presence of overt movement: active awake, resting awake, REM sleep and NREM sleep. VNS elicited VEPs in all sampled cortical areas. VEPs comprised early (<70 ms), intermediate (70-250 ms) and late (>250 ms) components. The magnitude of the intermediate and late components was largest during NREM sleep and smallest during wakefulness, whereas that of the early component was not modulated by brain state. VEPs during NREM were larger for stimuli delivered at the depolarized phase of ongoing delta oscillations. Higher pulsing frequencies generated larger VEPs. These short VNS trains did not affect brain state transitions during wakefulness or sleep. Our findings suggest that ongoing brain state modulates the evoked effects of VNS on cortical activity. This has implications for the role of ongoing cortical activity and brain state in shaping cortical responses to peripheral stimuli, for the modulation of vagal interoceptive signaling by cortical activity, and for the dose calibration of VNS therapies.

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir.

Broadly neutralizing antibodies (bNAbs) against HIV-1 are under evaluation for both prevention and therapy. HIV-1 sequence diversity observed in most HIV-infected individuals and archived variations in critical bNAb epitopes present a major challenge for the clinical application of bNAbs, as preexistent resistant viral strains can emerge, resulting in bNAb failure to control HIV. In order to identify viral resistance in patients prior to antibody therapy and to guide the selection of effective bNAb combination regimens, we developed what we believe to be a novel Bayesian machine-learning model that uses HIV-1 envelope protein sequences and foremost approximated glycan occupancy information as variables to quantitatively predict the half-maximal inhibitory concentrations (IC50) of 126 neutralizing antibodies against a variety of cross clade viruses. We then applied this model to peripheral blood mononuclear cell-derived proviral Env sequences from 25 HIV-1-infected individuals mapping the landscape of neutralization resistance within each individual's reservoir and determined the predicted ideal bNAb combination to achieve 100% neutralization at IC50 values <1 µg/ml. Furthermore, predicted cellular viral reservoir neutralization signatures of individuals before an analytical antiretroviral treatment interruption were consistent with the measured neutralization susceptibilities of the respective plasma rebound viruses, validating our model as a potentially novel tool to facilitate the advancement of bNAbs into the clinic.

Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review.

Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities.

Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys.

HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with nonsigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo, however, is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C simian-human immunodeficiency virus (SHIV) stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques. The animals were intravenously (i.v.) administered PGT121 or 3BNC117 at 10 and 2 mg/kg of body weight before being rectally challenged with a single high dose of SHIV-327c. PGT121 protected 6 out of 7 monkeys, while 6 out of 7 3BNC117-pretreated animals became infected, although with significantly delayed plasma viremia compared to the control animals. These data suggest that complete neutralization is not imperative for bnAbs to prevent infection but that with increasing levels of incomplete neutralization the sterilizing activity diminishes.IMPORTANCE Multiple antibodies have been identified that potently neutralize a broad range of circulating HIV strains. However, not every virus-antibody combination results in complete neutralization of the input virus, suggesting that a fraction of virus particles are resistant to antibody neutralization despite high antibody concentrations. This observation of "incomplete neutralization" is associated with nonsigmoidal neutralization curves plateauing below 100% neutralization, but the significance of the phenomenon for the ability of neutralizing antibodies to mediate protective effects in vivo is undetermined. In this study, we show that the broadly neutralizing antibody PGT121, which neutralized only up to 85% of the SHIV-327c challenge stock in vitro, protected 6 out of 7 rhesus macaques against infection while the antibody 3BNC117, which neutralized up to 70% of SHIV-327c in vitro, did not prevent, though it significantly delayed, establishment of infection, suggesting that with increasing levels of incomplete neutralization the ability of a bnAb to mediate sterilizing protection diminishes.

Radiofrequency microtenotomy is as effective as plantar fasciotomy in the treatment of recalcitrant plantar fasciitis.

BACKGROUND: Radiofrequency microtenotomy (RM) is effective for treating plantar fasciitis. No studies have compared it to the plantar fasciotomy (PF). We hypothesized that RM is equally effective and provides no additional benefit when performed with PF. METHODS: Between 2007 and 2014, all patients who underwent either or both procedures concurrently at our institution were analyzed. Data collected included demographics, SF-36 Health Survey, AOFAS Ankle-Hindfoot Scale, and two questions regarding satisfaction and expectations, all of which were assessed pre-operatively and post-operatively at 6-months and 1-year. ANOVA with Bonferroni correction was used to compare scores at each interval. Logistic regression was used to identify pre-operative factors that predicted for satisfaction and expectations. RESULTS: There were no differences in patient outcomes. No pre-operative factors predicted for satisfaction and expectations. CONCLUSIONS: RM is as effective as PF in the treatment of plantar fasciitis. Patients who underwent both procedures experienced no benefit and a higher rate of complications.

Ultrasound stylet for non-image-guided ventricular catheterization.

OBJECT Urgent ventriculostomy placement can be a lifesaving procedure in the setting of hydrocephalus or elevated intracranial pressure. While external ventricular drain (EVD) insertion is common, there remains a high rate of suboptimal drain placement. Here, the authors seek to demonstrate the feasibility of an ultrasound-based guidance system that can be inserted into an existing EVD catheter to provide a linear ultrasound trace that guides the user toward the ventricle. METHODS The ultrasound stylet was constructed as a thin metal tube, with dimensions equivalent to standard catheter stylets, bearing a single-element, ceramic ultrasound transducer at the tip. Ultrasound backscatter signals from the porcine ventricle were processed by custom electronics to offer real-time information about ventricular location relative to the catheter. Data collected from the prototype device were compared with reference measurements obtained using standard clinical ultrasound imaging. RESULTS A study of porcine ventricular catheterization using the experimental device yielded a high rate of successful catheter placement after a single pass (10 of 12 trials), despite the small size of pig ventricles and the lack of prior instruction on porcine ventricular architecture. A characteristic double-peak signal was identified, which originated from ultrasound reflections off of the near and far ventricular walls. Ventricular dimensions, as obtained from the width between peaks, were in agreement with standard ultrasound reference measurements (p < 0.05). Furthermore, linear ultrasound backscatter data permitted in situ measurement of the stylet distance to the ventricular wall (p < 0.05), which assisted in catheter guidance. CONCLUSIONS The authors have demonstrated the ability of the prototype ultrasound stylet to guide ventricular access in the porcine brain. The alternative design of the device makes it potentially easy to integrate into the standard workflow for bedside EVD placement. The availability of a fast, easy-to-use, inexpensive guidance system can play a role in reducing the complication rate for EVD placement.

Sequential activation of premotor, primary somatosensory and primary motor areas in humans during cued finger movements.

OBJECTIVE: Human voluntary movements are a final product of complex interactions between multiple sensory, cognitive and motor areas of central nervous system. The objective was to investigate temporal sequence of activation of premotor (PM), primary motor (M1) and somatosensory (S1) areas during cued finger movements. METHODS: Electrocorticography (ECoG) was used to measure activation timing in human PM, S1, and M1 neurons in preparation for finger movements in 5 subjects with subdural grids for seizure localization. Cortical activation was determined by the onset of high gamma (HG) oscillation (70-150Hz). The three cortical regions were mapped anatomically using a common brain atlas and confirmed independently with direct electrical cortical stimulation, somatosensory evoked potentials and detection of HG response to tactile stimulation. Subjects were given visual cues to flex each finger or pinch the thumb and index finger. Movements were captured with a dataglove and time-locked with ECoG. A windowed covariance metric was used to identify the rising slope of HG power between two electrodes and compute time lag. Statistical constraints were applied to the time estimates to combat the noise. Rank sum testing was used to verify the sequential activation of cortical regions across 5 subjects. RESULTS: In all 5 subjects, HG activation in PM preceded S1 by an average of 53±13ms (P=0.03), PM preceded M1 by 180±40ms (P=0.001) and S1 activation preceded M1 by 136±40ms (P=0.04). CONCLUSIONS: Sequential HG activation of PM, S1 and M1 regions in preparation for movements is reported. Activity in S1 prior to any overt body movements supports the notion that these neurons may encode sensory information in anticipation of movements, i.e., an efference copy. Our analysis suggests that S1 modulation likely originates from PM. SIGNIFICANCE: First electrophysiological evidence of efference copy in humans.

Multiportal robotic access to the anterior cranial fossa: a surgical and engineering feasibility study.

OBJECTIVE: Integration of robotic surgical technology into skull base surgery is limited due to minimum angle requirements between robotic tools (narrow funnel effect), steep angle of approach, and instrumentation size. The objectives of this study were to systematically analyze surgical approach portals using a computer model, determine optimal approaches, and assess feasibility of the derived approaches on robotic surgical systems. STUDY DESIGN: Computer analysis on 10 computed tomography scans was performed to determine approach trajectories, angles between robotic tools, and distances to specified skull base target locations for transorbital and transnasal surgical approach portals. SETTING: Dry laboratory and cadaver laboratory. SUBJECTS AND METHODS: The optimal combinations were tested on the da Vinci and Raven robotic systems. RESULTS: Multiportal analyses showed the angles between 2 robotic tools were 14.7, 28.3, and 52.0 degrees in the cases of 2 transnasal portals, combined transnasal and medial orbit portals, and bilateral superior orbit portals, respectively, approaching a prechiasmatic target. The addition of medial and superior transorbital portals improved the skull base trajectory angles 21 and 27 degrees, respectively. Two robotic tools required an angle of at least 20 degrees between them to function effectively at skull base targets. CONCLUSION: Technical feasibility of robotic transorbital and transnasal approaches to access sella and parasellar target locations was demonstrated. This technique addresses the 2 major drawbacks of (1) the narrow funnel effect generated from portals in close proximity and (2) the steep angle of approach to the skull base, as observed in previous studies analyzing transoral, transcervical, transmaxillary, and transhyoid portals.