Outcomes after PD-103 versus I-125 for low dose rate prostate brachytherapy monotherapy: An international, multi-institutional study.

BACKGROUND AND PURPOSE: Pd-103 and I-125 are commonly used in low dose rate (LDR) brachytherapy for prostate cancer. Comparisons of outcomes by isotope type are limited, but Pd-103 has distinct radiobiologic advantages over I-125 despite its lesser availability outside the United States. We evaluated oncologic outcomes after Pd-103 vs I-125 LDR monotherapy for prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed databases at 8 institutions for men who received definitive LDR monotherapy with Pd-103 (n = 1,597) or I-125 (n = 7,504) for prostate cancer. Freedom from clinical failure (FFCF) and freedom from biochemical failure (FFBF) stratified by isotope were analyzed by Kaplan-Meier univariate and Cox multivariate analyses. Biochemical cure rates (prostate-specific antigen level ≤ 0.2 ng/mL between 3.5 and 4.5 years of follow-up) by isotype were calculated for men with at least 3.5 years of follow-up and compared by univariate and multivariate logistic regression. RESULTS: Compared with I-125, Pd-103 led to higher 7-year rates of FFBF (96.2% vs 87.6%, P < 0.001) and FFCF (96.5% vs 94.3%, P < 0.001). This difference held after multivariate adjustment for baseline factors (FFBF hazard ratio [HR] = 0.31, FFCF HR = 0.49, both P < 0.001). Pd-103 was also associated with higher cure rates on univariate (odds ratio [OR] = 5.9, P < 0.001) and multivariate (OR = 6.0, P < 0.001) analyses. Results retained significance in sensitivity analyses of data from the 4 institutions that used both isotopes (n = 2,971). CONCLUSIONS: Pd-103 monotherapy was associated with higher FFBF, FFCF, and biochemical cure rates, and suggests that Pd-103 LDR may lead to improved oncologic outcomes compared with I-125.

Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor.

Recent progress in targeting KRASG12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRASG12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRASG12D with KD and IC50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRASG12D as compared to KRASWT. MRTX1133 also demonstrated potent inhibition of activated KRASG12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines, with median IC50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRASWT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRASG12D-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRASG12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRASG12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype.

Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of transformation. Our results demonstrate that NO induces DNA damage as indicated by γH2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.

Contrast-Specific Spherical Lesion Phantoms and Ancillary Analysis Software for the Objective Evaluation of Transrectal Ultrasound System Contrast Detectability.

Brachytherapy is an efficacious treatment option because of its benefits for patient recovery, dose localization and conformity, but these favorable outcomes can be ensured only if the transrectal ultrasound (TRUS) system is optimized for the specific application of ultrasound-guided prostate brachytherapy. The ability to delineate the prostate from surrounding tissue during TRUS-guided prostate brachytherapy is vital for treatment planning, and consequently, so is the contrast resolution. This study describes the development of task-specific contrast-detail phantoms with clinically relevant contrast and spherical target sizes for contrast-detail performance evaluation of TRUS systems used in the brachytherapy procedure. The procedure for objective assessment of the contrast detectability of the TRUS systems is also described; a program was developed in MATLAB (R2017a, The MathWorks, Natick, MA, USA) to quantitatively analyze image quality in terms of the lesion signal-to-noise ratio (LSNR) and validated with representative control test images. The LSNR of the Hitachi EUB-7500A (2013, Hitachi, Ltd, Tokyo, Japan) TRUS system was measured on sagittal and transverse TRUS images of the contrast-detail phantoms described in this work. Results revealed the efficacy of the device as an image quality evaluation tool and the impact of the size, depth and relative contrast of the targets to the surrounding tissue on the contrast detectability of a TRUS system for both transducer arrays. The MATLAB program objectively measured the contrast detectability of the TRUS system and has the potential to determine optimized imaging parameters that could be designed as part of standardization of the imaging protocol used in TRUS-guided prostate brachytherapy for prostate cancer.

A Case of Tumor Lysis Syndrome Complicated by Disseminated Intravascular Coagulation - Case Reports of the LifePACT Critical Care Transport Team.

Hematologic/Oncologic emergencies are rarely seen in the critical care transport environment but must be recognized and treated without delay. We report such a patient transported from a referring hospital to a tertiary care center by the LifePACT team, a 52-year-old male with a history of acute myeloid leukemia (AML). The patient presented to the referring hospital with known laboratory test abnormalities, suffered cardiac arrest, was resuscitated, accepted for transfer to a tertiary care center, and LifePACT was requested to perform the transport.

Live implant dosimetry may be an effective replacement for postimplant computed tomography in localized prostate cancer patients receiving low dose rate brachytherapy.

PURPOSE: To determine if Live Implant Dosimetry (LIDO) utilizing intraoperative transrectal ultrasound (TRUS) is equivalent to postimplant CT dosimetry (either day 0 or day 30) in patients with localized prostate cancer (PC) treated with low dose rate (LDR) prostate seed brachytherapy. METHODS AND MATERIALS: The treated population consisted of 628 men with localized (T1-T2) PC. All d'Amico risk categories (low, intermediate, and high) were included, and 437 patients were treated with monotherapy (160 Gy) [low and low tier intermediate], and the remainder (191) [high tier intermediate and high risk] with an implant boost (106 Gy) post external beam radiation, to a volume including the prostate and seminal vesicles (46 Gy). LIDO with intraoperative TRUS, postimplant CT (day 0 and day 30) were performed in all cases. Prostate volumes (V), V100 (prostate) and dose (D) D90 (prostate), D30 (urethra), and Rectum D2cc, were recorded. No urinary catheter was used on Day 30 CT. RESULTS: More than 91.33% of monotherapy patients reached the target D90 according to LIDO while only 82.99% of Day 0 CT and 92.82% of Day 30 CT achieved target D90. When considering V100, monotherapy patients recorded target dosimetry in 90.93%, 82.31%, and 92.02% of cases assessed by LIDO, Day 0 CT and Day 30 CT, respectively. Strong correlations are observed in D90, Rectum D2cc and Urethra D30 across imaging modalities but V100 and V150 were poorly correlated due to the relative quantification of this parameter and high degree of error in measurement. Of all monotherapy patients with satisfactory dosimetry on LIDO, 94.82% reached target D90 at day 30 CT and 94.19% reached target V100. CONCLUSIONS: LIDO and CT are both effective tools for assessing postimplant dosimetry. Patients with satisfactory LIDO dosimetry are highly likely to have equivalent dosimetry on CT at follow-up, indicating that postimplant CT may be eliminated in PC a patients implanted with this technique.

Ocean Acidification and Human Health.

The ocean provides resources key to human health and well-being, including food, oxygen, livelihoods, blue spaces, and medicines. The global threat to these resources posed by accelerating ocean acidification is becoming increasingly evident as the world's oceans absorb carbon dioxide emissions. While ocean acidification was initially perceived as a threat only to the marine realm, here we argue that it is also an emerging human health issue. Specifically, we explore how ocean acidification affects the quantity and quality of resources key to human health and well-being in the context of: (1) malnutrition and poisoning, (2) respiratory issues, (3) mental health impacts, and (4) development of medical resources. We explore mitigation and adaptation management strategies that can be implemented to strengthen the capacity of acidifying oceans to continue providing human health benefits. Importantly, we emphasize that the cost of such actions will be dependent upon the socioeconomic context; specifically, costs will likely be greater for socioeconomically disadvantaged populations, exacerbating the current inequitable distribution of environmental and human health challenges. Given the scale of ocean acidification impacts on human health and well-being, recognizing and researching these complexities may allow the adaptation of management such that not only are the harms to human health reduced but the benefits enhanced.

A prospective feasibility study of MammoSite accelerated partial breast irradiation for early breast Cancer.

BACKGROUND: Accelerated partial breast irradiation is a potential alternative to standard whole breast irradiation, following breast-conserving surgery, in the management of breast cancer. The MammoSite applicator-based technique allows for the delivery of a higher dose of radiation to the tumour bed and adjacent area, over a shorter treatment period. AIMS: To investigate the long-term feasibility of the MammoSite technique in early stage breast cancer in an Irish cohort. METHODS: Sixty-two patients with early stage breast cancer were enrolled in this prospective study between November 2005 and October 2012 at the University Hospital Galway. A single-entry MammoSite applicator was inserted post-operatively. A CT scan was performed to assess the balloon to skin distance, the conformance of target tissue to balloon surface and balloon symmetry. A total dose of 34 Gy was delivered over 10 fractions twice daily. RESULTS: Median follow-up was 10 years. 91.9% (57/62) completed the full course of MammoSite treatment. Technical issues with the MammoSite balloon precluded three patients from completing the full course of treatment. On last follow-up, 6.4% (4/62) of patients had developed an ipsilateral breast recurrence. Half of these recurrences occurred more than 10 years after the initial breast cancer treatment. The most common toxicities observed were fibrosis (67.7%), pain (61.3%) and skin erythema (35.5%). CONCLUSION: The use of the MammoSite technique, as an alternative to standard whole breast irradiation, is feasible in a typical Irish clinical setting with integrated multidisciplinary team input.

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator.

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.

Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?

BACKGROUND: Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test-Lung Cancer Scotland Study). METHODS: Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n = 95) and normal CT groups (n = 174) at 3 and 6 months follow-up. RESULTS: No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3- and 6-month time points: 3.04, 95% CI: 0.95, 9.73; P = 0.06). CONCLUSION: Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation.

Lung cancer CT screening: Psychological responses in the presence and absence of pulmonary nodules.

OBJECTIVES: To determine the psychological response (thoughts, perceptions and affect) to a diagnosis of pulmonary nodules following a novel antibody blood test and computed tomography (CT) scans within a UK population. MATERIALS AND METHODS: This study was nested within a randomised controlled trial of a blood test (Early CDT®-Lung test), followed by a chest x-ray and serial CT-scanning of those with a positive blood test for early detection of lung cancer (ECLS Study). Trial participants with a positive Early CDT®-Lung test were invited to participate (n = 338) and those agreeing completed questionnaires assessing psychological outcomes at 1, 3 and 6 months following trial recruitment. Responses of individuals with pulmonary nodules on their first CT scan were compared to those without (classified as normal CT) at 3 and 6 months follow-up using random effects regression models to account for multiple observations per participant, with loge transformation of data where modelling assumptions were not met. RESULTS: There were no statistically significant differences between the nodule and normal CT groups in affect, lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts at 3 or 6 months post-recruitment. The nodule group had statistically significantly fewer avoidance symptoms compared to the normal CT group at 3 months (impact of events scale avoidance (IES-A) difference between means -1.99, 95%CI -4.18, 0.21) than at 6 months (IES-A difference between means 0.88, 95%CI -1.32, 3.08; p-value for change over time = 0.003) with similar findings using loge transformed data. CONCLUSION: A diagnosis of pulmonary nodules following an Early CDT®-Lung test and CT scan did not appear to result in adverse psychological responses compared to those with a normal CT scan.

Measuring a new facet of post traumatic growth: Development of a scale of physical post traumatic growth in men with prostate cancer.

PURPOSE: This study developed a measure of physical post traumatic growth (physical post traumatic growth inventory; P-PTGI) in men with prostate cancer. METHODS: A pool of items was created from themes identified in a qualitative study. A quantitative study was then conducted to assess the psychometric properties of the P-PTGI in a sample of 693 prostate cancer survivors. RESULTS: Tests of dimensionality revealed that the 20-item P-PTGI contained two factors: Health Autonomy and Health Awareness. Results demonstrated that scale score reliability for the P-PTGI and its subscales was excellent. In support of the scale's convergent validity, scores on the P-PTGI correlated positively with mindfulness and quality of life, and correlated negatively with depression and anxiety. A statistically significant correlation between the P-PTGI and another robust indicator of post traumatic growth attests to its concurrent validity. CONCLUSIONS: While further investigation of the P-PTGI's psychometric properties is required, preliminary findings are promising.

What predicts emotional response in men awaiting prostate biopsy?

BACKGROUND: Incidence of prostate cancer is increasing as opportunistic screening becomes widespread and life expectancy rises. Despite screening availability, research reveals conflicting results on medical outcomes, for example, disease specific mortality. However the gold standard in early diagnosis of potentially curable organ confined prostate cancer is transrectal ultrasound-guided systematic prostate biopsy (TRUS-BX). While focus has been given to medical sequalae there is a paucity of research on the psychological impact of biopsy. Awaiting biopsy may be inherently stressful but no studies to date, have assessed men's perception of stress and its impact on emotional response. This study, therefore, examines the role of stress and also personal resources namely, self-efficacy and sense of coherence in emotional adjustment in men awaiting a prostate biopsy. METHODS: Men attending a Rapid Access Prostate Cancer Clinic for a transrectal prostate biopsy (N = 114) participated in the study. They completed self report questionnaires on perceived stress (PSS), generalised self-efficacy (GSES), and sense of coherence (SOC). Adjustment was measured by the Profile of Mood States (POMS-B) which assesses tension, depression, anger, fatigue, confusion and vigour. RESULTS: Hierarchical regression analyses demonstrated that the set of predictors accounted for 17%-34% of variance across six mood states and predicted 46% of total mood disturbance. Perceived stress explained variance on all domains (11%-26%) with high stress linked to poor functioning. CONCLUSION: Perceived stress was the strongest and most consistent predictor of emotional adjustment. This is an important finding as stress appraisal has not been examined previously in this context and suggests that stress management is an important target to enhance emotional wellbeing of men attending for a prostate biopsy.

A Model to Predict Psychological- and Health-Related Adjustment in Men with Prostate Cancer: The Role of Post Traumatic Growth, Physical Post Traumatic Growth, Resilience and Mindfulness.

Background: Post traumatic growth (PTG) can be defined as positive change following a traumatic event. The current conceptualization of PTG encompasses five main dimensions, however, there is no dimension which accounts for the distinct effect of a physical trauma on PTG. The purpose of the present research was to test the role of PTG, physical post traumatic growth (PPTG), resilience and mindfulness in predicting psychological and health related adjustment. Method: Ethical approval was obtained from relevant institutional ethics committees. Participants (N = 241), who were at least 1 year post prostate cancer treatment, were invited to complete a battery of questionnaires either through an online survey or a paper and pencil package received in the post The sample ranged in age from 44 to 88 years (M = 64.02, SD = 7.76). Data were analysis using confirmatory factor analysis and structural equation modeling. Results: The physical post traumatic growth inventory (P-PTGI) was used to evaluate the role of PPTG in predicting adjustment using structural equation modeling. P-PTGI predicted lower distress and improvement of quality of life, whereas conversely, the traditional PTG measure was linked with poor adjustment. The relationship between resilience and adjustment was found to be mediated by P-PTGI. Conclusion: Findings suggest the central role of PTG in the prostate cancer survivorship experience is enhanced by the inclusion of PPTG. Adjusting to a physical trauma such as illness (internal transgressor) is unlike a trauma with an external transgressor as the physical trauma creates an entirely different framework for adjustment. The current study demonstrates the impact of PPTG on adjustment. This significantly adds to the theory of the development of PTG by highlighting the interplay of resilience with PTG, PPTG, and adjustment.

Ghost Attack: The East Providence Carbon Monoxide Mass Casualty Incident.

A routine call for a common medical emergency was expeditiously identified by the responding emergency medical service as a multiple victim carbon monoxide exposure. The event circumstances, exemplary fire department emergency medical services response, and ensuing hos- pital emergency department response are described. [Full article available at http://rimed.org/rimedicaljournal-2018-02.asp].

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic 'activated' state that enhances prostate cancer cell migration.

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3-educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3-educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and α-smooth muscle actin (αSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient-derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3-educated and DU145-educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient-derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells.

A Woman with a Necrotizing Soft-Tissue Infection.

[Full article available at http://rimed.org/rimedicaljournal-2017-12.asp].

Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways.

Inflammation is implicated in triple negative breast cancer (TNBC) progression. TNBC carries a worse prognosis than other breast cancer subtypes, and with the clinical and molecular heterogeneity of TNBC, there is a lack of effective therapeutic targets available. Identification of molecular targets for TNBC subtypes is crucial towards personalized patient stratification. Inducible nitric oxide synthase (iNOS) has been shown to induce p53 mutation accumulation, basal-like gene signature enrichment and transactivation of the epidermal growth factor receptor (EGFR) via s-nitrosylation. Herein we report that iNOS is associated with disease recurrence, distant metastasis and decreased breast cancer specific survival in 209 cases of TNBC. Employing TNBC cell lines representing normal basal breast, and basal-like 1 and basal-like 2 tumors, we demonstrate that nitric oxide (NO) induces EGFR-dependent ERK phosphorylation in basal-like TNBC cell lines. Moreover NO mediated cell migration and cell invasion was found to be dependent on EGFR and ERK activation particularly in basal-like 2 TBNC cells. This occurred in conjunction with NF-κB activation and increased secretion of pro-inflammatory cytokines IL-8, IL-1ß and TNF-α. This provides substantial evidence for EGFR as a therapeutic target to be taken into consideration in the treatment of a specific subset of basal-like TNBC overexpressing iNOS.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.