The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

BACKGROUND: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. RESULTS: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. CONCLUSION: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Noninvasive treatment of cutaneous neurofibromas (cNFs): Results of a randomized prospective, direct comparison of four methods.

BACKGROUND: People with Neurofibromatosis Type 1 (NF1) suffer disfigurement and pain when hundreds to thousands of cutaneous neurofibromas (cNFs) appear and grow throughout life. Surgical removal of cNFs under anesthesia is the only standard therapy, leaving surgical scars. OBJECTIVE: Effective, minimally-invasive, safe, rapid, tolerable treatment(s) of small cNFs that may prevent tumor progression. METHODS: Safety, tolerability, and efficacy of 4 different treatments were compared in 309, 2-4 mm cNFs across 19 adults with Fitzpatrick skin types (FST) I-IV: radiofrequency (RF) needle coagulation, 755 nm alexandrite laser with suction, 980 nm diode laser, and intratumoral injection of 10 mg/mL deoxycholate. Regional pain, clinical responses, tumor height and volume (by 3D photography) were assessed before, 3 and 6 months post-treatment. Biopsies were obtained electively at 3 months. RESULTS: There was no scarring or adverse events > grade 2. Each modality significantly (P < .05) reduced or cleared cNFs, with large variation between tumors and participants. Alexandrite laser and deoxycholate were fast and least painful; 980 nm laser was most painful. Growth of cNFs was not stimulated by treatment(s) based on height and volume values at 3 and 6 months compared to baseline. LIMITATIONS: Intervention was a single treatment session; dosimetry has not been optimized. CONCLUSIONS: Small cNFs can be rapidly and safely treated without surgery.

Patient-Reported Receipt of Oncology Clinician-Delivered Brief Tobacco Treatment (5As) Six Months following Cancer Diagnosis.

INTRODUCTION: Smoking after a cancer diagnosis represents a modifiable health risk. It is recommended that oncology clinicians address tobacco use among their patients using the 5As brief model: Asking about use, Advising users to quit, Assessing willingness to quit, Assisting in quit attempts (counseling and medication), and Arranging follow-up. However, cross-sectional studies have found limited adoption of 5As (especially Assist and Arrange) in oncology settings. Further investigation is needed to understand changes in, and factors associated with, 5As delivery over time. METHODS: Patients recently diagnosed with cancer and reporting current smoking (N = 303) enrolled in a smoking cessation clinical trial and completed three longitudinal surveys; at pre-intervention baseline and 3- and 6-month follow-up post-enrollment. Patient-level correlates of 5As receipt at baseline, 3 months, and 6 months were identified using multilevel regression models. RESULTS: At baseline, patient-reported rates of 5As receipt from oncology clinicians ranged from 85.17% (Ask) to 32.24% (Arrange). Delivery declined from baseline to 6-month follow-up for all 5As, with the largest declines observed for Ask, Advise, Assess, and Assist-Counseling. Diagnosis of a smoking-related cancer was associated with greater odds of 5As receipt at baseline but lower odds at 6-month follow-up. At each time point, female gender, religiosity, advanced disease, cancer-related stigma, and smoking abstinence were associated with lower odds of 5As receipt, while reporting a recent quit attempt prior to enrollment was associated with higher odds of 5As receipt. CONCLUSION: Oncology clinicians' 5As delivery declined over time. Clinician delivery of the 5As varied based on patients' sociodemographics, clinical and smoking characteristics, and psychosocial factors.

Right-to-left ventricular ratio is higher in systole than diastole in patients with acute pulmonary embolism.

OBJECTIVES: In acute pulmonary embolism (PE), the right ventricle (RV) may dilate compromising left ventricular (LV) size, thereby increasing RV/LV ratio. End-diastolic RV/LV ratio is often used in PE risk stratification, though the cause of death is RV systolic failure. We aimed to confirm our pre-clinical observations of higher RV/LV ratio in systole compared to diastole in human patients with PE. METHODS: We blinded and independently analyzed echocardiograms from 606 patients with PE, evaluated by a Pulmonary Embolism Response Team. We measured RV/LV ratios in end-systole and end-diastole and fractional area change (FAC). Our primary outcome was a composite of 7-day clinical deterioration, treatment escalation or death. Secondary outcomes were 7-day and 30-day all-cause mortality. RESULTS: RV/LV ratio was higher in systole compared to diastole (median 1.010 [.812-1.256] vs. .975 [.843-1.149], p < .0001). RV/LV in systole and diastole were correlated (slope = 1.30 [95% CI 1.25-1.35], p < .0001 vs. slope = 1). RV/LV ratios in both systole and diastole were associated with the primary composite outcome but not with all-cause mortality. CONCLUSION: The RV/LV ratio is higher when measured in systole versus in diastole in patients with acute PE. The two approaches had similar associations with clinical outcomes, that is, it appears reasonable to measure RV/LV ratio in diastole.

Phase II Study of Cabozantinib in Patients With Bone Metastasis.

Bone metastases are often difficult to manage as they can be symptomatic and skeletal-related events (SREs) can contribute to significant morbidity and declines in performance status. We sought to identify a novel medical treatment for bone metastasis by testing the safety and efficacy of cabozantinib in patients with bone metastasis arising from non-breast, non-prostate, malignant solid tumors. Patients were administered cabozantinib as an oral drug starting at 60 mg per day and radiologic measurements were performed at baseline and every 8 weeks. Thirty-seven patients were enrolled. No SREs were observed throughout the study. Twenty patients had disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Four of 20 had a partial response by RECIST. An additional 12 patients had some decrease in tumor burden with nine of these having a decrease in tumor burden of at least 10% by RECIST. Six of the patients with at least a minor response had sarcoma. Sixteen patients had biomarkers of bone turnover measured before and after treatment. Most of these patients demonstrated decrease in urine and serum N-telopeptide and serum C-telopeptide. However, these changes in biomarkers of bone turnover did not correlate with radiographic changes measured by RECIST. This study demonstrates clinical activity and safety for cabozantinib in heavily pretreated patients with bone metastasis and shows activity for cabozantinib in patients with metastatic sarcoma.

Longitudinal Electronic Cigarette Use Among Patients Recently Diagnosed With Cancer Enrolled in a Smoking Cessation Trial.

INTRODUCTION: Many cancer patients who smoke report concurrent e-cigarette use. Using a mixed-methods approach, we aimed to (1) describe longitudinal e-cigarette use over 6 months after a cancer diagnosis and (2) assess the association between e-cigarette use and smoking cessation, among cancer patients in a smoking cessation trial. AIMS AND METHODS: Data were from a 2-site randomized controlled trial of Standard (brief counseling) versus Intensive treatment (sustained counseling plus smoking cessation medication) in individuals who smoke recently diagnosed with cancer. Participants (n = 303) reported e-cigarette use at baseline, 3 months, and 6 months. Biochemically-verified past 7-day cigarette abstinence was collected at 6 months. Qualitative interviews at 6 months explored factors related to e-cigarette use. RESULTS: E-cigarette use prevalence was highest between baseline and 3 months (16%) and declined over time. Participants using e-cigarettes at follow-up had higher baseline cigarette dependence and smoked more heavily. Multivariable analyses found no significant association between follow-up e-cigarette use and 6-month cigarette abstinence. E-cigarette use at follow-up was higher in the Standard versus Intensive treatment group (p = .003 and .001 at 3 and 6 mo, respectively). Smoking cessation and health concerns were primary reasons for using e-cigarettes. CONCLUSIONS: Among individuals who smoke recently diagnosed with cancer and enrolled in a smoking cessation intervention trial, e-cigarette use during trial participation was not associated with smoking abstinence. Individuals who chose to use e-cigarettes were less likely to be receiving intensive cessation support as part of the trial. Further studies are needed to evaluate the association between e-cigarette use and smoking cessation in cancer patients. IMPLICATIONS: E-cigarette use was not associated with cigarette abstinence at 6 months among adults who smoke recently diagnosed with cancer enrolled in a smoking cessation trial. Individuals with easier access to evidence-based smoking cessation treatment may be less likely to use e-cigarettes.

Investigating documentation of alcohol and non-medical substance use in oncology treatment: an electronic health record review.

PURPOSE: Little is known about non-tobacco substance use (SU) and its treatment in cancer patients. National guidelines address tobacco only, and assessment of SU in cancer patients is not standardized. It is not clear how oncology clinicians assess, document, and follow-up on SU. METHODS: We conducted an electronic health record review of patients enrolled in a smoking cessation trial at one large hospital site (N = 176). Chart review of oncology treatment notes assessed whether SU assessment was documented, the content of the documentation/assessment (e.g., frequency of use), and details about documentation (e.g., where/who documented). RESULTS: Sixty-nine percent (121/176) of cancer patients had SU documented. Many patients (42%, 74/176) had only one substance documented; 66% (116/176) had alcohol use documented. For a substantial minority of patients (43/176; 24%), the provider did not specify the substance assessed (e.g., "drug use," "illicits"). SU was primarily documented by physicians (84%, 102/121), in routine progress notes (56%, 68/121), in the "social history" section of the note (84%, 102/121). Only 4 patients had a documented SU follow-up plan. When examining the subset of patients who reported problematic alcohol use (N = 27), the content of documentation was inconsistent (e.g., number of drinks/day vs. qualitative descriptors of use). CONCLUSIONS: About 1/3 of oncology patients did not have SU assessment documented. SU other than alcohol use was infrequently documented, many clinicians documented SU but did not specify substance type, and few clinicians documented a follow-up plan for problematic SU. Oncology settings should utilize standardized assessment and referral for SU treatment.

Study protocol for a hybrid type 1 effectiveness-implementation trial testing virtual tobacco treatment in oncology practices [Smokefree Support Study 2.0].

BACKGROUND: Persistent smoking among patients diagnosed with cancer is associated with adverse clinical outcomes, yet an evidence-based tobacco use intervention has not been well-integrated into cancer care in community oncology settings. This paper describes the protocol of a nation-wide clinical trial conducted by the ECOG-ACRIN National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base to assess the effectiveness of a virtual tobacco treatment intervention and the process of implementing tobacco treatment in NCORP community oncology settings. METHODS/DESIGN: This two-arm, multisite (n: 49 NCORP sites) hybrid type 1 effectiveness-implementation randomized controlled trial compares the effectiveness of a Virtual Intervention Treatment (VIT) versus an Enhanced Usual Control (EUC) among English and Spanish speaking patients recently diagnosed with cancer, reporting current smoking and receiving care at a participating NCORP Community or Minority/Underserved Site. The VIT includes up to 11 virtual counseling sessions with a tobacco treatment specialist and up to 12 weeks of nicotine replacement therapy (NRT). The EUC arm receives a referral to the NCI Quitline. The primary study outcome is biochemically confirmed 7-day point prevalence smoking abstinence. Moderators of treatment effect will be assessed. The study evaluates implementation processes from participating NCORP site staff via survey, administrative, and focus group data, including reach, acceptability, appropriateness, fidelity, feasibility, adoption, cost and sustainability outcomes. DISCUSSION: This trial will generate findings about the effectiveness of an evidence-based virtual tobacco treatment intervention targeting patients diagnosed with cancer and illuminate barriers and facilitators that influence implementing tobacco treatment into community oncology settings nationally. In the era of COVID-19, virtual care solutions are vital for maximizing access and utilization of tobacco treatment delivery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03808818) on January 18th, 2019; Last update posted: May 21st, 2020.

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.

Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

Defining Treatment-Related Adverse Effects in Patients with Glioma: Distinctive Features of Pseudoprogression and Treatment-Induced Necrosis.

BACKGROUND: Pseudoprogression (PP) and treatment-induced brain tissue necrosis (TN) are challenging cancer treatment-related effects. Both phenomena remain insufficiently defined; differentiation from recurrent disease frequently necessitates tissue biopsy. We here characterize distinctive features of PP and TN to facilitate noninvasive diagnosis and clinical management. MATERIALS AND METHODS: Patients with glioma and confirmed PP (defined as appearance <5 months after radiotherapy [RT] completion) or TN (>5 months after RT) were retrospectively compared using clinical, radiographic, and histopathological data. Each imaging event/lesion (region of interest [ROI]) diagnosed as PP or TN was longitudinally evaluated by serial imaging. RESULTS: We identified 64 cases of mostly (80%) biopsy-confirmed PP (n = 27) and TN (n = 37), comprising 137 ROIs in total. Median time of onset for PP and TN was 1 and 11 months after RT, respectively. Clinically, PP occurred more frequently during active antineoplastic treatment, necessitated more steroid-based interventions, and was associated with glioblastoma (81 vs. 40%), fewer IDH1 mutations, and shorter median overall survival. Radiographically, TN lesions often initially manifested periventricularly (n = 22/37; 60%), were more numerous (median, 2 vs. 1 ROIs), and contained fewer malignant elements upon biopsy. By contrast, PP predominantly developed around the tumor resection cavity as a non-nodular, ring-like enhancing structure. Both PP and TN lesions almost exclusively developed in the main prior radiation field. Presence of either condition appeared to be associated with above-average overall survival. CONCLUSION: PP and TN occur in clinically distinct patient populations and exhibit differences in spatial radiographic pattern. Increased familiarity with both conditions and their unique features will improve patient management and may avoid unnecessary surgical procedures. IMPLICATIONS FOR PRACTICE: Pseudoprogression (PP) and treatment-induced brain tissue necrosis (TN) are challenging treatment-related effects mimicking tumor progression in patients with brain cancer. Affected patients frequently require surgery to guide management. PP and TN remain arbitrarily defined and insufficiently characterized. Lack of clear diagnostic criteria compromises treatment and may adversely affect outcome interpretation in clinical trials. The present findings in a cohort of patients with glioma with PP/TN suggest that both phenomena exhibit unique clinical and imaging characteristics, manifest in different patient populations, and should be classified as distinct clinical conditions. Increased familiarity with PP and TN key features may guide clinicians toward timely noninvasive diagnosis, circumvent potentially unnecessary surgical procedures, and improve response assessment in neuro-oncology.

Randomized Trial of a Smartphone Mobile App to Improve Symptoms and Adherence to Oral Therapy for Cancer.

BACKGROUND: Patients with cancer are increasingly prescribed oral therapies, bearing greater responsibility for self-management of treatment adherence and adverse events. We conducted a randomized trial to test the use of a smartphone mobile app to improve symptoms and adherence to oral cancer therapy. MATERIALS AND METHODS: From February 18, 2015, through December 31, 2016, 181 patients with diverse cancers who were prescribed oral therapy were randomized to receive either the smartphone mobile app or standard care. The mobile app included a medication plan with reminders, a symptom-reporting module, and patient education. Primary outcomes were adherence (per electronic pill caps), symptom burden (per MD Anderson Symptom Inventory), and quality of life (per the Functional Assessment of Cancer Therapy-General). Participants also completed self-report measures of medication adherence, anxiety and depression symptoms, social support, quality of care, and healthcare utilization. Linear regression was used to assess intervention effects on adherence and change in self-report outcomes from baseline to week 12, controlling for baseline scores and social support. RESULTS: Study groups did not differ across any outcome measure, with an overall mean adherence of 78.81% (SD, 26.66%) per electronic pill caps. However, moderation analyses showed that intervention effects on the primary adherence measure varied by baseline self-reported adherence and anxiety symptoms. Specifically, adherence rates per electronic pill caps were higher in patients randomized to the mobile app versus standard care within the subsamples of patients who reported baseline adherence problems (mean difference, -22.30%; 95% CI, -42.82 to -1.78; P=.034) and elevated anxiety (mean difference, -16.08%; 95% CI, -31.74 to -0.41; P=.044). CONCLUSIONS: Although the mobile app may not improve outcomes for all patients prescribed oral cancer therapy, the intervention may be beneficial for those with certain risk factors, such as difficulties with adherence or anxiety.

An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma.

Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent.

Effect of Sustained Smoking Cessation Counseling and Provision of Medication vs Shorter-term Counseling and Medication Advice on Smoking Abstinence in Patients Recently Diagnosed With Cancer: A Randomized Clinical Trial.

Importance: Persistent smoking may cause adverse outcomes among patients with cancer. Many cancer centers have not fully implemented evidence-based tobacco treatment into routine care. Objective: To determine the effectiveness of sustained telephone counseling and medication (intensive treatment) compared with shorter-term telephone counseling and medication advice (standard treatment) to assist patients recently diagnosed with cancer to quit smoking. Design, Setting, and Participants: This unblinded randomized clinical trial was conducted at Massachusetts General Hospital/Dana-Farber/Harvard Cancer Center and Memorial Sloan Kettering Cancer Center. Adults who had smoked 1 cigarette or more within 30 days, spoke English or Spanish, and had recently diagnosed breast, gastrointestinal, genitourinary, gynecological, head and neck, lung, lymphoma, or melanoma cancers were eligible. Enrollment occurred between November 2013 and July 2017; assessments were completed by the end of February 2018. Interventions: Participants randomized to the intensive treatment (n = 153) and the standard treatment (n = 150) received 4 weekly telephone counseling sessions and medication advice. The intensive treatment group also received 4 biweekly and 3 monthly telephone counseling sessions and choice of Food and Drug Administration-approved cessation medication (nicotine replacement therapy, bupropion, or varenicline). Main Outcome and Measures: The primary outcome was biochemically confirmed 7-day point prevalence tobacco abstinence at 6-month follow-up. Secondary outcomes were treatment utilization rates. Results: Among 303 patients who were randomized (mean age, 58.3 years; 170 women [56.1%]), 221 (78.1%) completed the trial. Six-month biochemically confirmed quit rates were 34.5% (n = 51 in the intensive treatment group) vs 21.5% (n = 29 in the standard treatment group) (difference, 13.0% [95% CI, 3.0%-23.3%]; odds ratio, 1.92 [95% CI, 1.13-3.27]; P < .02). The median number of counseling sessions completed was 8 (interquartile range, 4-11) in the intensive treatment group. A total of 97 intensive treatment participants (77.0%) vs 68 standard treatment participants (59.1%) reported cessation medication use (difference, 17.9% [95% CI, 6.3%-29.5%]; odds ratio, 2.31 [95% CI, 1.32-4.04]; P = .003). The most common adverse events in the intensive treatment and standard treatment groups, respectively, were nausea (n = 13 and n = 6), rash (n = 4 and n = 1), hiccups (n = 4 and n = 1), mouth irritation (n = 4 and n = 0), difficulty sleeping (n = 3 and n = 2), and vivid dreams (n = 3 and n = 2). Conclusions and Relevance: Among smokers recently diagnosed with cancer in 2 National Cancer Institute-designated Comprehensive Cancer Centers, sustained counseling and provision of free cessation medication compared with 4-week counseling and medication advice resulted in higher 6-month biochemically confirmed quit rates. However, the generalizability of the study findings is uncertain and requires further research. Trial Registration: ClinicalTrials.gov Identifier: NCT01871506.

Randomized Trial of a Tailored Cognitive-Behavioral Therapy Mobile Application for Anxiety in Patients with Incurable Cancer.

BACKGROUND: The aim of this study was to test the efficacy of a tailored cognitive-behavioral therapy (CBT) mobile application (app) to treat anxiety in patients with incurable cancer. MATERIALS AND METHODS: Patients with incurable cancers (n = 145) who reported elevated anxiety symptoms at two cancer centers were randomized to receive either the CBT mobile app for anxiety or a mobile health education program (control) delivered via tablet computers, which patients self-administered over 12 weeks. To assess anxiety, depression symptoms, and quality of life (QOL), we used the Hamilton Anxiety Rating Scale (HAM-A, primary outcome), Clinical Global Impression Scale, Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-9, and Functional Assessment of Cancer Therapy-General at baseline and 12 weeks. Analysis of covariance models were calculated to assess intervention effects on patient outcomes. RESULTS: Patients (73.8% female; 91.0% white; mean age = 56.45 years, SD = 11.30) in both study groups reported improvements in anxiety, depression symptoms, and QOL from baseline to postassessment, with no significant differences in any outcome measure between groups. Secondary analyses showed that, among the subgroup of patients with severe baseline anxiety, those randomized to the CBT app had greater improvements on the HAM-A (Mean Difference = 7.44, standard error [SE] = 3.35, p = .037) and HADS-Anxiety Subscale (Mean Difference = 4.44, SE = 1.60, p = .010) compared with the control group. CONCLUSION: Both the tailored CBT app for anxiety and the health education program were associated with improvements in anxiety, mood, and QOL, but these outcomes did not differ between study groups. The CBT app was more beneficial than health education for patients with severe baseline anxiety. IMPLICATIONS FOR PRACTICE: A cognitive-behavioral therapy mobile application tailored to treat anxiety in patients with advanced cancer helps improve access to evidence-based supportive care in a convenient, private, and timely manner.

Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results.

OBJECTIVE: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). METHODS: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). RESULTS: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. INTERPRETATION: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

Problems in the reproducibility of classification of small lung adenocarcinoma: an international interobserver study.

AIMS: The 2015 WHO classification for lung adenocarcinoma (ACA) provides criteria for adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (INV), but differentiating these entities can be difficult. As our understanding of prognostic significance increases, inconsistent classification is problematic. This study assesses agreement within an international panel of lung pathologists and identifies factors contributing to inconsistent classification. METHODS AND RESULTS: Sixty slides of small lung ACAs were reviewed digitally by six lung pathologists in three rounds, with consensus conferences and examination of elastic stains in round 3. The panel independently reviewed each case to assess final diagnosis, invasive component size and predominant pattern. The kappa value for AIS and MIA versus INV decreased from 0.44 (round 1) to 0.30 and 0.34 (rounds 2 and 3). Interobserver agreement for invasion (AIS versus other) decreased from 0.34 (round 1) to 0.29 and 0.29 (rounds 2 and 3). The range of the measured invasive component in a single case was up to 19.2 mm among observers. Agreement was excellent in tumours with high-grade cytology and fair with low-grade cytology. CONCLUSIONS: Interobserver agreement in small lung ACAs was fair to moderate, and improved minimally with elastic stains. Poor agreement is primarily attributable to subjectivity in pattern recognition, but high-grade cytology increases agreement. More reliable methods to differentiate histological patterns may be necessary, including refinement of the definitions as well as recognition of other features (such as high-grade cytology) as a formal part of routine assessment.

Angiotropism in primary cutaneous melanoma is associated with disease progression and distant metastases: A retrospective study of 179 cases.

BACKGROUND: Angiotropism is the histopathological correlate of pericytic mimicry and extravascular migratory metastasis (EVMM), a mechanism of melanoma spread by migration along the external surface of blood and lymphatic vessels. The frequency of angiotropism in primary cutaneous melanoma and the clinical utility of its detection remain unclear. METHODS: We investigated angiotropism in 179 primary cutaneous melanomas by hematoxylin and eosin (H&E), CD31, and S100/D240 stains. RESULTS: We detected angiotropism in 31 cases (17%) by H&E. CD31 immunohistochemistry increased detection to 59 cases (33%). When lymphatic vessels were included by using S100/D240 stains, 67 cases (37%) cases were positive. Angiotropism was associated with lymphatic invasion and mitotic rate with all detection methods. There was an association with increased tumor thickness when detected by H&E and CD31. No association with sentinel lymph node status was seen. By H&E and CD31 staining, angiotropism was associated with disease progression and distant metastases by univariate, but not multivariate analysis. Overall survival was not affected by the presence of angiotropism. CONCLUSIONS: Angiotropism is relatively common in primary melanoma when immunohistochemical stains are used for detection and associated with mitotic rate and intravascular lymphatic invasion. The association with disease progression and distant metastasis suggests that it represents an alternative pathway of metastasis, that is, EVMM/pericytic mimicry vs intravascular spread.

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages.

Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti-Ang-2-neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti-colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Correction to: Septal bowing and pulmonary artery diameter on computed tomography pulmonary angiography are associated with short-term outcomes in patients with acute pulmonary embolism.

The above article was published online with an error in an author's last name: It should be Muzikansky (and not Muzikanski). The correct name is presented here. The original article has been corrected.