Phylogenomics of nontuberculous mycobacteria respiratory infections in people with cystic fibrosis.

Nontuberculous mycobacteria (NTM) can cause severe pulmonary disease in people with cystic fibrosis (pwCF). These infections present unique challenges for diagnosis and treatment, prompting a recent interest in understanding NTM transmission and pathogenesis during chronic infection. Major gaps remain in our knowledge regarding basic pathogenesis, immune evasion strategies, population dynamics, recombination potential, and the evolutionary implications of host and antibiotic pressures of long-term NTM infections in pwCF. Phylogenomic techniques have emerged as an important tool for tracking global patterns of transmission and are beginning to be used to ask fundamental biological questions about adaptation to the host during pathogenesis. In this review, we discuss the burden of NTM lung disease (NTM-LD), highlight the use of phylogenomics in NTM research, and address the clinical implications associated with these studies.

Adapting to the Adaptive Radiation Workflow: Incorporating Video Sign Out for Improved Safety and Efficiency as Part of Magnetic Resonance Image Guided Adaptive Radiation.

 : Magnetic resonance image guided adaptive radiation therapy (MRgART) represents a significant improvement in our ability to deliver therapeutic radiation. However, for the process of MRgART to be carried out safely and efficiently, the covering radiation oncologist must be aware of all aspects of a patient's case, because they will be required to recontour and replan the patient before each treatment. In this report, we will demonstrate our initial experience with a video sign-out process to convey the detailed level of information required for the covering physician to treat patients safely and effectively with MRgART. We then describe our optimized video sign-out process to allow for other centers to adopt a similar approach.

Guided therapy selection in rheumatoid arthritis using a molecular signature response classifier: an assessment of budget impact and clinical utility.

BACKGROUND: Patients with moderate to severe rheumatoid arthritis (RA) can be treated with a range of targeted therapies following inadequate response to conventional synthetic disease-modifying antirheumatic drugs such as methotrexate. Whereas clinical practice guidelines provide no formal recommendations for initial targeted therapies, the tumor necrosis factor alpha inhibitor (TNFi) class is the prevalent first-line selection based on clinician experience, its safety profile, and/or formulary requirements, while also being the costliest. Most patients do not achieve adequate clinical response with a first-line TNFi, however. A molecular signature response classifier (MSRC) test that assesses RA-related biomarkers can identify patients who are unlikely to achieve adequate response to TNFi-class therapies. OBJECTIVE: To model cost-effectiveness of MSRC-guided, first-line targeted therapy selection compared with current standard care. METHODS: This budget impact analysis used data sourced from August to September 2020. The prevalence of each first-line targeted therapy was obtained using market intelligence from Datamonitor/Informa PLC Rheumatology Dashboard Forecast 2020, and the average first-year cost of treatment for each class was calculated using wholesale acquisition costs from IBM Micromedex RED BOOK Online. Average effectiveness for each class was based on manufacturer-reported ACR50 response rates (American College of Rheumatology adequate response criteria of 50% improvement at 6 months after therapy initiation). The impact of MSRC testing on first therapy selection was predicted based on a third party-generated decision-impact study that analyzed potential alterations in rheumatologist prescribing patterns after receiving MSRC test reports. Sensitivity analysis evaluated potential impacts of variation in first-year medication cost, adherence to MSRC report, and test price on the first-year cost of treatment. Cost for response (first-year therapy cost therapy divided by probability of achieving ACR50) was compared between standard care and MSRC-guided care. RESULTS: The estimated cost for first-year, standard-care treatment was $65,117, with 80% of patients initiating treatment with a TNFi. Cost for achieving ACR50 response was $177,046. After applying MSRC-guided patient stratification and therapy selection, the first-year cost was $56,543, net of test price, with 49.0% of patients initiating with a TNFi. First-year MSRC-guided care cost, including test price, was estimated at $117,103, a 33.9% improvement over standard care. Sensitivity analysis showed a net cost improvement for guided care vs standard care across all scenarios. Patients predicted to be inadequate TNFi responders, when modeled with lower-priced alternatives, were predicted to show increased ACR50 response rates. Those with MSRC test results indicating a first-line TNFi were predicted to show an ACR50 response rate superior to that for any other class. In this model, if implemented clinically, MSRC-guided care might save the US health care system more than $850 million annually and improve ACR50 by up to 31.3%. CONCLUSIONS: Precision medicine using MSRC-guided patient stratification and therapy selection may both decrease cost and improve efficacy of targeted RA therapies. DISCLOSURES: This work was funded in full by Scipher Medicine Corporation, which participated in data analysis and interpretation and drafting, reviewing, and approving the publication. All authors contributed to data analysis and interpretation and publication preparation, maintaining control over the final content. Arnell, Withers, and Connolly-Strong are employees of and have stock ownership in Scipher Medicine Corporation. Bergman has received consulting fees from AbbVie, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Sanofi, and Scipher Medicine and owns stock or stock options in Johnson & Johnson. Kenney, Logan, and Lim-Harashima are consultants for Scipher Medicine Corporation. Basu has nothing to disclose.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

(Reprinted with permission from Am J Geriatr Psychiatry 2020; 28:933-945).

Prolonged postictal hemianopsia after a focal extraoccipital onset seizure.

We report a case of a prolonged postictal hemianopsia occurring after a focal extraoccipital seizure. A 55-year-old man with a history of neurosyphilis, treated with penicillin, presented to our epilepsy monitoring unit (EMU) for diagnostic evaluation of his spells occurring for 2 years. The spell semiology was stereotypical, described as oral and manual automatisms, speech difficulty and unresponsiveness. During the EMU stay, after his typical seizure was recorded, he experienced right hemianopsia lasting for 2 hours. Electrographically, the ictal pattern was prominent over the left temporal derivation and propagated to the left occipital derivation as the seizure progressed. Interictal epileptiform activity was over the left temporal derivations. We support the view that postictal phenomenon may represent merely a seizure termination zone and not be necessarily localising to the seizure onset zone. Furthermore, prolonged isolated postictal symptom of hemianopsia could also be noted in rare situations.

Prognostic capabilities and clinical utility of cell cycle progression testing, prostate imaging reporting and data system, version 2, and clinicopathologic data in management of localized prostate cancer.

OBJECTIVES: To compare the prognostic capabilities and clinical utility of the cell cycle progression (CCP) gene expression classifier test, multiparametric magnetic resonance imaging (mpMRI) with Prostate Imaging Reporting and Data System (PI-RADS) scoring, and clinicopathologic data in select prostate cancer (PCa) medical management scenarios. PATIENTS AND METHODS: Retrospective, observational analysis of patients (N = 222) ascertained sequentially from a single urology practice from January 2015 to June 2018. Men were included if they had localized PCa, a CCP score, and an mpMRI PI-RADS v2 score. Cohort 1 (n = 156): men with newly diagnosed PCa, with or without a previous negative biopsy. Cohort 2 (n = 66): men who initiated active surveillance (AS) without CCP testing, but who received the test during AS. CCP was combined with the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score to produce a clinical cell-cycle risk (CCR) score, which was reported in the context of a validated AS threshold. Spearman's rank correlation test was used to evaluate correlations between variables. Generalized linear models were used to predict binary Gleason score category and medical management selection (AS or curative therapy). Likelihood-ratio tests were used to determine predictor significance in both univariable and multivariable models. RESULTS: In the combined cohorts, modest but significant correlations were observed between PI-RADS score and CCP (rs = 0.22, P = 8.1 × 10-4), CAPRA (rs= 0.36, P = 4.8 × 10-8), or CCR (rs = 0.37, P = 2.0 × 10-8), suggesting that much of the prognostic information captured by these measures is independent. When accounting for CAPRA and PI-RADS score, CCP was a significant predictor of higher-grade tumor after radical prostatectomy, with the resected tumor approximately 4 times more likely to harbor Gleason ≥4+3 per 1-unit increase in CCP in Cohort 1 (Odds Ratio [OR], 4.10 [95% confidence interval [CI], 1.46, 14.12], P = 0.006) and in the combined cohorts (OR, 3.72 [95% CI, 1.39, 11.88], P = 0.008). On multivariable analysis, PI-RADS score was not a significant predictor of post-radical prostatectomy Gleason score. Both CCP and CCR were significant and independent predictors of AS versus curative therapy in Cohort 1 on multivariable analysis, with each 1-unit increase in score corresponding to an approximately 2-fold greater likelihood of selecting curative therapy (CCP OR, 2.08 [95% CI, 1.16, 3.94], P = 0.014) (CCR OR, 2.33 [95% CI, 1.48, 3.87], P = 1.5 × 10-4). CCR at or below the AS threshold significantly reduced the probability of selecting curative therapy over AS (OR, 0.28 [95% CI, 0.13, 0.57], P = 4.4 × 10-4), further validating the clinical utility of the AS threshold. CONCLUSION: CCP was a better predictor of both tumor grade and subsequent patient management than was PI-RADS. Even in the context of targeted biopsy, molecular information remains essential to ensure precise risk assessment for men with newly diagnosed PCa.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing.

Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM, commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2 and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p<0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p<0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results.

Trends in Radiation for Bone Metastasis During a Period of Multiple National Quality Improvement Initiatives.

PURPOSE: To evaluate trends in fractionation and cost of radiation for bone metastasis during a time period of multiple national quality improvement initiatives that focused on reducing the number of fractions per radiation episode. METHODS: Using nationwide Medicare claims from 2011 to 2014, we identified radiation episodes for bone metastasis from prostate, lung, and breast cancer. Details regarding fractionation, radiation therapy (RT) modality, and sociodemographic characteristics were abstracted from claims. Time trends in use of 10 or fewer RT fractions per episode were evaluated using the Cochran-Armitage test. Total cost per episode was calculated from a payer's perspective and reported in 2017 dollars; time trends in cost were assessed using linear regression. Generalized linear models identified predictors of treatment with 10 or fewer fractions. RESULTS: Of 51,533 episodes identified, 46,326 used 2D/3D RT, 3,199 used intensity-modulated RT, and 2,008 used stereotactic body RT. The proportion of 2D/3D RT episodes using 10 or fewer fractions increased from 65.5% to 79.7% ( Ptrend < .001), and mean total cost per episode decreased from $6,742 to $6,067 ( Ptrend < .001). Use of single-fraction radiation increased modestly for 2D/3D treatment (6.5% to 8.1%; Ptrend < .001). Predictors of 10 or fewer fractions included treatment in recent years, advanced age (≥ 85 years), and higher comorbidity score. Variation was noted based on geographic region and primary cancer. CONCLUSION: During a period with quality initiatives launched by the American Society for Radiation Oncology, American Board of Internal Medicine, and National Quality Forum, use of 10 or fewer fractions for bone metastasis increased by 14.2%, but single-fraction regimens increased by only 1.6%, highlighting opportunities for quality improvement.

Hereditary Cancer Risk Assessment and Genetic Testing in the Community-Practice Setting.

OBJECTIVE: To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor. METHODS: This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up. Outcomes related to hereditary cancer assessment and testing were measured during an 8-week postintervention period. Patients and health care providers were surveyed about satisfaction with the process. Data also were collected during the 8 weeks before the intervention to assess the effects of screening process improvements. RESULTS: A total of 4,107 patients were seen during the postintervention period, and 92.8% (3,811) were assessed for hereditary cancer risk. Among those assessed, 906 of 3,811 (23.8%) women met National Comprehensive Cancer Network guidelines for genetic testing, and 813 of 906 (89.7%) eligible patients were offered genetic testing. A total of 165 of 4,107 (4.0%) women completed genetic testing and received a final test result. This represents a fourfold increase over genetic testing immediately before the intervention (1.1%) and an eightfold increase over the previous year (0.5%). Testing identified pathogenic variants in 9 of 165 (5.5%) tested women. All health care providers (15/15) reported that they will continue to use the established hereditary cancer risk assessment process. In addition, 98.8% (167/169) of patients who submitted a sample for genetic testing and completed a patient satisfaction survey stated that they were able to understand the information provided, and 97.6% (165/169) expressed satisfaction with the overall process. CONCLUSION: It is feasible to incorporate hereditary cancer risk assessment, education, and testing into community obstetrics and gynecology practices. As a result, multigene panel testing identified significant cancer risks that otherwise would not have been recognized.

Correction to: A predictive model for distinguishing radiation necrosis from tumour progression after gamma knife radiosurgery based on radiomic features from MR images.

The original version of this article, published on 24 November 2017, unfortunately contained a mistake.

A predictive model for distinguishing radiation necrosis from tumour progression after gamma knife radiosurgery based on radiomic features from MR images.

OBJECTIVES: To develop a model using radiomic features extracted from MR images to distinguish radiation necrosis from tumour progression in brain metastases after Gamma Knife radiosurgery. METHODS: We retrospectively identified 87 patients with pathologically confirmed necrosis (24 lesions) or progression (73 lesions) and calculated 285 radiomic features from four MR sequences (T1, T1 post-contrast, T2, and fluid-attenuated inversion recovery) obtained at two follow-up time points per lesion per patient. Reproducibility of each feature between the two time points was calculated within each group to identify a subset of features with distinct reproducible values between two groups. Changes in radiomic features from one time point to the next (delta radiomics) were used to build a model to classify necrosis and progression lesions. RESULTS: A combination of five radiomic features from both T1 post-contrast and T2 MR images were found to be useful in distinguishing necrosis from progression lesions. Delta radiomic features with a RUSBoost ensemble classifier had an overall predictive accuracy of 73.2% and an area under the curve value of 0.73 in leave-one-out cross-validation. CONCLUSIONS: Delta radiomic features extracted from MR images have potential for distinguishing radiation necrosis from tumour progression after radiosurgery for brain metastases. KEY POINTS: • Some radiomic features showed better reproducibility for progressive lesions than necrotic ones • Delta radiomic features can help to distinguish radiation necrosis from tumour progression • Delta radiomic features had better predictive value than did traditional radiomic features.

Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control.

BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). RESULTS: The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). CONCLUSIONS: In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.

Effects of heat stress on risk perceptions and risk taking.

Exposure to extreme heat at work is a serious occupational hazard, as exposure can result in heat-related illnesses, and it has been linked to increased risk of accidents and injuries. The current study aimed to examine whether heat exposure is related to changes in individuals' psychological process of risk evaluation, and whether acclimatization can mitigate the effect of heat exposure. A study with quasi-experiment research design was used to compare participants' risk perceptions and risk-taking behaviors at baseline, initial exposure to heat, and exposure after acclimatization across male participants who were exposed to heat (N = 6), and males (N = 5) and females (N = 6) who were in the control group who were exposed to ambient temperature. Results show that participants perceived the same risky behaviors to be less risky (p = 0.003) and demonstrated increased risk-taking behaviors (p = 0.001) after initial heat exposure. While their risk perceptions returned to baseline level after acclimatization, their risk-taking behaviors remained heightened (p = 0.031). Participants who were not exposed to heat showed no significant fluctuation in their risk perceptions and risk-taking. Our findings support that risk-related processes may explain the effects of heat exposure on increased accidents and injuries beyond its direct impact on heat-related illnesses.

Analysis of Factors Affecting Successful Clinical Trial Enrollment in the Context of Three Prospective, Randomized, Controlled Trials.

PURPOSE: Challenges can arise when attempting to maximize patient enrollment in clinical trials. There have been limited studies focusing on the barriers to enrollment and the efficacy of alternative study design to improve accrual. We analyzed barriers to clinical trial enrollment, particularly the influence of timing, in context of three prospective, randomized oncology trials where one arm was considered more aggressive than the other. METHODS AND MATERIALS: From June 2011 to March 2015, patients who were enrolled on 3 prospective institutional protocols (an oligometastatic non-small cell lung cancer [NSCLC] trial and 2 proton vs intensity modulated radiation therapy trials in NSCLC and esophageal cancer) were screened for protocol eligibility. Eligible candidates were approached about trial participation, and patient characteristics (age, sex, T/N categorization) were recorded along with details surrounding trial presentation (appointment number). Fisher's exact test, Student's t tests, and multivariate analysis were performed to assess differences between enrolled and refusal patients. RESULTS: A total of 309 eligible patients were approached about trial enrollment. The enrollment success rate during this time span was 52% (n=160 patients). Enrolled patients were more likely to be presented trial information at an earlier appointment (oligometastatic protocol: 5 vs 3 appointments [P<.001]; NSCLC protocol: 4 vs 3 appointments [P=.0018]; esophageal protocol: 3 vs 2 appointments [P=.0086]). No other factors or patient characteristics significantly affected enrollment success rate. CONCLUSION: Improvement in enrollment rates for randomized control trials is possible, even in difficult accrual settings. Earlier presentation of trial information to patients is the most influential factor for success and may help overcome accrual barriers without compromising trial design.

Combining Radiation Therapy with Immune Checkpoint Blockade for Central Nervous System Malignancies.

Malignancies of the central nervous system (CNS), particularly glioblastoma and brain metastases from a variety of disease sites, are difficult to treat despite advances in multimodality approaches consisting of surgery, chemotherapy, and radiation therapy (RT). Recent successes of immunotherapeutic strategies including immune checkpoint blockade (ICB) via anti-PD-1 and anti-CTLA-4 antibodies against aggressive cancers, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, have presented an exciting opportunity to translate these strategies for CNS malignancies. Moreover, via both localized cytotoxicity and systemic proinflammatory effects, the role of RT in enhancing antitumor immune response and, therefore, promoting tumor control is being re-examined, with several preclinical and clinical studies demonstrating potential synergistic effect of RT with ICB in the treatment of primary and metastatic CNS tumors. In this review, we highlight the preclinical evidence supporting the immunomodulatory effect of RT and discuss the rationales for its combination with ICB to promote antitumor immune response. We then outline the current clinical experience of combining RT with ICB in the treatment of multiple primary and metastatic brain tumors. Finally, we review advances in characterizing and modifying tumor radioimmunotherapy responses using biomarkers and microRNA (miRNA) that may potentially be used to guide clinical decision-making in the near future.

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant. SIGNIFICANCE: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis.

Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).