Patterns of brain metastases response to immunotherapy with pembrolizumab.

PURPOSE: Central nervous system (CNS) metastases from lung cancers and melanoma, significantly contribute to morbidity and mortality. Despite advances in local therapies, there is a need for effective systemic treatments. Pembrolizumab, a PD-1 inhibitor, has shown promise for some patients with untreated brain metastases from melanoma and non-small cell lung cancer (NSCLC). This study aims to analyze the response of brain metastasis to pembrolizumab and associate characteristics like size and location with treatment outcome. METHODS: This retrospective study used imaging data from a phase II trial of pembrolizumab in melanoma or NSCLC patients with untreated brain metastases. MRI evaluations were conducted at 2 month intervals, with each brain metastasis treated as a distinct tumor for response assessment, based on modified RECIST criteria (maximum 5 lesions, 5 mm target lesions). RESULTS: Of 130 individual target metastases (> 5 mm), in 65 patients with NSCLC (90 metastases) and Melanoma (40 metastases), 32 (24.6%) demonstrated complete resolution, 24 (18.5%) had partial resolution, 32 (24.6%) were SD and 42 (32.3%) demonstrated PD. Those smaller than 10 mm were more likely to show complete resolution (p = 0.0218), while those ≥ 10 mm were more likely to have PR. There was no significant association between size, number or location (supratentorial vs. infratentorial) and lesion progression. The median time to metastatic lesion progression in the brain was 5.7-7 weeks. CONCLUSION: Pembrolizumab is effective in brain metastases from NSCLC and melanoma, showing response (CR + PR) in 43% and progression (PD) in 32% of metastases. With the median time to CNS progression of 5.7-7 weeks, careful radiographic monitoring is essential to guide timely local treatment decisions.

Cost-Effectiveness of CT, CTA, MRI, and Specialized MRI for Evaluation of Patients Presenting to the Emergency Department With Dizziness.

BACKGROUND. Underlying stroke is often misdiagnosed in patients presenting with dizziness. Although such patients are usually ineligible for acute stroke treatment, accurate diagnosis may still improve outcomes through selection of patients for secondary prevention measures. OBJECTIVE. The purpose of our study was to investigate the cost-effectiveness of differing neuroimaging approaches in the evaluation of patients presenting to the emergency department (ED) with dizziness who are not candidates for acute intervention. METHODS. A Markov decision-analytic model was constructed from a health care system perspective for the evaluation of a patient presenting to the ED with dizziness. Four diagnostic strategies were compared: noncontrast head CT, head and neck CTA, conventional brain MRI, and specialized brain MRI (including multiplanar high-resolution DWI). Differing long-term costs and outcomes related to stroke detection and secondary prevention measures were compared. Cost-effectiveness was calculated in terms of lifetime expenditures in 2022 U.S. dollars for each quality-adjusted life year (QALY); deterministic and probabilistic sensitivity analyses were performed. RESULTS. Specialized MRI resulted in the highest QALYs and was the most cost-effective strategy with US$13,477 greater cost and 0.48 greater QALYs compared with noncontrast head CT. Conventional MRI had the next-highest health benefit, although was dominated by extension with incremental cost of US$6757 and 0.25 QALY; CTA was also dominated by extension, with incremental cost of US$3952 for 0.13 QALY. Non-contrast CT alone had the lowest utility among the four imaging choices. In the deterministic sensitivity analyses, specialized MRI remained the most cost-effective strategy. Conventional MRI was more cost-effective than CTA across a wide range of model parameters, with incremental cost-effectiveness remaining less than US$30,000/QALY. Probabilistic sensitivity analysis yielded similar results as found in the base-case analysis, with specialized MRI being more cost-effective than conventional MRI, which in turn was more cost-effective than CTA. CONCLUSION. The use of MRI in patients presenting to the ED with dizziness improves stroke detection and selection for subsequent preventive measures. MRI-based evaluation leads to lower long-term costs and higher cumulative QALYs. CLINICAL IMPACT. MRI, incorporating specialized protocols when available, is the preferred approach for evaluation of patients presenting to the ED with dizziness, to establish a stroke diagnosis and to select patients for secondary prevention measures.

A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better.

BACKGROUND: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. METHODS: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. RESULTS: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. CONCLUSIONS: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03502330.

CT With CTA Versus MRI in Patients Presenting to the Emergency Department With Dizziness: Analysis Using Propensity Score Matching.

BACKGROUND. CT with CTA is widely used to exclude stroke in patients with dizziness, although MRI has higher sensitivity. OBJECTIVE. The purpose of this article was to compare patients presenting to the emergency department (ED) with dizziness who undergo CT with CTA alone versus those who undergo MRI in terms of stroke-related management and outcomes. METHODS. This retrospective study included 1917 patients (mean age, 59.5 years; 776 men, 1141 women) presenting to the ED with dizziness from January 1, 2018, to December 31, 2021. A first propensity score matching analysis incorporated demographic characteristics, medical history, findings from the review of systems, physical examination findings, and symptoms to construct matched groups of patients discharged from the ED after undergoing head CT with head and neck CTA alone and patients who underwent brain MRI (with or without CT and CTA). Outcomes were compared. A second analysis compared matched patients discharged after CT with CTA alone and patients who underwent specialized abbreviated MRI using multiplanar high-resolution DWI for increased sensitivity for posterior circulation stroke. Sensitivity analyses were performed involving MRI examinations performed as the first or only neuroimaging examination and involving alternative matching and imputation techniques. RESULTS. In the first analysis (406 patients per group), patients who underwent MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.1% vs 4.7%, p = .005), change in secondary stroke prevention medication (9.6% vs 3.2%, p = .001), and subsequent echocardiography evaluation (6.4% vs 1.0%, p < .001). In the second analysis (100 patients per group), patients who underwent specialized abbreviated MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.0% vs 2.0%, p = .04), change in secondary stroke prevention medication (14.0% vs 1.0%, p = .001), and subsequent echocardiography evaluation (12.0% vs 2.0%, p = .01) and lower frequency of 90-day ED readmissions (12.0% vs 28.0%, p = .008). Sensitivity analyses showed qualitatively similar findings. CONCLUSION. A proportion of patients discharged after CT with CTA alone may have benefitted from alternative or additional evaluation by MRI (including MRI using a specialized abbreviated protocol). CLINICAL IMPACT. Use of MRI may motivate clinically impactful management changes in patients presenting with dizziness.

Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis.

INTRODUCTION: The study aimed to describe the brain metastases (BM) incidence, at diagnosis and follow-up, in patients initially presenting with stage III or IV melanoma and characterize their metastatic brain lesions. We also sought to describe the association of common genetic mutations and immunotherapy with BM development in advanced melanoma. METHODS: Using our institution's tumor registry, we identified patients with initial diagnoses of stage III and stage IV melanoma. In this cohort, we obtained BM incidence at diagnosis and follow-up, characterized the metastatic brain lesions and primary tumor's genetic profile. RESULTS: During the follow-up period, 22.9% of patients with an initial diagnosis of stage III developed BM. In this cohort, the median time for BM occurrence was 20 months; [95% CI (14-29)]. Likewise, 37.7% of patients with Stage IV melanoma presented with BM at the time of diagnosis, and 22.7% of remaining patients developed BM at follow-up over a median duration of 6 months [95% CI (4-11)]. Therefore, suggesting an overall incidence of 51.9% in stage IV melanoma. Next, we observed that the incidence of BM development during the follow-up period significantly decreased from 2012 to 2017 (p < 0.001). Lastly, we found a significantly higher frequency of mutational BRAF in the primary tumor of patients with BM (68.7% vs. 31.2%; p = 0.02). CONCLUSIONS: While the overall incidence of BM remains high, the decreasing incidence of BM over the follow-up period is promising. Similar BM incidence in patients with an initial diagnosis of stage III or stage IV warrants appropriate imaging surveillance regimen for stage III patients.

The Spectrum of Neuroimaging Findings on CT and MRI in Adults With COVID-19.

Neurologic involvement is well-recognized in COVID-19. This article reviews the neuroimaging manifestations of COVID-19 on CT and MRI, presenting cases from the New York City metropolitan region encountered by the authors during the first surge of the pandemic. The most common neuroimaging manifestations are acute infarcts with large clot burden and intracranial hemorrhage, including microhemorrhages. However, a wide range of additional imaging patterns occur, including leukoencephalopathy, global hypoxic injury, acute disseminated encephalomyelitis, cytotoxic lesions of the corpus callosum, olfactory bulb involvement, cranial nerve enhancement, and Guillain-Barré syndrome. The described CNS abnormalities largely represent secondary involvement from immune activation that leads to a prothrombotic state and cytokine storm; evidence for direct neuroinvasion is scant. Comorbidities such as hypertension, complications of prolonged illness and hospitalization, and associated supportive treatments also contribute to the CNS involvement in COVID-19. Routine long-term neurologic follow-up may be warranted, given emerging evidence of long-term microstructural and functional changes on brain imaging after COVID-19 recovery.

Treatment of Recurrent Respiratory Papillomatosis: Case Series and Review of Technique.

Adult Recurrent Respiratory Papillomatosis (RRP) is a rare disease caused by the human papilloma virus in which papilloma grows from the respiratory epithelium. Patients can suffer from significant respiratory distress secondary to tracheal or bronchial obstruction by papilloma and the mainstay of treatment is bronchoscopic debridement. There are a variety of techniques to resect the endoluminal tumor, including CO2 or YAG laser, argon plasma coagulation, microdebrider and cold forceps. There have been documented cases of healthcare workers contracting HPV after exposure to surgical smoke during ablation of papilloma and measures should be taken to avoid inhalation of the smoke plume. For proximal lesions that are accessible to a microdebrider, this appears to be a safe and effective technique that does not generate heat or surgical smoke. The rate of recurrence of adult-onset respiratory papilloma after initial debulking varies and adjuvant medical therapy including intralesional cidofovir, interferon, or oral indole-3-carbinol has been used to slow recurrence. Malignant transformation of adult-onset RRP to squamous cell carcinoma has been reported to occur in 3-7% of cases. Therefore, ongoing surveillance is needed to monitor for disease progression and malignant transformation. Here we describe three patients whose tracheal disease was managed with an Nd-YAG laser and microdebrider. One patient was treated with adjuvant systemic indole-3 carbinol and another was maintained with serial debridement only. The third patient presented with obstructing squamous cell carcinoma of the trachea and was treated with definitive chemoradiation. She presented with a new left mainstem lesion 6 months later which was diagnosed as RRP. She was started on indole-3 carbinol, but unfortunately it transformed to squamous cell carcinoma 8 months later.

Safety of Laser and Thermal Therapy During Rigid Bronchoscopy Using Manual Hand Jet Ventilation.

INTRODUCTION: Thermal ablative therapies (laser, radiofrequency ablation, electrocautery, argon plasma coagulation) are often used during rigid bronchoscopy for the treatment of central airway obstructions (CAO). An airway fire is a feared complication that can occur during endobronchial thermal ablation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study. A total of 175 patients were reviewed undergoing rigid bronchoscopy in the operating room and bronchoscopy suite requiring manual hand jet ventilation and thermal therapy between September 2014 and September 2018. The study objective was to determine the safety of manual hand jet ventilation during endobronchial thermal therapies with rigid bronchoscopy. RESULTS: Over a five-year period, 175 patients underwent endobronchial thermal therapy during rigid bronchoscopy with manual hand jet ventilation for the treatment CAOs. Immediately prior to thermal therapy activation, jet ventilation was paused. No incidences (0/175) of airway fires occurred despite immediate delivery of thermal energy following a jet ventilation hold. CONCLUSIONS: Results of our study show that performing thermal ablative therapy during rigid bronchoscopy with jet ventilation using a breath-hold technique is safe.

Sphenoidal artery: review of the literature and analysis of a dissected arterially injected fetal orbit.

PURPOSE: The sphenoidal artery is considered a component of the complex and dangerous arterial anastomoses of the human orbitocranial region, particularly with the advent of interventional neuroimaging. The objective of this publication was to analyze the various descriptions of the sphenoidal artery in the literature as related to relevant photographs of a dissected arterially injected fetal middle cranial fossa and orbit. METHODS: Publications dealing with middle meningeal-ophthalmic arterial anastomoses, focusing on the sphenoidal artery, were reviewed. A relevant dissection of a fetal specimen was analyzed. RESULTS: The literature dealing with the sphenoidal artery is at times not in agreement. The nomenclature and anatomy of its passage through the superior orbital fissure or Hyrtl canal have variable descriptions. Photographs of the skull base of a dissected arterially injected fetal specimen show bilateral prominent orbital branches of the middle meningeal arteries. These branches entered both orbits in a course similar to the diagrammatic representations of the sphenoidal artery, and give rise to several major intraorbital arteries. This study provides the only photographic image in the literature of this variation in a human fetal anatomic dissection. CONCLUSIONS: Review of the literature dealing with the sphenoidal artery shows inconsistent nomenclature and conflicting descriptions of its anastomotic connections, and varying evolutionary and embryologic theories. Analysis of the dissected fetal skull base indicates that the sphenoidal artery is not a distinct artery but just a middle meningeal orbital arterial branch, an important component of the complex and dangerous arterial anastomoses of the human orbitocranial region.

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.

BACKGROUND: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. METHODS: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070. FINDINGS: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. INTERPRETATION: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. FUNDING: Merck and the Yale Cancer Center.

PET/CT radiomics signature of human papilloma virus association in oropharyngeal squamous cell carcinoma.

PURPOSE: To devise, validate, and externally test PET/CT radiomics signatures for human papillomavirus (HPV) association in primary tumors and metastatic cervical lymph nodes of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We analyzed 435 primary tumors (326 for training, 109 for validation) and 741 metastatic cervical lymph nodes (518 for training, 223 for validation) using FDG-PET and non-contrast CT from a multi-institutional and multi-national cohort. Utilizing 1037 radiomics features per imaging modality and per lesion, we trained, optimized, and independently validated machine-learning classifiers for prediction of HPV association in primary tumors, lymph nodes, and combined "virtual" volumes of interest (VOI). PET-based models were additionally validated in an external cohort. RESULTS: Single-modality PET and CT final models yielded similar classification performance without significant difference in independent validation; however, models combining PET and CT features outperformed single-modality PET- or CT-based models, with receiver operating characteristic area under the curve (AUC) of 0.78, and 0.77 for prediction of HPV association using primary tumor lesion features, in cross-validation and independent validation, respectively. In the external PET-only validation dataset, final models achieved an AUC of 0.83 for a virtual VOI combining primary tumor and lymph nodes, and an AUC of 0.73 for a virtual VOI combining all lymph nodes. CONCLUSION: We found that PET-based radiomics signatures yielded similar classification performance to CT-based models, with potential added value from combining PET- and CT-based radiomics for prediction of HPV status. While our results are promising, radiomics signatures may not yet substitute tissue sampling for clinical decision-making.

Bronchoscope-Guided Percutaneous Endoscopic Gastrostomy Tube Placement by Interventional Pulmonologists: A Feasibility and Safety Study.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tube placement is a procedure frequently done in the intensive care unit. The use of a traditional endoscope can be difficult in cases of esophageal stenosis and theoretically confers an increased risk of infection due to its complex architecture. We describe a technique using the bronchoscope, which allows navigation through stenotic esophageal lesions and also minimizes the risk of endoscopy-associated infections. METHODS: Prospective series of patients who had PEG tube placement guided by a bronchoscope. Procedural outcomes including successful placement, duration of the entire procedure, time needed for passage of the bronchoscope from the oropharynx to the major curvature, PEG tube removal rate, and mortality were collected. Procedural adverse events, including infections and long-term PEG-related complications, were recorded. RESULTS: A total of 84 patients underwent bronchoscope-guided PEG tube placement. Percutaneous endoscopic gastrostomy tube insertion was completed successfully in 82 (97.6%) patients. Percutaneous endoscopic gastrostomy tube placement was performed immediately following percutaneous tracheostomy in 82.1%. Thirty-day mortality and 1-year mortality were 11.9% and 31%, respectively. Overall, minor complications occurred in 2.4% of patients, while there were no major complications. No serious infectious complications were identified and no endoscope-associated hospital acquired infections were documented. CONCLUSIONS: The use of the bronchoscope can be safely and effectively used for PEG tube placement. The use of bronchoscope rather than a gastroscope has several advantages, which include the ease of navigating through complex aerodigestive disorders such as strictures and fistulas as well as decreased health-care utilization. In addition, it may have a theoretical advantage of minimizing infections related to complex endoscopes.

Accuracy of a Robotic Endoscopic System in Cadaver Models with Simulated Tumor Targets: ACCESS Study.

BACKGROUND: Bronchoscopy for the diagnosis of peripheral pulmonary lesions continues to present clinical challenges, despite increasing experience using newer guided techniques. Robotic bronchoscopic platforms have been developed to potentially improve diagnostic yields. Previous studies in cadaver models have demonstrated increased reach into the lung periphery using robotic systems compared to similarly sized conventional bronchoscopes, although the clinical impact of additional reach is unclear. OBJECTIVES: This study was performed to evaluate the performance of a robotic bronchoscopic system's ability to reach and access artificial tumor targets simulating peripheral nodules in human cadaveric lungs. METHODS: Artificial tumor targets sized 10-30 mm in axial diameter were implanted into 8 human cadavers. CT scans were performed prior to procedures and all cadavers were intubated and mechanically ventilated. Electromagnetic navigation, radial probe endobronchial ultrasound, and fluoroscopy were used for all procedures. Robotic-assisted bronchoscopy was performed on each cadaver by an individual bronchoscopist to localize and biopsy peripheral lesions. RESULTS: Sixty-seven nodules were evaluated in 8 cadavers. The mean nodule size was 20.4 mm. The overall diagnostic yield was 65/67 (97%) and there was no statistical difference in diagnostic yield for lesions <20 mm compared with lesions measuring 21-30 mm, the presence of a concentric or eccentric radial ultrasound image, or relative distance from the pleura. CONCLUSIONS: The robotic bronchoscopic system was successful at biopsying 97% of peripheral pulmonary lesions 10-30 mm in size in human cadavers. These findings support further exploration of this technology in prospective clinical trials in live human subjects.

Choice of imaging modality for pre-treatment staging of head and neck cancer impacts TNM staging.

PURPOSE: The purpose of this retrospective cohort study was to determine whether there is a difference in the sensitivity of chest computed tomography (CT) versus 18F-fluorodeoxyglucose positron emission tomography with low-dose nonenhanced CT (18F-FDG PET/CT or PET/CT) in the detection of distant metastases in head and neck cancer, within a tertiary care setting. MATERIALS AND METHODS: Patients with head and neck cancer, and known distant metastases, who underwent both 18F-FDG PET/CT with integrated low-dose nonenhanced CT and diagnostic chest CT prior to initiation of therapy from 2008 to 2017 were included. Two head and neck radiologists, blinded to all patient information and to each other's readings, reviewed the PET/CT or CT chest images for each patient and identified whether distant metastases were present. No radiologist read both modalities for a single patient. Concordance between imaging modalities was quantitatively analyzed using McNemar's test. RESULTS: 27 patients were included. McNemar's mid p-value analysis showed no significant difference in the detection of distant metastases (p = .6875). However, PET/CT detected distant metastases in three patients that chest CT did not, while chest CT identified distant metastatic disease in two patients that were negative on PET/CT. CONCLUSIONS: While this study did not identify a statistically significant difference in sensitivity, five patients had distant metastases identified on only one of the two modalities. Use of a single modality would have resulted in inaccurate staging in 7-11% of patients in our study. The use of both modalities offers the greatest accuracy when providing stage-adapted oncologic treatment.

Lung Nodule Management: An Interventional Pulmonology Perspective.

With the rising number of screening and incidentally detected lung nodules, there is an increasing need for evaluation in the safest and least invasive manner. The last two decades have seen substantial evolution in bronchoscopic approaches to diagnose these nodules. Innovative bronchoscopic techniques, often used in conjunction with each other, have significantly improved our ability to navigate to almost any part of the lung. A comprehensive knowledge of available technologies and the factors affecting diagnostic yield is essential to decide on the best way to approach a particular scenario. This article provides an overview of the technical aspects, yield, and limitations of these modalities.

Comparing available criteria for measuring brain metastasis response to immunotherapy.

The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial. The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5 mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM. Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5 mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5 mm threshold for target brain lesions when using high resolution MRI with ≤2 mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

Peripheral Vascular Disease in Patients with Diabetic Foot Ulcers - An Emerging Trend: A Prospective Study from North India.

BACKGROUND: Diabetic foot ulcer is one of the chronic complications of diabetes mellitus (DM) with 25% of patients with diabetes developing a foot ulcer during their lifetime leading to amputation. Diabetic foot is classified into 2 main types: neuropathic ulcers (NPU) and neuro-ischemic ulcer (NIU) where in addition to neuropathy peripheral vascular disease (PVD) is also present. AIMS: We aimed to a) assess the prevalence of Peripheral vascular disease (PVD) in patients of type 2 diabetes mellitus (T2DM) presenting with New Diabetic Foot ulcers (DFU). b) To compare the clinical profile and risk factors responsible for development of NPU and NIU in North Indian population. SETTING AND DESIGN: Cross sectional study conducted on first 100 T2DM patients presenting with new DFU in tertiary referral institute for one year period from August 2012 to July 2013. METHODS AND MATERIAL: Detailed relevant clinical history including age, sex and duration of diabetes, history of smoking and hypertension (HTN) and prevalence of other complications like retinopathy, nephropathy, coronary artery disease (CAD) and stroke was obtained. Patients were examined for neuropathy, loss of pulsations, ankle brachial pressure index (ABI) and investigated for HbA1C, blood urea nitrogen (BUN) and serum creatinine. Statistical analysis used: t test, Fisher exact test and univariate analysis. RESULTS: NIU was present in 30 and NPU in 70 out of 100 patients. NIU were commoner among males as compared to females (21/64 males vs 9/36 females). Strong association of smoking (20/30 patients), hypertension (24/30 patients) and longer duration of DM (14 vs 8 years) with NIU was found. Even other complications of DM like CAD (8/30 patients), stroke (4/30 patients), retinopathy (24/30 patients) and nephropathy (15/30 patients) were more prevalent in patients with NIU. CONCLUSIONS: Prevalence of PVD is 30% in our study which is more than previous studies showing an increasing trend. NPU are two times more common than NIU. Hypertensive male patients with smoking habits and longer duration of T2DM are most prone to develop NIU. NIU share the similar risk factors with CAD and coexist with other complications of DM which should be looked for and treated.

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.

Unleashing the Full Sustainable Potential of Thick Films of Lead-Free Potassium Sodium Niobate (K0.5Na0.5NbO3) by Aqueous Electrophoretic Deposition.

A current challenge for the fabrication of functional oxide-based devices is related with the need of environmental and sustainable materials and processes. By considering both lead-free ferroelectrics of potassium sodium niobate (K0.5Na0.5NbO3, KNN) and aqueous-based electrophoretic deposition here we demonstrate that an eco-friendly aqueous solution-based process can be used to produce KNN thick coatings with improved electromechanical performance. KNN thick films on platinum substrates with thickness varying between 10 and 15 µm have a dielectric permittivity of 495, dielectric losses of 0.08 at 1 MHz, and a piezoelectric coefficient d33 of ∼70 pC/N. At TC these films display a relative permittivity of 2166 and loss tangent of 0.11 at 1 MHz. A comparison of the physical properties between these films and their bulk ceramics counterparts demonstrates the impact of the aqueous-based electrophoretic deposition (EPD) technique for the preparation of lead-free ferroelectric thick films. This opens the door to the possible development of high-performance, lead-free piezoelectric thick films by a sustainable low-cost process, expanding the applicability of lead-free piezoelectrics.