Publications by authors named "Jeffrey Crawford"

199 Publications

Cancer Patients' Perspectives and Experiences of Chemotherapy-Induced Myelosuppression and Its Impact on Daily Life.

Patient Prefer Adherence 2021 25;15:453-465. Epub 2021 Feb 25.

Duke University Medical Center, Durham, NC, USA.

Purpose: To evaluate which side effects of chemotherapy are considered most burdensome by patients with cancer, identify which health care professionals pay most attention to symptoms associated with chemotherapy-induced myelosuppression (CIM) from the patient perspective, and capture the "patient voice" describing how CIM impacts their daily lives.

Participants And Methods: Online survey of participants with breast, lung, or colorectal cancer who had received chemotherapy within the past 12 months and experienced ≥1 episode of CIM in the past year. Participants were asked to answer close-ended questions and provide qualitative responses to: "In your own words, please describe how side effects from myelosuppression have impacted your life."

Results: Among 301 survey participants, fatigue was the most frequently reported side effect of chemotherapy; 55% of participants rated fatigue as highly bothersome (9 or 10 on a 1-10 scale of "bothersomeness"). Participants rated symptoms associated with CIM, including fatigue, weakened immune system (infections), bleeding and/or bruising, and shortness of breath, as being as bothersome as other side effects of chemotherapy, including alopecia, neuropathy, and nausea/vomiting. Overall, 24-43% of participants thought that CIM and its symptoms had a negative impact on their daily lives, including their ability to complete tasks at home and work, and to socialize. Qualitative responses supported these findings; participants highlighted that CIM-related symptoms, particularly fatigue and fear of infections, affected their ability to be physically active, complete work, or continue meaningful relationships with friends and family.

Conclusion: Participants described a real-world impact of CIM that often isolates them from family and friends, and means that they are unable to work or perform tasks of daily living. Using measures that help patients to recognize and communicate the signs and symptoms of CIM might increase the likelihood of maintaining daily lives as close to normal as possible, during and after chemotherapy treatment.
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http://dx.doi.org/10.2147/PPA.S292462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920579PMC
February 2021

Treatment at Integrated Centers Might Bridge the Academic-Community Survival Gap in Patients With Metastatic Non-Small Cell Carcinoma of the Lung.

Clin Lung Cancer 2021 Jan 7. Epub 2021 Jan 7.

Duke Cancer Institute, Durham, NC. Electronic address:

Background: Non-small cell lung cancer (NSCLC) is responsible for the most cancer-related deaths in the United States. A better understanding of treatment-related disparities and ways to address them are important to improving survival for patients with metastatic NSCLC.

Materials And Methods: We performed a retrospective analysis using the National Cancer Database. Included in this analysis were 107,116 patients with metastatic NSCLC who were treated at academic centers (AC), community-based centers (CC), and integrated centers (IC) between 2004 and 2015. The primary end point was overall survival, with comparisons of AC, CC, and IC.

Results: The survival disparity between AC and CC continued to grow over the study period, from a 5.7% difference in 2-year survival to a 7.5% difference. Treatment at IC was initially associated with survival similar to CC (hazard ratio [HR], 0.93), however, later in the study period treatment at IC improved (HR, 0.74) outpacing the improvement in survival in CC (HR, 0.82) but not to the same degree as the improvement in AC (HR, 0.64). The improvement in survival at IC was noted predominantly in patients with adenocarcinoma (HR, 0.72; P < .001) but not in squamous-cell carcinoma (HR, 0.89; P value not significant).

Conclusion: Treatment of metastatic NSCLC at IC was associated with improved survival during our study period compared with treatment at CC. This appeared to be histology-dependent, suggesting a treatment-related improvement in survival because over this period newer therapies were preferentially available for adenocarcinoma. Integrating care across treatment facilities might be one way to bridge the growing gap in survival between AC and CC.
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http://dx.doi.org/10.1016/j.cllc.2020.12.013DOI Listing
January 2021

RNA splicing and aggregate gene expression differences in lung squamous cell carcinoma between patients of West African and European ancestry.

Lung Cancer 2021 Mar 14;153:90-98. Epub 2021 Jan 14.

Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA. Electronic address:

Objectives: Despite disparities in lung cancer incidence and mortality, the molecular landscape of lung cancer in patients of African ancestry remains underexplored, and race-related differences in RNA splicing remain unexplored.

Materials And Methods: We identified differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in biobanked lung squamous cell carcinoma (LUSC) between patients of West African and European ancestry, using ancestral genotyping and Affymetrix Clariom D array. DSGs and DEGs were validated independently using the National Cancer Institute Genomic Data Commons. Associated biological processes, overlapping canonical pathways, enriched gene sets, and cancer relevance were identified using Gene Ontology Consortium, Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, and CancerMine, respectively. Association with LUSC survival was conducted using The Cancer Genome Atlas.

Results: 4,829 DSGs and 267 DEGs were identified, including novel targets in NSCLC as well as genes identified previously to have relevance to NSCLC. RNA splicing events within 3 DSGs as well as 1 DEG were validated in the independent cohort. 853 DSGs and 29 DEGs have been implicated as potential drivers, oncogenes and/or tumor suppressor genes. Biological processes enriched among DSGs and DEGs included metabolic process, biological regulation, and multicellular organismal process and, among DSGs, ion transport. Overlapping canonical pathways among DSGs included neuronal signaling pathways and, among DEGs, cell metabolism involving biosynthesis. Gene sets enriched among DSGs included KRAS Signaling, UV Response, E2 F Targets, Glycolysis, and Coagulation. 355 RNA splicing events within DSGs and 18 DEGs show potential association with LUSC patient survival.

Conclusion: These DSGs and DEGs, which show potential biological and clinical relevance, could have the ability to drive novel biomarker and therapeutic development to mitigate LUSC disparities.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.015DOI Listing
March 2021

Do Patients Regret Having Received Systemic Treatment for Advanced Non-Small Cell Lung Cancer: A Prospective Evaluation.

Oncologist 2021 Mar 10;26(3):224-230. Epub 2020 Nov 10.

Feinstein Institute for Medical Research, Manhasset, New York, USA.

Background: Thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision-making parameters, or clinical progress early in the treatment course predicts regret.

Materials And Methods: Patients receiving systemic treatment for advanced NSCLC completed every 3-week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS-QL), including the 3-Item Global Index (3-IGI; assessing overall distress, activities, and quality of life [QL]). A prespecified secondary aim was to determine the frequency of regret evaluated at 3 months after starting treatment. Patients were randomized to usual care or enhanced care (which included use of the DecisionKEYS decision aid).

Results: Of 164 patients entered, 160 received treatment and 142 were evaluable for regret. In total, 11.5% of patients and 9% of their supporters expressed regret. Baseline characteristics did not predict regret; regret was rarely expressed by those who had a less than 20% decline or improvement in the 3-IGI PRO score after two treatment cycles. In contrast, when asked if they would make the same decision again, only 1% not having a 20% 3-IGI decline expressed regret, versus 14% with a 3-IGI decline (p = .01).

Conclusion: The majority of patients having regret were identified early using the PRO 3-IGI of the eLCSS-QL measure. Identifying patients at risk for regret allows for interventions, including frank discussions of progress and goals early in the treatment course, which could address regret in patients and their supporters.

Implications For Practice: This report documents prospectively, for the first time, the incidence of treatment-related regret in patients with advanced lung cancer and outlines that risk of regret is associated with patient-determined worsening health status early in the course of treatment. Identifying patients at risk for regret early in treatment (before the third cycle of treatment) appears to be crucial. Counseling at that time should include a discussion of consideration of treatment change and the reason for this change.
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http://dx.doi.org/10.1002/onco.13571DOI Listing
March 2021

Patient Burden and Real-World Management of Chemotherapy-Induced Myelosuppression: Results from an Online Survey of Patients with Solid Tumors.

Adv Ther 2020 08 8;37(8):3606-3618. Epub 2020 Jul 8.

Duke University Medical Center, Durham, NC, USA.

Introduction: Chemotherapy-induced myelosuppression (CIM) is one of the most common dose-limiting complications of cancer treatment, and is associated with a range of debilitating symptoms that can significantly impact patients' quality of life. The purpose of this study was to understand patients' perspectives on how the side effects of CIM are managed in routine clinical practice.

Methods: An online survey was conducted of participants with breast, lung, or colorectal cancer who had received chemotherapy treatment within the past 12 months, and had experienced at least one episode of myelosuppression in the past year. The survey was administered with predominantly close-ended questions, and lay definitions of key terms were provided to aid response selection.

Results: Of 301 participants who completed the online survey, 153 (51%) had breast cancer, 100 (33%) had lung cancer, and 48 (16%) had colorectal cancer. Anemia, neutropenia, lymphopenia, and thrombocytopenia were reported by 61%, 59%, 37%, and 34% of participants, respectively. Most participants (79%) reported having received treatment for CIM, and 64% of participants recalled chemotherapy dose modifications as a result of CIM. Although most participants believed their oncologist was aware of the side effects of CIM, and treated them quickly, 30% of participants felt their oncologists did not understand how uncomfortable they were due to the side effects of CIM. Overall, 88% of participants considered CIM to have a moderate or major impact on their lives.

Conclusion: The data highlight that despite the various methods used to address CIM, and the patient-focused approach of oncologists, the real-world impact of CIM on patients is substantial. Improving communication between patients and health care providers may help improve patients' understanding of CIM, and foster shared decision-making in terms of treatment. Additional insights from patients should be obtained to further elucidate the totality of life burden associated with CIM.
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http://dx.doi.org/10.1007/s12325-020-01419-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340862PMC
August 2020

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

J Thorac Oncol 2020 10 13;15(10):1611-1623. Epub 2020 Jun 13.

Division of Hematology and Oncology, University of California San Francisco, San Francisco, California. Electronic address:

Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.

Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.

Results: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.

Conclusions: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529990PMC
October 2020

Hybrid management approach for superior mesenteric artery and branch aneurysms.

J Vasc Surg Cases Innov Tech 2019 Dec 19;5(4):521-524. Epub 2019 Nov 19.

Division of Vascular Surgery, Department of Surgery, University of Florida College of Medicine, Gainesville, Fla.

Visceral artery aneurysms are rare, with a 25% rupture risk and an associated 70% mortality. A 55-year-old woman with progressive epigastric pain was found to have multiple large superior mesenteric artery (SMA), branch, and gastroduodenal artery aneurysms along with an occluded celiac artery trunk with hepatic flow dependent on the aneurysm branch. Management included antegrade aortohepatic artery bypass with gastroduodenal artery ligation, followed by SMA stenting and aneurysm coiling. This case is novel, given the diffuse pattern and rarity of SMA and branch aneurysms. This hybrid surgical management highlights innovative strategies to minimize morbidity without compromising definitive treatment of complex visceral artery aneurysms.
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http://dx.doi.org/10.1016/j.jvscit.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939184PMC
December 2019

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis.

J Thorac Oncol 2020 04 27;15(4):637-648. Epub 2019 Dec 27.

Department of Clinical Oncology, State Key Laboratory in Translational Oncology, Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Introduction: Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFR-positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3).

Methods: Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies.

Results: For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs.

Conclusions: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).
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http://dx.doi.org/10.1016/j.jtho.2019.12.113DOI Listing
April 2020

Sarcopenia: A Time for Action. An SCWD Position Paper.

J Cachexia Sarcopenia Muscle 2019 10 15;10(5):956-961. Epub 2019 Sep 15.

BIH Center for Regenerative Therapies (BCRT), Charité Uinversitätsmedizin Berlin, Berlin, Germany.

The term sarcopenia was introduced in 1988. The original definition was a "muscle loss" of the appendicular muscle mass in the older people as measured by dual energy x-ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-related and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.
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http://dx.doi.org/10.1002/jcsm.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818450PMC
October 2019

High Availability of the α7-Nicotinic Acetylcholine Receptor in Brains of Individuals with Mild Cognitive Impairment: A Pilot Study Using F-ASEM PET.

J Nucl Med 2020 03 16;61(3):423-426. Epub 2019 Aug 16.

Department of Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a radioligand for estimating the availability of α7-nAChR in the brain in vivo with PET. In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Higher F-ASEM binding was observed in MCI patients than in controls across all regions, supporting higher availability of α7-nAChR in MCI. F-ASEM binding was not associated with verbal memory in this small MCI sample. These data support use of F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.
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http://dx.doi.org/10.2967/jnumed.119.230979DOI Listing
March 2020

Therapeutic outcomes in non-small cell lung cancer with mutations: a single institution, retrospective cohort study.

Transl Lung Cancer Res 2019 Jun;8(3):258-267

Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Background: Data describing therapeutic outcomes in patients with non-small cell lung cancers (NSCLC) with mutations remains limited.

Methods: We conducted a retrospective cohort study of 31 patients with metastatic NSCLC treated at Duke University Hospital who had been identified by next-generation sequencing methods to bear a mutation in their tumor in order to evaluate clinical response to immunotherapy and chemotherapy.

Results: Sixty-five percent of patients identified in this cohort were current or former smokers. Fourteen (45.2%) of patients had a V600E mutation and 17 (54.8%) had a non-V600E mutation. Median progression-free survival (PFS) in the 23 patients who received first-line chemotherapy was 6.4 months [95% confidence interval (CI), 2.3 to 13.0]. Overall survival (OS) in patients who received first-line chemotherapy showed a median survival of 18 months (95% CI, 7.4 to 28.6). OS comparing patients who had never received immunotherapy at any point was 18.4 months (95% CI, 4.1 to NE) compared to 19.0 months (95% CI, 9.9 to 28.6) in those who had received immunotherapy. We did not find a statistically significant difference in OS in patients with V600E, amplification, or non-V600E mutations. There was also no difference in OS in patients treated with targeted BRAF inhibitors compared to those who were not treated with targeted BRAF inhibitors.

Conclusions: We describe therapeutic outcomes for patients with metastatic NSCLC with mutations treated with either cytotoxic chemotherapy or immunotherapy. Although the sample size is small, the survival curves do not suggest improved clinical activity in this population when treated with immunotherapy.
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http://dx.doi.org/10.21037/tlcr.2019.04.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626861PMC
June 2019

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

Support Care Cancer 2020 Feb 7;28(2):925-932. Epub 2019 Jun 7.

Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA.

Purpose: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC.

Methods: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models.

Results: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality.

Conclusions: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.
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http://dx.doi.org/10.1007/s00520-019-04875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954126PMC
February 2020

SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).

J Thorac Oncol 2019 10 31;14(10):1839-1846. Epub 2019 May 31.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: S1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC).

Methods: Eligible patients had tumoral phosphatidylinositol-4,5-biphosphate 3 kinase catalytic subunit alpha (PIK3CA) alterations by next-generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4-mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival and duration of response.

Results: Twenty-six patients treated with taselisib comprised the full evaluable population (FEP); 21 patients comprised the PAP. Median age for patients in the FEP was 68 years (range: 53-83 years), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% response rate, 95% confidence interval [CI]: 0%-24%). Two possibly treatment-related deaths (one respiratory failure, one cardiac arrest) were observed; one patient had grades 4 and 11 had grade 3 adverse events. Median progression-free survival and overall survival in the PAP group were 2.9 months (95% CI: 1.8-4.0 mo) and 5.9 months (95% CI: 4.2-7.8 mo), respectively. These numbers were nearly the same in the FEP.

Conclusions: Study S1400B evaluating taselisib in PIK3CA-altered sqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in sqNSCLC.
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http://dx.doi.org/10.1016/j.jtho.2019.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017958PMC
October 2019

Relationship between neuropsychological behavior and brain white matter in first-episode psychosis.

Schizophr Res 2019 06 13;208:49-54. Epub 2019 Apr 13.

Department Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA; Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Mental Health, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

We addressed the relationship between white matter architecture, represented by MRI fractional anisotropy (FA), and cognition in individuals with first-episode psychosis (FEP) by applying for a new methodology that allows whole brain parcellation of core and peripheral white matter in a biologically meaningful fashion. Regionally specific correlations were found in FEP between three specific domains of cognition (processing speed, attention/working memory, and executive functioning) and FA at the deep (cerebral peduncles, sagittal striatum, uncinate, internal/external capsule, cingulum) and peripheral white matter (adjacent to inferior temporal, angular, supramarginal, insula, occipital, rectus gyrus).
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http://dx.doi.org/10.1016/j.schres.2019.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544495PMC
June 2019

What are the criteria for response to cachexia treatment?

Authors:
Jeffrey Crawford

Ann Palliat Med 2019 Jan;8(1):43-49

Duke Cancer Institute, Duke University, Durham, NC, USA.

The treatment of cancer cachexia remains an unmet medical need. One of the barriers to the development and approval of effective interventions has been the lack of agreement on the proper endpoints for study. The international consensus definition of cancer cachexia focuses on 3 major components of the syndrome. This includes altered body composition characterized specifically by loss of skeletal muscle mass. The muscle loss in turn is a result of negative protein and energy balance secondary to reduced food intake and abnormal metabolism. The result of muscle loss is progressive functional impairment. The assessment of interventions for cancer cachexia should include measures of all 3 components of cancer cachexia. For patients with cancer cachexia, body composition measurements of lean body mass (LBM) and fat mass may be best determined by CT imaging. Nutritional endpoints and measures of metabolism can be quite complex. However, change in appetite and body weight remain extremely useful measures of clinical benefit. The most controversial area relates to assessment of physical function. While stair climb power, 6-minute walk, hand grip strength and other measures have been used in clinical trials, none of them have shown consistent benefit that correlates with change in LBM. While we have much to learn about the inter-relationship between muscle mass and muscle function, improvement in physical function may be best measured by patient reported outcomes. Ongoing and future clinical trials in cancer cachexia should assess all 3 domains, which will improve our understanding of this syndrome and ultimately lead to better treatment options for our patients.
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http://dx.doi.org/10.21037/apm.2018.12.08DOI Listing
January 2019

Assessing Brain Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With First-Episode Psychosis.

JAMA Psychiatry 2019 03;76(3):314-323

Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: The use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants.

Objective: To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance.

Design, Setting, And Participants: Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated.

Main Outcomes And Measures: Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests.

Results: The mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F1,162 = 8.63, P = .02), N-acetylaspartate (F1,161 = 5.93, P = .03), GABA (F1,163 = 6.38, P = .03), and glutathione (F1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F1,136 = 7.23, P = .05) and thalamus (F1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01).

Conclusions And Relevance: Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.3637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439827PMC
March 2019

The availability of the α7 nicotinic acetylcholine receptor in recent-onset psychosis: a study using F-ASEM PET.

J Nucl Med 2018 Dec 20. Epub 2018 Dec 20.

Johns Hopkins Medical Institutions, United States.

Limited postmortem evidence suggests a diminished availability of the α7 nicotinic acetylcholine receptor (α7-nAChR) in hippocampus in psychosis. In this cross-sectional PET study, we used F-ASEM, a radiotracer targeting the α7-nAChR, with positron emission tomography to compare the binding of F-ASEM in hippocampus between individuals with recent-onset psychosis and healthy controls. Individuals with recent-onset psychosis [non-affective psychosis (NP) or affective psychosis], and particularly those with NP, showed lower hippocampal binding of F-ASEM than healthy controls. Among patients, lower binding was associated with lower performance in two cognitive domains after controlling for age. Low availability of the α7-nAChR in hippocampus may be linked to recent-onset of psychosis. Further study is needed to assess its clinical relationship to neuropsychiatric symptoms.
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http://dx.doi.org/10.2967/jnumed.118.213686DOI Listing
December 2018

Contributions of olfactory and neuropsychological assessment to the diagnosis of first-episode schizophrenia.

Neuropsychology 2019 Feb 26;33(2):203-211. Epub 2018 Nov 26.

Department of Psychiatry and Behavioral Sciences.

Objective: First-episode schizophrenia and schizoaffective patients (SZ+) show olfactory impairments, but how these relate to cognitive dysfunction remains unclear. We examined the relationship between cognitive and olfactory dysfunction in SZ+ and the clinical utility of these measures in the assessment of SZ+ patients.

Method: First-episode SZ+ patients (n = 63) and controls (n = 63) were administered tests of odor identification and discrimination in addition to measures of manual dexterity, processing speed, attention and working memory, executive functioning, ideational fluency, and memory. We analyzed the relationships between olfactory and cognitive variables and conducted stepwise multiple regressions to identify which cognitive indices best predicted olfactory performance within the SZ+ group. Linear discriminant analysis was used to identify which measures best distinguished cases from controls.

Results: Among patients, odor discrimination correlated with perseverative errors and odor identification correlated with bilateral manual dexterity. Odor discrimination performance was best predicted by perseverative errors and letter fluency, whereas odor identification ability was best predicted by manual dexterity. Stepwise linear discriminant analysis revealed that manual dexterity, letter-guided word fluency, and odor discrimination best distinguished SZ+ from healthy adults.

Conclusions: These findings indicate that manual dexterity, letter-guided word fluency, and odor discrimination may provide incremental information that strengthens a diagnosis of SZ+. Although odor discrimination tasks have received limited attention in schizophrenia studies, the extant data along with the present results indicate that odor discrimination tasks may have utility over odor identification measures as a neurodevelopmental risk marker. Additional studies examining odor discrimination as a predictor of SZ spectrum illness are warranted. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000502DOI Listing
February 2019

Survival Comparison in Patients with Stage IV Lung Cancer in Academic versus Community Centers in the United States.

J Thorac Oncol 2018 Dec 9;13(12):1842-1850. Epub 2018 Oct 9.

Duke Cancer Institute, Duke University, Durham, North Carolina. Electronic address:

Introduction: Although metastatic NSCLC is widely treated in both academic centers (ACs) and community-based centers (CCs), it is unclear whether outcomes are similar across both settings. A growing variety of chemotherapies and targeted agents for an increasingly histology- and molecular-based treatment strategy could provide an advantage to patients treated in ACs. Using the National Cancer Database, we investigated whether treatment at ACs was associated with a survival advantage in metastatic NSCLC.

Methods: We conducted a retrospective analysis of the National Cancer Database after the introduction of novel NSCLC chemotherapy agents from 1998 to 2010. The primary outcome was 2-year survival, which was analyzed by using a multivariable regression model controlling for age, year of diagnosis, sex, primary payer, histologic type, facility type (AC versus CC), and an interaction term allowing a time-based comparison of survival between ACs and CCs. Alpha was set to 0.001 because of the size of the data set.

Results: There were 193,279 patients included in this study. The percentage of patients achieving 2-year survival was higher in ACs versus in CCs in 1998 (11.5% versus 9.2% [+2.3%]), and by 2010, the difference had increased to 17.4% versus 13.1% (+4.3%). Multivariable analysis confirmed a significant relative increase in 2-year survival associated with ACs versus with CCs from 1998 to 2010 (p = 0.0005). A histology-dependent survival difference was also noted in adenocarcinoma versus in squamous cell carcinoma (10.2% versus 9.9% in 1998 [+0.3%], increasing to 17.3% versus 10.1% in 2010 [+7.2%]). Adenocarcinoma survival also varied by treatment facility, with the difference in 2-year survival in ACs versus in CCs increasing from 12.3% versus 9.1% (+3.2%) in 1998 to 20.5% versus 15.5% (+5%) in 2010, with a trend toward significance in our multivariable model (p = 0.005).

Conclusions: A greater increase in survival was noted in ACs than in CCs over this time period, and it was particularly pronounced among patients with adenocarcinoma versus in those with squamous cell carcinoma. Given the known advances in adenocarcinoma treatment compared with in squamous cell lung cancer over this time period, our study suggests that potential treatment-related disparities may exist between ACs and CCs. Further study will be needed to validate this disparity in health care and address opportunities to improve survival in patients with stage IV NSCLC across treatment settings.
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http://dx.doi.org/10.1016/j.jtho.2018.09.007DOI Listing
December 2018

Contemporary outcomes of thoracofemoral bypass.

J Vasc Surg 2019 04 3;69(4):1150-1159.e1. Epub 2018 Oct 3.

Division of Vascular Surgery & Endovascular Therapy, University of Florida, Gainesville, Fla.

Objective: Thoracofemoral bypass (TFB) is an alternative to aortofemoral bypass (AFB) or extra-anatomic bypass for severe aortoiliac occlusive disease (AIOD). TFB may be particularly useful in select patients with concurrent visceral aortic branch vessel disease, infrarenal aortic occlusions, or after failed AFB. However, there are few contemporary series describing the indications and outcomes for TFB. Therefore, the purpose of this analysis was to review our experience with TFB.

Methods: All patients undergoing TFB for occlusive disease from 2002 to 2017 were reviewed. All patients underwent left thoracoretroperitoneal exposure of the supraceliac aorta with division of the diaphragmatic crus and supraceliac cross-clamping. An end-to-side aortic anastomosis was created and each graft limb was tunneled in the retroperitoneum to the femoral bifurcation. Adjunctive visceral/infrainguinal revascularization was performed selectively based on symptoms, end-organ function, and/or preoperative imaging. The primary end points were major complications and 30-day mortality. Secondary end points included limb patency, freedom from major adverse limb events, and survival. Kaplan-Meier methodology was used to characterize the end points.

Results: Forty-one patients (age 61 ± 9 years; 54% female; 7% in a hypercoaguable state) underwent TFB. The mean preoperative ankle-brachial index was 0.4 bilaterally. Indications included critical limb ischemia (56%), claudication (30%), acute limb ischemia (7%), and combined AIOD and mesenteric ischemia (7%). Seven patients (17%) had previously undergone AFB and 15 (38%) had previously undergone any prior aortic operation. Adjunctive visceral bypass occurred in 8 patients (20%; N = 14 grafts, n = 6 renal, n = 5 superior mesenteric artery, and n = 3 celiac). The postoperative duration of stay was 11 days (interquartile range [IQR], 7-16 days) and the 30-day mortality was 5% (n = 2). Major complications occurred in 34% of patients (N = 14; pulmonary, 15%; cardiac, 12%; bleeding, 7%; accidental splenectomy, 5%; renal, 5%; wound, 2%). The mean postoperative ankle-brachial index was 0.9 bilaterally. At a median follow-up of 7 months (IQR, 1-17 months), 5 patients (12%) underwent some form of reintervention (graft/limb related, n = 4 [n = 2 graft thrombosis, n = 2 graft infection], n = 1 mesenteric bypass revision). The estimated 3-year primary limb patency and freedom from major adverse limb events were 80 ± 10%, and 70 ± 10%, respectively. The estimated 5-year survival was 93 ± 5% (median, 27.3; IQR, 14.5-35.2; 95% confidence interval, 17.9-32.8).

Conclusions: This experience represents one of the largest and most current series of retroperitoneal TFB. We demonstrate that TFB can be performed with good outcomes for patients with severe AIOD, especially if concomitant visceral/infrainguinal reconstruction is warranted. These results support a continued role for TFB in select patients.
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http://dx.doi.org/10.1016/j.jvs.2018.07.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433534PMC
April 2019

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Crit Rev Oncol Hematol 2018 Sep 19;129:79-90. Epub 2018 Jun 19.

Indiana University Health, Indianapolis, IN, USA.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.
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http://dx.doi.org/10.1016/j.critrevonc.2018.06.010DOI Listing
September 2018

Predictors of Physical and Functional Loss in Advanced-Stage Lung Cancer Patients Receiving Platinum Chemotherapy.

J Thorac Oncol 2018 09 4;13(9):1294-1301. Epub 2018 Jul 4.

Division of Medical Oncology, Duke Cancer Institute, Durham, North Carolina.

Introduction: Muscle wasting has detrimental effects, including increased mortality. Identifying patients at risk can guide treatment efforts.

Methods: POWER 1 and 2 were randomized, double-blind, placebo-controlled, multinational phase III trials that studied 600 patients with lung cancer at the start of chemotherapy; the studies' aim was to assess the efficacy of enobosarm on prevention and treatment of muscle loss. We performed a secondary analysis restricted to the control group, using a cumulative logit model for ordinal outcome to determine which baseline characteristics predicted physical and functional loss during chemotherapy.

Results: In all, 53% of patients had loss of lean body mass and 49% had loss of stair climb power (SCP) at day 84 of treatment. Of the 322 patients who received placebo, 232 with observable outcome and baseline covariates were included for lean body mass analysis and 236 for SCP analysis. More advanced disease predicted a higher probability of greater physical loss (OR = 1.96; 95% confidence interval [CI]: 1.14-3.36). Three factors predicted higher probability of SCP loss: taxane chemotherapy (OR = 1.73; 95% CI: 1.06-2.83), tobacco use before chemotherapy (OR = 2.15, 95% CI: 1.10-4.18), and SCP at baseline (OR = 1.01, 95% CI: 1.004-1.015). Higher body mass index was a protective factor for functional loss (OR = 0.85; 95% CI: 0.73-0.98). A higher Eastern Cooperative Oncology Group Performance Status trended toward being predictive of greater probability of both physical loss (0.767) and functional loss (0.070), but the results were not statistically significant.

Conclusions: Approximately 50% of patients with advanced lung cancer who were undergoing chemotherapy had ongoing loss of muscle mass and muscle function. Advanced stage predicted physical loss. Tobacco use and taxane chemotherapy predicted functional loss. Body mass index was a protective factor for functional loss. We identified predictors of physical and functional loss that could be used as therapeutic targets or to guide treatment efforts.
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http://dx.doi.org/10.1016/j.jtho.2018.05.029DOI Listing
September 2018

Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer.

Clin Breast Cancer 2018 10 16;18(5):380-386. Epub 2018 Feb 16.

Duke University Medical Center, Durham, NC.

Background: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer.

Patients And Methods: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models.

Results: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality.

Conclusion: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.
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http://dx.doi.org/10.1016/j.clbc.2018.02.003DOI Listing
October 2018

A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer.

Oncologist 2018 07 23;23(7):782-790. Epub 2018 Mar 23.

Duke Cancer Institute, Durham, North Carolina, USA

Purpose: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen.

Materials And Methods: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation.

Results: Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively.

Conclusion: The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma.

Implications For Practice: This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.
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http://dx.doi.org/10.1634/theoncologist.2016-0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058343PMC
July 2018

Tibial artery duplex ultrasound-derived peak systolic velocities may be an objective performance measure after above-knee endovascular therapy for arterial stenosis.

J Vasc Surg 2018 08 6;68(2):481-486. Epub 2018 Mar 6.

Division of Vascular Surgery, Department of Surgery, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Ore. Electronic address:

Objective: The ankle-brachial index (ABI) is a well-established measure of distal perfusion in lower extremity ischemia; however, the ABI is of limited value in patients with noncompressible lower extremity arteries. We sought to demonstrate whether duplex ultrasound-determined tibial artery velocities can be used as an alternative to ABI as an objective performance measure after endovascular treatment of above-knee arterial stenosis.

Methods: Thirty-six patients undergoing above-knee endovascular intervention had preprocedure and postprocedure duplex ultrasound examination within 6 months of intervention. Preprocedure vs postprocedure changes in tibial artery mean peak systolic velocity (PSV; mean of proximal, mid, and distal velocities) were compared with changes in ABI and a reference (control) cohort of 68 patients without peripheral vascular disease.

Results: Thirty-six patients (41 limbs) had an above-knee endovascular intervention and had preprocedure and postprocedure duplex ultrasound examinations of the ipsilateral extremity including the tibial arteries. Before the procedure, mean tibial artery PSVs in the 36 patients undergoing intervention were outside (below) the 95% confidence intervals for the control patients. In comparing preprocedure and postprocedure PSVs, the mean anterior tibial (P < .01), mean peroneal (P < .01), and mean posterior tibial (P < .01) PSVs all increased and correlated with an increase in ABI (P < .01). After endovascular intervention, duplex ultrasound-derived mean PSVs fell within or near established reference ranges for patients without peripheral arterial disease. Mean tibial artery PSV increases were similar in patients with and without noncompressible vessels.

Conclusions: Tibial artery PSVs increase, correlate with an increase in ABI, and fall within or near confidence intervals for normal controls after above-knee endovascular interventions. After endovascular intervention, tibial artery PSVs can supplement ABI as an objective performance measure in patients with and in particular without compressible tibial arteries.
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http://dx.doi.org/10.1016/j.jvs.2017.11.092DOI Listing
August 2018

Analysis of Factors Associated With In-hospital Mortality in Lung Cancer Chemotherapy Patients With Neutropenia.

Clin Lung Cancer 2018 03 28;19(2):e163-e169. Epub 2017 Oct 28.

Department of Medicine and Cancer Institute, Duke University Medical Center, Durham, NC. Electronic address:

Lung cancer, compared with other solid tumors, is associated with high mortality rates from febrile neutropenia. The risk factors associated with in-hospital mortality were identified and compared for patients with lung cancer and patients with other solid tumors. Hospitalization data from the University Health Consortium database inclusive of 2004 to 2012 were analyzed. The study population included all adult patients with solid tumors who developed neutropenia. Cancer type, the presence of neutropenia, and further subgroups were determined using International Classification of Diseases, 9th revision, Clinical Modification codes. The primary study outcome was in-hospital mortality in lung cancer patients versus those with other solid tumors. Further analysis concentrated on comparisons of the 2 groups. The analysis included data from 11,111 lung cancer patients and 49,975 patients with other solid tumors. Overall, 4290 patients (7.0%) died. Lung cancer was associated with highest mortality (11.2% compared with other solid tumors, 6.1%; P < .0001). The lung cancer patients were older and more likely to have multiple comorbidities, and the risk of mortality was directly related to the number of comorbidities. Four additional risk factors for mortality were identified: pneumonia, sepsis, any infection, and intensive care unit stay. Pneumonia occurred more commonly in the lung cancer patients (26.4% vs. 10.3%) and was associated with comorbid pulmonary disease, which also occurred more often in the lung cancer patients (52.1% vs. 24.0%). We found that lung cancer patients presenting with febrile neutropenia were older, had more comorbidities, had a greater incidence of comorbid pulmonary disease, and were more likely to have pneumonia. Awareness of these risk factors for mortality should guide clinicians for more personalized approaches to chemotherapy, supportive care decisions, pneumonia and comorbidities.
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http://dx.doi.org/10.1016/j.cllc.2017.10.013DOI Listing
March 2018

Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 12;15(12):1520-1541

Myeloid growth factors (MGFs) are given as supportive care to patients receiving myelosuppressive chemotherapy to reduce the incidence of neutropenia. This selection from the NCCN Guidelines for MGFs focuses on the evaluation of regimen- and patient-specific risk factors for the development of febrile neutropenia (FN), the prophylactic use of MGFs for the prevention of chemotherapy-induced FN, and assessing the risks and benefits of MGF use in clinical practice.
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http://dx.doi.org/10.6004/jnccn.2017.0175DOI Listing
December 2017

Cancer cachexia: Are we ready to take a step forward?

Authors:
Jeffrey Crawford

Cancer 2018 02 4;124(3):456-458. Epub 2017 Dec 4.

Solid Tumor Therapeutics Program, Duke Cancer Institute, Durham, North Carolina.

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http://dx.doi.org/10.1002/cncr.31126DOI Listing
February 2018

Intraluminal thrombus is associated with early rupture of abdominal aortic aneurysm.

J Vasc Surg 2018 04 13;67(4):1051-1058.e1. Epub 2017 Nov 13.

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Ore.

Background: The implications of intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) are currently unclear. Previous studies have demonstrated that ILT provides a biomechanical advantage by decreasing wall stress, whereas other studies have associated ILT with aortic wall weakening. It is further unclear why some aneurysms rupture at much smaller diameters than others. In this study, we sought to explore the association between ILT and risk of AAA rupture, particularly in small aneurysms.

Methods: Patients were retrospectively identified and categorized by maximum aneurysm diameter and rupture status: small (<60 mm) or large (≥60 mm) and ruptured (rAAA) or nonruptured (non-rAAA). Three-dimensional AAA anatomy was digitally reconstructed from computed tomography angiograms for each patient. Finite element analysis was then performed to calculate peak wall stress (PWS) and mean wall stress (MWS) using the patient's systolic blood pressure. AAA geometric properties, including normalized ILT thickness (mean ILT thickness/maximum diameter) and % volume (100 × ILT volume/total AAA volume), were also quantified.

Results: Patients with small rAAAs had PWS of 123 ± 51 kPa, which was significantly lower than that of patients with large rAAAs (242 ± 130 kPa; P = .04), small non-rAAAs (204 ± 60 kPa; P < .01), and large non-rAAAs (270 ± 106 kPa; P < .01). Patients with small rAAAs also had lower MWS (44 ± 14 kPa vs 82 ± 20 kPa; P < .02) compared with patients with large non-rAAAs. ILT % volume and normalized ILT thickness were greater in small rAAAs (68% ± 11%; 0.16 ± 0.04 mm) compared with small non-rAAAs (53% ± 16% [P = .02]; 0.11 ± 0.04 mm [P < .01]) and large non-rAAAs (57% ± 12% [P = .02]; 0.12 ± 0.03 mm [P < .01]). Increased ILT % volume was associated with both decreased MWS and decreased PWS.

Conclusions: This study found that although increased ILT is associated with lower MWS and PWS, it is also associated with aneurysm rupture at smaller diameters and lower stress. Therefore, the protective biomechanical advantage that ILT provides by lowering wall stress seems to be outweighed by weakening of the AAA wall, particularly in patients with small rAAAs. This study suggests that high ILT burden may be a surrogate marker of decreased aortic wall strength and a characteristic of high-risk small aneurysms.
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http://dx.doi.org/10.1016/j.jvs.2017.08.069DOI Listing
April 2018