Randomized phase 2 dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.

BACKGROUND: Belzutifan is a first-in-class HIF-2α inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed death receptor (or ligand)-1 (PD-[L]1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether belzutifan dose could be optimized is unclear. PATIENTS AND METHODS: The phase 2 LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after 1-3 prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1:1 to receive belzutifan 120 mg or 200 mg once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% vs 23.1% for the 120 mg and 200 mg groups, respectively (P = 0.5312; -0.5% [95% CI, -14.0 to 12.9]. Median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS (HR 0.94 [95% CI 0.63-1.40]) or OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. CONCLUSION: The efficacy of belzutifan was similar between the 120-mg dose and the 200-mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial.

BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214. PATIENTS AND METHODS: Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. RESULTS: With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. CONCLUSIONS: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Using content-based image retrieval of dermoscopic images for interpretation and education: A pilot study.

BACKGROUND: Dermoscopic content-based image retrieval (CBIR) systems provide a set of visually similar dermoscopic (magnified and illuminated) skin images with a pathology-confirmed diagnosis for a given dermoscopic query image of a skin lesion. Although recent advances in machine learning have spurred novel CBIR algorithms, we have few insights into how end users interact with CBIRs and to what extent CBIRs can be useful for education and image interpretation. MATERIALS AND METHODS: We developed an interactive user interface for a CBIR system with dermoscopic images as a decision support tool and investigated users' interactions and decisions with the system. We performed a pilot experiment with 14 non-medically trained users for a given set of annotated dermoscopic images. RESULTS: Our pilot showed that the number of correct classifications and users' confidence levels significantly increased with the CBIR interface compared with a non-CBIR interface, although the timing also increased significantly. The users found the CBIR interface of high educational value, engaging and easy to use. CONCLUSION: Overall, users became more accurate, found the CBIR approach provided a useful decision aid, and had educational value for learning about skin conditions.

Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions.

In recent years, there has been dramatic expansion of the treatment armamentarium for patients with advanced renal cell carcinoma (aRCC), including drugs targeting vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways. Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action. The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies. Specifically, drugs targeting the programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, non-small cell lung cancer, aRCC, advanced squamous cell carcinoma of the head and neck, urothelial cancer and Hodgkin lymphoma. In aRCC, the PD-1 inhibitor nivolumab was approved in both the United States and Europe for the treatment of patients who have received prior therapy, based on improved overall survival compared with the mTOR inhibitor everolimus. Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC. In this review, current evidence related to the clinical use of checkpoint inhibitors for the treatment of patients with aRCC is discussed, including information on the frequency and management of unconventional responses and the management of immune-related adverse events. In addition, perspectives on the future use of checkpoint inhibitors are discussed, including the potential value of treatment beyond progression, the potential use in earlier lines of care or in combination with other agents, and the identification of biomarkers to guide patient selection and enable individualization of therapy.

Antibody screening tests variably overestimate the prevalence of hepatitis C virus infection among HIV-infected adults in Ghana.

HIV coinfection with HCV has been poorly studied in sub-Saharan Africa, and the reliability of available seroprevalence estimates remains uncertain. The study aim was to determine HCV RNA prevalence in HIV-infected subjects receiving care in Kumasi, Ghana, and relate the findings to HCV antibody detection. From a population of 1520 HIV-infected adults, all HBsAg-positive subjects (n = 236) and a random subset of HBsAg-negative subject (n = 172) were screened for HCV RNA using pooled plasma; positive samples were genotyped by core and NS5B sequencing. HCV antibodies were detected by three commercial screening assays and confirmed by the line immunoassay. HCV RNA was detected in 4/408 subjects (1.0%, 95% confidence interval 0.0-1.9%), comprising 3/236 (1.3%; 0.0-2.8%) HBsAg-positive and 1/172 (0.6%; 0.0-1.8%) HBsAg-negative subjects. HCV RNA-positive subjects showed reactivity in all three antibody screening assays. Among HCV RNA-negative subjects, 5/67 (7.5%), 5/67 (7.5%) and 19/67 (28.4%) showed antibody reactivity by each screening assay, respectively, including two (3.0%) with reactivity by all three assays. Only one sample (1.5%) had confirmed antibody reactivity by line immunoassay indicating past HCV infection. HCV-positive subjects (three males, two females) were aged 30-46 years, by questionnaire-based interview reported surgical procedures and blood transfusion as risk factors for infection. HCV genotypes were 2 (subtypes 2j, 2l, 2k/unassigned) and 1 (subtype unassigned). Without further testing, HCV antibody screening assays variably overestimated HCV prevalence among HIV-infected subjects in Ghana. These findings inform the interpretation of previous seroprevalence estimates based upon screening assays alone.

Application of RT-Bst to enhance detection of pathogenic viruses of the respiratory tract.

Inefficiency of RT-PCR can be associated with the suboptimal process of reverse transcription as only 40-80% of RNA is converted to cDNA. We employed a novel method, RT-Bst, to enrich the concentration of cDNA for subsequent multiplex PCR detection of selected RNA viruses. The RT-Bst method amplifies cDNA through reverse transcription of viral RNA using reverse transcriptase and amplification of cDNA using Bst DNA polymerase. Viral RNA was extracted from 25 nasopharyngeal samples for detection of influenza A, B and C; parainfluenza 1-4; human coronaviruses 229E and OC43; respiratory syncytial virus (RSV) and rhinovirus. Both multiplex one-step RT-PCR and RT-Bst PCR were used to compare their performances for detection of virus sequences. These findings were compared with routine laboratory detection. When using RT-Bst PCR, 28% of samples yielded a viral pathogen compared to 20% with RT-PCR and 12% using routine diagnostic tests. RT-Bst PCR was shown to have particular utility in the detection of RSV RNA as this was present in 20% of the samples studied compared to 8% when using RT-PCR. For one patient, RT-Bst PCR was able to detect RSV five days earlier than conventional hospital diagnostic testing. RT-Bst and RT-Bst PCR can be used as alternative approaches to reverse transcription and one-step RT-PCR, respectively, for sequence-independent amplification of RNA virus sequences and a larger scale analysis of this new diagnostic approach is warranted.

Detection of Changes in Surgical Difficulty: Evidence From Pupil Responses.

BACKGROUND: Assessing the workload of surgeons requires technology to continuously monitor surgeons' behaviors without interfering with their performance. We investigated the feasibility of using eye-tracking to reveal surgeons' response to increasing task difficulty. METHODS: A controlled study was conducted in a simulated operating room, where 14 subjects were required to perform a laparoscopic procedure that includes 9 subtasks. The subtasks could be divided into 3 types with different levels of task difficulty, calculated by the index of task difficulty (ID) proposed by Fitts in 1954. Pupillary responses of subjects in performing the procedure were recorded using Tobii eye-tracking equipment. Peak pupil dilation and movement time were compared between subtasks with different IDs as well as between fast moving and slow aiming phases within each subtask. RESULTS: When the task difficulty was increased, task completion time increased. Meanwhile, the subjects' peak pupil size also increased. As the entire procedure was performed continuously, we found that pupil responses were not only affected by the ID in the current subtask but also influenced by subtasks before and after. DISCUSSION: Decomposing a surgical procedure into meaningful subtasks and examining the surgeon's pupil response to each subtask enables us to identify the challenging steps within a continuous surgical procedure. Psychomotor evidence on surgeon's performance may lead to an innovation for designing a task-specific training curriculum.

Video processing to locate the tooltip position in surgical eye-hand coordination tasks.

INTRODUCTION: Trajectories of surgical instruments in laparoscopic surgery contain rich information about surgeons' performance. In a simulation environment, instrument trajectories can be taken by motion sensors attached to the instruments. This method is not accepted by surgeons working in the operating room due to safety concerns. In this study, a novel approach of acquiring instrument trajectories from surgical videos is reported. METHODS: A total of 12 surgical videos were obtained for this study. The videos were captured during simulated laparoscopic procedures where subjects were required to pick up and transport an object over 3 different targets using a laparoscopic grasper. An algorithm was developed to allow the computer to identify the tip of the grasper on each frame of video, and then compute the trajectories of grasper movement. RESULTS: The newly developed algorithm successfully identified tool trajectories from all 12 surgical videos. To validate the accuracy of this algorithm, the location of the tooltip in these videos were also manually labeled. The rate of accurate matching between these 2 methods was 98.4% of all video frames. DISCUSSION: Identifying tool movement from surgical videos creates an effective way to track instrument trajectories. This builds up the foundation for assessing psychomotor performance of surgeons in the operating room without jeopardizing patient safety.

PD-L1 expression in nonclear-cell renal cell carcinoma.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown. METHODS: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data [time to recurrence (TTR) and overall survival (OS)] were correlated with PD-L1 staining. RESULTS: Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively). CONCLUSION: In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.

Persistent erythema multiforme associated with Epstein-Barr virus infection.

Erythema multiforme (EM) is a common, self-limiting condition. Recurrent EM is a well-recognised variant, often associated with herpes simplex virus infection. It is frequently managed with prophylactic aciclovir. Anecdotal reports suggest that recurrent EM may be associated with the use of corticosteroids. Persistent EM, however, is a rare variant, with few cases reported in the literature. It has a protracted course often with atypical and inflammatory lesions. It has been associated with occult viral infections, particularly Epstein-Barr Virus (EBV), as well as inflammatory bowel disease and malignancy. We report a case of EM associated with EBV infection.

Comparison of Novel and Traditional Bleeding Techniques in Neonatal and Juvenile Mice.

Blood collection is frequently used for neonatal and juvenile mice in toxicology, developmental, and immunology studies and is often a terminal procedure. However, the use of nonterminal blood collection techniques, including the submandibular and the submental collection techniques described for adult mice, may offer opportunities to reduce animal numbers and refine current methods. The use of the submental technique has not been described for neonatal or juvenile mice. In this study, we compared the submental and submandibular blood collection techniques to determine their suitability for use in neonatal and juvenile mice. Male and female CD1 mice, ages 7, 14, 21, and 28 d, were randomized by sex into submental (n = 16), submandibular (n = 16), or control (n = 8) groups. Each mouse was weighed, bled per its assigned group (or only restrained in the case of control mice), and then decapitated without anesthesia for terminal blood collection. Blood collection volume and corticosterone concentrations were measured. The 2 methods showed significant differences in the volume of blood collected at ages 14 and 28, with the submandibular technique yielding significantly higher volumes. No significant differences were detected in corticosterone levels between the 2 techniques based on age or sex. A subset of mice (n = 8, 2 per age group) were bled via submental or submandibular technique and were evaluated 48 h later for gross and histopathologic evidence of trauma. Seven of the 8 mice showed expected inflammation and healing at the collection sites, with 4 mice having embedded strands of fur in the tissue. These data indicate that the submental blood collection is a viable method for nonterminal blood collection method in neonatal and juvenile mice, especially when smaller amounts of blood are needed.

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts.

BACKGROUND: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. METHODS: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. RESULTS: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. CONCLUSION: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.

Routine HIV testing in the emergency department: tough lessons in sustainability.

OBJECTIVES: Routine HIV testing in nonspecialist settings has been shown to be acceptable to patients and staff in pilot studies. The question of how to embed routine HIV testing, and make it sustainable, remains to be answered. METHODS: We established a service of routine HIV testing in an emergency department (ED) in London, delivered by ED staff as part of routine clinical care. All patients aged 16 to 65 years were offered an HIV test (latterly the upper age limit was removed). Meetings were held weekly and two outcome measures examined: test offer rate (coverage) and test uptake. Sustainability methodology (process mapping; plan-do-study-act (PDSA) cycles) was applied to maximize these outcome measures. RESULTS: Over 30 months, 44,582 eligible patients attended the ED. The mean proportion offered an HIV test was 14%, varying from 6% to 54% per month over the testing period. The mean proportion accepting a test was 63% (range 33-100%). A total of 4327 HIV tests have been performed. Thirteen patients have been diagnosed with HIV infection (0.30%). PDSA cycles having the most positive and sustained effects on the outcome measures include the expansion to offer blood-based HIV tests in addition to the original oral fluid tests, and the engagement of ED nursing staff in the programme. CONCLUSIONS: HIV testing can be delivered in the ED, but constant innovation and attention have been required to maintain it over 30 months. Patient uptake remains high, suggesting acceptability, but time will be required before true embedding in routine clinical practice is achieved.

Automatic oral fluid-based HIV testing in HIV screening programmes: automatic for the people.

OBJECTIVES: UK guidelines recommend routine HIV testing in general clinical settings when the local HIV prevalence is > 0.2%. During pilot programmes evaluating the guidelines, we used laboratory-based testing of oral fluid from patients accepting tests. Samples (n = 3721) were tested manually using the Bio-Rad Genscreen Ultra HIV Ag-Ab test (Bio-Rad Laboratories Ltd, Hemel Hempstead, UK). This was a methodologically robust method, but handling of samples was labour intensive. We performed a validation study to ascertain whether automation of oral fluid HIV testing using the fourth-generation HIV test on the Abbott Architect (Abbott Diagnostics, Maidenhead, UK) platform was possible. METHODS: Oral fluid was collected from 143 patients (56 known HIV-positive volunteers and 87 others having contemporaneous HIV serological tests) using the Oracol+ device (Malvern Medicals, Worcester, UK). Samples were tested concurrently: manually using the Genscreen Ultra test and automatically on the Abbott Architect. RESULTS: For oral fluid, the level of agreement of results between the platforms was 100%. All results agreed with HIV serology. The use of the Oracol+ device produced high-quality samples. Subsequent field use of the test has shown a specificity of 99.97% after nearly 3000 tests. CONCLUSIONS: Laboratory-based HIV testing of oral fluid requires less training of local staff, with fewer demands on clinical time and space than near-patient testing. It is acceptable to patients. The validation exercise and subsequent clinical experience support automation, with test performance preserved. Automation reduces laboratory workload and speeds up the release of results. Automated oral fluid testing is thus a viable option for large-scale HIV screening programmes.

What do surgeons see: capturing and synchronizing eye gaze for surgery applications.

Recording eye motions in surgical environments is challenging. This study describes the authors' experiences with performing eye-tracking for improving surgery training, both in the laboratory and in the operating room (OR). Three different eye-trackers were used, each with different capabilities and requirements. For monitoring eye gaze shifts over the room scene in a simulated OR, a head-mounted system was used. The number of surgeons' eye glances on the monitor displaying patient vital signs was successfully captured by this system. The resolution of the head-mounted eye-tracker was not sufficient to obtain the gaze coordinates in detail on the surgical display monitor. The authors then selected a high-resolution eye-tracker built in to a 17-inch computer monitor that is capable of recording gaze differences with resolution of 1° of visual angle. This system enables one to investigate surgeons' eye-hand coordination on the surgical monitor in the laboratory environment. However, the limited effective tracking distance restricts the use of this system in the dynamic environment in the real OR. Another eye-tracker system was found with equally high level of resolution but with more flexibility on the tracking distance, as the eye-tracker camera was detached from the monitor. With this system, the surgeon's gaze during 11 laparoscopic procedures in the OR was recorded successfully. There were many logistical challenges with unobtrusively integrating the eye-tracking equipment into the regular OR workflow and data processing issues in the form of image compatibility and data validation. The experiences and solutions to these challenges are discussed.

Capturing and evaluating blinks from video-based eyetrackers.

Blinks are related to several emotional states, and the present report describes a simple, reliable way to measure blinks from the video stream of an eye obtained during eyetracking, where the source of the eye video is a video camera attached to a head-mounted eyetracker. Computer vision techniques are employed to determine the moments that a blink starts and ends, for the purpose of calculating blink frequency and duration. The video is first processed to show blocks of eyelid and pupil movements, and is then analyzed for blink starts and ends. The moment of a blink start is reported when the eyelid starts to move quickly, exceeding a predetermined threshold. The end of a blink arises when the pupil size increases by less than a separate threshold. We observed several different blink patterns from different subjects, and our algorithm was designed to work for all of these patterns. We evaluated our algorithm by manually measuring the true blinks of five different subjects while they were eyetracked. To test the sensitivity and specificity of the algorithm, we employed a series of threshold values to plot the receiver operating characteristic curves. Using the best thresholds, we achieved excellent sensitivity (>90 %) and specificity (>99 %) over the five subjects. Potential applications of this research include real-time, nonintrusive, continuous and automated measurements of mental workload and other emotional states related to blink rates and durations.

Pupil response to precision in surgical task execution.

Task-evoked pupil response (TEPR) has been extensively studied and well proven to be sensitive to mental workload changes. We aimed to explore how TEPR reflects mental workload changes in a surgical environment. We conducted a simulated surgical task that has 3 different subtasks with different levels of motor precision and different mental workload requirements. We found a significant effect among these different subtask groups by measuring pupil diameter change rate. This finding may improve patient safety in a real operating room by non-intrusively monitoring the surgeon's mental workload while performing a surgery using an eye-tracking system.

Identifying eye gaze mismatch during laparoscopic surgery.

During a laparoscopic operation, the surgical team should have a common understanding of the action plan which can be aided by focusing on the same surgical site. We show how measuring the overlap between two spatially and temporally aligned gaze recordings can be used to identify periods during which the primary operator and assistant were focused on different areas of the surgical display.

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma.

BACKGROUND: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed. RESULTS: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization. CONCLUSIONS: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing. TRIAL REGISTRATION: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006.