bluuebunny/crossref_metadata_2025 huggingface dataset:
Office-Based Cholesterol Testing: Impact on Process-of-Care in Patients with Hypercholesterolemia a Pilot Study
Authors: Ruffin David M , McKenney James M
Published: July 2017

Objective:

To determine whether providing cholesterol results during a patient-physician office encounter would affect the process-of-care in patients with hypercholesterolemia.

Methods:

We used a randomized, parallel-group, control design to conduct the study. Thirty-five participants had a lipoprotein analysis performed using the L.D.X. cholesterol analyzer. Patients randomly assigned to the intervention group (n = 19) had their results provided to the physician during the office visit; the results of those in the control group (n = 16) were not made available to the physician. Each participant's medical record was reviewed to determine the physican's process-of-care with respect to cholesterol management. The indicators of the process-of-care for which we sought documentation included therapeutic interventions and the physician's assessment of risk for coronary heart disease. We used Fisher's exact test to determine statistical significance of the intervention. Descriptive analysis was also performed.

Results:

We were unable to detect a statistically significant difference in therapeutic interventions (p = 0.183). However, we did observe a statistically significant difference in the physician's assessment of risk for coronary heart disease (p = 0.0001).

Conclusions:

Our data suggest that providing a cholesterol test result during a patient-physician office encounter positively affects the process-of-care in patients with hypercholesterolemia. Future studies should include larger numbers of patients and longer follow-up periods.
Well-Being and Functional Status of Pharmacy Students: A Preliminary Assessment
Authors: Edgell Eric T , Caplette Michael D , Gregor Karl J , Flynn Mark T , Coons Stephen Joel
Published: July 2017

Objective:

To initiate the research process of investigating how pharmacy education affects the health status of pharmacy students.

Design:

Student functioning and well-being were assessed within two pharmacy classes at two points in time.

Setting:

College of Pharmacy, The University of Arizona, Tucson, AZ.

Participants:

Students enrolled in either their first (class of 1997) or third (class of 1995) professional year of The University of Arizona's 4-year Doctor of Pharmacy degree program.

Main Outcome Measure:

The RAND 36-Item Health Survey 1.0.

Results:

No significant mean score differences were found between the classes, and the mean scores for the first-year class remained stable during the semester. The third-year class's mean scores for the emotional well-being and emotional problem-related role functioning scales decreased significantly during the semester.

Conclusions:

Pharmacy school may affect students' functioning and well-being in different and unique ways compared with medical school. Additional research should be conducted to assess changes in pharmacy student health status and to develop mechanisms to help counter any negative impact that may occur during pharmacy school.
Predictive Performance of Estimated Creatinine Clearance in HIV-Infected Individuals
Authors: Noormohamed Saleem E , Flanigan Michael J
Published: July 2017

Objective:

To evaluate the predictive performance of published creatinine clearance (Clcr) predictor equations in individuals infected with HIV.

Methods:

A retrospective review of medical records of patients with a 24-hour urine collection to determine Clcr was conducted. Clcr was estimated with each of six published equations. Estimated Clcr was compared with actual values, and bias and precision were calculated.

Results:

Clcr determined using the 24-hour urine collections were only moderately related to various patient factors such as weight and serum creatinine. The Cockcroft—Gault method significantly overestimated Clcr in patients with HIV (ANOVA; p = 0.0087) and demonstrated greatest bias (mean percentage prediction error, 52; 95% CI 18 to 87) and least precision (percentage root mean-squared error, 76; 95% CI −26 to 177) of the estimator methods.

Conclusions:

None of the six equations evaluated were precise predictors of Clcr in individuals with HIV. Using these equations, particularly the Cockcroft—Gault method, to predict renal function in patients with HIV could lead to overdosing renally eliminated medications in this population. Accurate assessment of renal function in these patients warrants a 24-hour urine collection or isotopic clearance measurement.
Amiodarone-Associated Depression
Authors: Maidment Ian D , Helme Tim
Published: July 2017

Objective:

To report a case of depression secondary to or aggravated by amiodarone-induced hypothyroidism.

Case Summary:

An 84-year-old white man was admitted to a psychiatric unit with severe depression approximately seven months after amiodarone had been initiated to treat paroxysmal supraventricular tachycardia. On admission, the thyroid-stimulating hormone (TSH) concentration was 11.50 μU/mL (normal 0.17–4.00) and the total thyroxine concentration was 3.9 μg/dL (4.0–11.0). About 21 months before initiation of amiodarone therapy, the TSH concentration was 2.4 μU/mL; this was the only previous TSH result available. Seven days after admission, thyroxine (levothyroxine) 25 μg/d was started. Twenty-eight days after admission, the patient's mood had improved, and the TSH concentration (2.67 μU/mL) was within normal range. The patient was discharged four days later.

Discussion:

Amiodarone contains 37.2% iodine. This is a greatly increased iodine load compared with normal intake. Amiodarone may therefore have three possible effects on thyroid function: (1) the serum concentration of thyroid hormones in clinically euthyroid patients may change, complicating assessment; (2) hyperthyroidism may occur (1–5% of patients); and (3) hypothyroidism may occur (6–10% of patients). Thus, thyroid function should be checked at least every six months. The elevated TSH concentration could indicate mild hypothyroidism or possibly be a symptom of the depressive illness. Furthermore, our patient's mood appeared to improve after he had received six to seven weeks of treatment with fluoxetine; he had also experienced depressive episodes throughout his life. Thus, particularly because the TSH concentration was only moderately raised, it is possible that amiodarone-induced hypothyroidism worsened rather than caused the depressive episode. The usual treatment for amiodarone-induced hypothyroidism is continuation of amiodarone and initiation of thyroxine at a dosage of 25–50 μg/d.

Conclusions:

This case illustrates the need to be vigilant for amiodarone-induced hypothyroidism, which may cause depression or exacerbate an underlying depressive illness. Supplemental treatment with levothyroxine may effect a rapid mood response.
Proteomic profile of cystic fibrosis sputum cells in adults chronically infected withPseudomonas aeruginosa
Authors: Pattison Sally H. , Gibson David S. , Johnston Elinor , Peacock Samantha , Rivera Keith , Tunney Michael M. , Pappin Darryl J. , Elborn J. Stuart
Published: July 2017

Lung disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and involves chronic infection and perturbed immune responses. Tissue damage is mediated mostly by extracellular proteases, but other cellular proteins may also contribute to damage through their effect on cell activities and/or release into sputum fluid by means of active secretion or cell death.

We employed MudPIT (multidimensional protein identification technology) to identify sputum cellular proteins with consistently altered abundance in adults with CF, chronically infected withPseudomonas aeruginosa, compared with healthy controls. Ingenuity Pathway Analysis, Gene Ontology, protein abundance and correlation with lung function were used to infer their potential clinical significance.

Differentially abundant proteins relate to Rho family small GTPase activity, immune cell movement/activation, generation of reactive oxygen species, and dysregulation of cell death and proliferation. Compositional breakdown identified high abundance of proteins previously associated with neutrophil extracellular traps. Furthermore, negative correlations with lung function were detected for 17 proteins, many of which have previously been associated with lung injury.

These findings expand our current understanding of the mechanisms driving CF lung disease and identify sputum cellular proteins with potential for use as indicators of disease status/prognosis, stratification determinants for treatment prescription or therapeutic targets.
Cardiometabolic correlates of sleep disordered breathing in Andean highlanders
Authors: Pham Luu V. , Miele Catherine H. , Schwartz Noah G. , Arias Rafael S. , Rattner Adi , Gilman Robert H. , Miranda J. Jaime , Polotsky Vsevolod Y. , Checkley William , Schwartz Alan R.
Published: July 2017

Associations between sleep disordered breathing (SDB) and cardiometabolic outcomes have not been examined in highlanders.

We performed nocturnal polygraphy in Peruvian highlanders (3825 m). Multivariable linear regression models examined associations between SDB metrics and haemoglobin, glucose tolerance (haemoglobin A1c (HbA1c)), fasting glucose, homeostatic model-based assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively), blood pressure, and lipids, while adjusting for age, sex, body mass index (BMI) and wake oxygenation.

Participants (n=187; 91 men) were (median (interquartile range)) 52 (45–62) years old, and had a BMI of 27.0 (24.3–29.5) kg·m−2and 87% (85–88%) oxyhaemoglobin (arterial oxygen) saturation during wakefulness. In fully adjusted models, worsening nocturnal hypoxaemia was associated with haemoglobin elevations in men (p=0.03), independent of wake oxygenation and apnoea–hypopnoea index (AHI), whereas worsening wake oxygenation was associated with haemoglobin elevations in older women (p=0.02). In contrast, AHI was independently associated with HbA1c elevations (p<0.05). In single-variable models, nocturnal hypoxaemia was associated with higher HbA1c, HOMA-IR and HOMA-β (p<0.001, p=0.02 and p=0.04, respectively), whereas AHI was associated with HOMA-IR, systolic blood pressure and triglyceride elevations (p=0.02, p=0.01 and p<0.01, respectively). These associations were not significant in fully adjusted models.

In highlanders, nocturnal hypoxaemia and sleep apnoea were associated with distinct cardiometabolic outcomes, conferring differential risk for excessive erythrocytosis and glucose intolerance, respectively.
Pulmonary artery to aorta ratio and risk of all-cause mortality in the general population: the Rotterdam Study
Authors: Terzikhan Natalie , Bos Daniel , Lahousse Lies , Wolff Lennard , Verhamme Katia M.C. , Leening Maarten J.G. , Felix Janine F. , Gall Henning , Ghofrani Hossein A. , Franco Oscar H. , Ikram M. Arfan , Stricker Bruno H. , van der Lugt Aad , Brusselle Guy
Published: July 2017

A pulmonary artery to aorta ratio (PA:A) >1 is a proxy of pulmonary hypertension. It is not known whether this measure carries prognostic information in the general population and in individuals with chronic obstructive pulmonary disease (COPD).

Between 2003 and 2006, 2197 participants from the population-based Rotterdam Study (mean±sdage 69.7±6.7 years; 51.3% female), underwent cardiac computed tomography (CT) scanning with PA:A quantification, defined as the ratio between the diameters of the pulmonary artery and the aorta. COPD was diagnosed based on spirometry or clinical presentation and obstructive lung function measured by a treating physician. Cox regression was used to investigate the risk of mortality.

We observed no association between 1-sdincrease of PA:A and mortality in the general population. Larger PA:A was associated with an increased risk of mortality in individuals with COPD, particularly in moderate-to-severe COPD (hazard ratio 1.36, 95% CI 1.03–1.79). We demonstrated that the risk of mortality in COPD was driven by severe COPD, and that this risk increased with decreasing diffusing capacity.

Larger PA:A is not associated with mortality in an older general population, but is an independent determinant of mortality in moderate-to-severe COPD. Measuring PA:A in CT scans obtained for other indications may yield important prognostic information in individuals with COPD.
Trends in mechanical ventilation: are we ventilating our patients in the best possible way?
Authors: Dellaca’ Raffaele L. , Veneroni Chiara , Farre’ Ramon
Published: July 2017

This review addresses how the combination of physiology, medicine and engineering principles contributed to the development and advancement of mechanical ventilation, emphasising the most urgent needs for improvement and the most promising directions of future development.

Several aspects of mechanical ventilation are introduced, highlighting on one side the importance of interdisciplinary research for further development and, on the other, the importance of training physicians sufficiently on the technological aspects of modern devices to exploit properly the great complexity and potentials of this treatment.

Educational aims

To learn how mechanical ventilation developed in recent decades and to provide a better understanding of the actual technology and practice.

To learn how and why interdisciplinary research and competences are necessary for providing the best ventilation treatment to patients.

To understand which are the most relevant technical limitations in modern mechanical ventilators that can affect their performance in delivery of the treatment.

To better understand and classify ventilation modes.

To learn the classification, benefits, drawbacks and future perspectives of automatic ventilation tailoring algorithms.
Treating symptomatic uterine fibroids with myomectomy: current practice and views of UK consultants
Authors: Sirkeci R. Fusun , Belli Anna Maria , Manyonda Isaac T.
Published: July 2017

Background

The demand for uterus-sparing treatments is increasing as more women postpone childbirth to their 30–40s, when fibroids are more symptomatic. With an increasing choice of treatment options and changing care-provider profiles, now is an opportune time to survey current practices and opinions. Using a 25-stem questionnaire, a web-based survey was used to capture the practices and opinions of UK consultant gynecologists on the treatment of symptomatic fibroids, including the types of procedure most frequently used, methods used to reduce blood loss, and awareness and acceptability of treatment options, and to assess the impact of gender and experience of the treating gynecologist.

Results

The response rate was 22%. Laparascopic myomectomy is used least frequently, with 80% of the respondents using GnRHa preoperatively to minimize blood loss and correct anemia, while vasopressin is most frequently used to reduce intraoperative blood loss. Female consultants operate significantly less frequently than males. Those with more than 10 years consultant experience are more likely to perform an open myomectomy compared to those with less than 10 years experience.

Conclusions

Compared to a similar survey performed 10 years ago, surgical methods remain to be the most common treatments, but use of less invasive treatments such as UAE has increased. Consultants’ attitudes appear to be responding to the patient demand for less radical treatments. However, it is yet to be seen if the changing consultant demographics will keep up with this demand. The low response rate warrants cautious interpretation of the results, but they provide an interesting snapshot of current views and practices.
Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000–2014
Authors: Hayes Joseph F. , Marston Louise , Walters Kate , King Michael B. , Osborn David P. J.
Published: July 2017

Background

Bipolar disorder and schizophrenia are associated with increased mortality relative to the general population. There is an international emphasis on decreasing this excess mortality.

Aims

To determine whether the mortality gap between individuals with bipolar disorder and schizophrenia and the general population has decreased.

Method

A nationally representative cohort study using primary care electronic health records from 2000 to 2014, comparing all patients diagnosed with bipolar disorder or schizophrenia and the general population. The primary outcome was all-cause mortality.

Results

Individuals with bipolar disorder and schizophrenia had elevated mortality (adjusted hazard ratio (HR) = 1.79, 95% CI 1.67–1.88 and 2.08, 95% CI 1.98–2.19 respectively). Adjusted HRs for bipolar disorder increased by 0.14/year (95% CI 0.10–0.19) from 2006 to 2014. The adjusted HRs for schizophrenia increased gradually from 2004 to 2010 (0.11/year, 95% CI 0.04–0.17) and rapidly after 2010 (0.34/year, 95% CI 0.18–0.49).

Conclusions

The mortality gap between individuals with bipolar disorder and schizophrenia, and the general population is widening.
Occurrence of ALK fusions in cancers other than non-small cell lung cancer in a wide variety of tumor types and response to anti-ALK targeted therapy.
Authors: Ross Jeffrey S. , Ali Siraj Mahamed , Elvin Julia Andrea , Schrock Alexa Betzig , Suh James , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Philip J. , Gay Laurie M.
Published: July 2017

11595

Background: Genomic fusions of the anaplastic lymphoma kinase gene ( ALK) are an established therapy target for patients with non-small cell lung cancer (NSCLC), but are not well-characterized in non-NSCLC malignancies. Methods: Comprehensive genomic profiling (CGP) of 92,784 clinically advanced malignancies was performed using a hybrid-capture, adaptor ligation based NGS assay to a mean coverage depth of >600X. Tumor mutational burden (TMB) was calculated from a minimum of 1.1 Mb of sequenced DNA. Results: 17,127/92,784 (18.5%) were NSCLC and 75,657 (81.5%) were non-NSCLC. Of the 697 (0.8%) of cases with ALK fusions, 554 (79%) were identified in NSCLC and 143 (21%) in non-NSCLC including 67 carcinomas; 39 sarcomas including 30 non-uterine and uterine leiomyosarcomas and inflammatory myofibroblastic tumors; 24 in hematolymphoid malignancies including non-Hodgkins lymphomas, myelomas and histiocytic malignancies; 3 in gliomas; 2 each in mesotheliomas, neuroblastomas and undifferentiated malignancies and 1 in melanoma. ALK fusions were significantly more frequently identified in NSCLC (3.2%) than in non-NSCLC (p<0.0001). The non-NSCLC ALK fusion positive patients were significantly older (p<0.0001) and more often female (p<0.0001) than the NSCLC ALK fusion positive patients. At 84%, the more frequent finding of EML4 as the fusion partner in the NSCLC patients versus non-NSCLC patients at 31% was significant (p<0.0001). ALK fusion positive non-NSCLC had significantly lower TMB (mean 5.01 mutations/Mb) than non- ALK altered non-NSCLC (p=0.006). Non-NSCLC ALKfusion positive cases responding to ALK inhibitors will be presented. Conclusions: In non-NSCLC patients ALK fusions are rare and found in both epithelial and mesenchymal malignancies. Initial evidence strongly suggests that anti-ALK therapies can be effective in ALK fusion driven non-NSCLC .
Molecular landscape of BRAF mutations in large cell neuroendocrine carcinoma of lung: An analysis of BRAF mutations and a case report of a BRAF non-V600E mutated tumor responding to targeted therapy.
Authors: Tamragouri Keerthi , Chae Young Kwang , Chung Jon , Miller Vincent A. , Ali Siraj Mahamed , Giles Francis J.
Published: July 2017

11621

Background: In advanced stages, large cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small cell lung cancer (SCLC) despite its traditional classification as a non-small cell lung cancer (NSCLC). Here we present a focused analysis of BRAF mutations in this population. Methods: Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site. Results: 14 unique BRAF alterations (amplifications, mutations) were identified in 13 patients. The importance of biomarker driven therapy is subsequently highlighted with our case of a 69 year-old male diagnosed with metastatic L-LCNEC that did not respond to cisplatin/etoposide. He then demonstrated a significant durable response with therapy targeted toward a BRAF non-V600E mutation (G469R) associated with biomarker response identified through circulating cell free tumor DNA analysis. A change in clonal allele frequency from nearly 50% to non-detectable was observed. Conclusions: Though uncommon, L-LCNEC does appear to contain activating and therefore actionable alterations. We thus highlight the value of pursuing NGS for these patients. [Table: see text]
The age specific genomic landscape of cancer.
Authors: Connelly Caitlin F. , Severson Eric Allan , Lieu Christopher Hanyoung , Meyer Joshua E. , Stephens Phil , Frampton Garrett Michael
Published: July 2017

1568

Background: The frequency of genomic alterations in cancer is known to differ based on a patient’s age. Many studies have characterized the genomic characteristics of pediatric cancers; however, less is known about how the genomic landscape of mutations changes with age in adult patients. Accurately characterizing these differences will help guide personalized treatment strategies and illuminate differences in the genetic etiology of cancer at different ages of onset. Methods: Comprehensive genomic profiling was performed on > 100,000 patients in the course of routine care for patients with predominantly relapsed, refractory or metastatic cancer. For 117 types of cancer with ≥ 100 cases, logistic regression was used to identify genomic features with statistically significant dependence on patient age. Results: Many known associations with age were identified, including increased prevalence of BRCA1/2 mutations in younger breast and ovarian cancer patients and increased prevalence of mismatch repair mutations in younger colorectal and endometrial adenocarcinoma patients. In lung adenocarcinoma, we identified 19 genes for which alteration prevalence was significantly associated with patient age. The genes ALK, ROS1, and RET were more commonly altered in younger patients, KRAS and MET were altered more frequently in older patients, and TP53 was most frequently altered at intermediate ages (40-60). Interestingly, a set of genes that have previously been associated with clonal hematopoiesis (CH) were found to be more frequently detected in older patients across a wide variety of cancer types. Based on the statistical power provided by this large cohort, several novel age based differences in gene alteration rates across multiple tumor types were detected and will be presented. Conclusions: Clear differences in genomics based on patient age were observed. This methodology can be used to identify novel associations between germline alterations and cancer types and somatic alterations that occur predominantly in young or elderly patients. These results also highlight the importance of accurately identifying and properly reporting somatic CH mutations during tumor genomic profiling.
Development and validation of a real-world clinicogenomic database.
Authors: Singal Gaurav , Miller Peter Grant , Agarwala Vineeta , He Jie , Gossai Anala , Frank Shannon , Bourque David , Bowser Bryan , Caron Thomas , Baydur Ezra , Seidl-Rathkopf Kathi , Ivanov Ivan , Parker Alex , Guria Ameet , Frampton Garrett Michael , Jaskiw Ann , Feuchtbaum Dana , Nussbaum Nathan Coleman , Abernethy Amy Pickar , Miller Vincent A.
Published: July 2017

2514

Background: Genomic findings have diagnostic, prognostic, and predictive utility in clinical oncology. Population studies have been limited by reliance on trials, registries, or institutional chart review, which are costly and represent narrow populations. Integrating electronic health record (EHR) and genomic data collected as part of routine clinical practice may overcome these hurdles. Methods: Patients in the Flatiron Health Database with non-small cell lung cancer (NSCLC) who underwent comprehensive genomic profiling (CGP) by Foundation Medicine were included. EHR processing included structured data harmonization and abstraction of variables from unstructured documents. EHR and CGP data were de-identified and linked in a HIPAA-compliant process. Data included clinical characteristics, alterations across > 300 genes, tumor mutation burden (TMB), therapies and associated real-world responses, progression, and overall survival (OS). Results: The cohort (n = 1619) had expected clinical (mean age 66; 75% with smoking hx; 80% non-squamous) and genomic (18% EGFR; 4% ALK; 1% ROS1) properties of NSCLC. Presence of a driver mutation (EGFR, ALK, ROS1, MET, BRAF, RET, or ERBB2; n = 576) was associated with younger age, female gender, non-smoking, improved OS (35 vs 19 mo, LR p < 0.0001), and prolonged survival when treated with NCCN-recommended therapy (42 vs 28 mo, LR p = 0.001). CGP identified false negative results in up to 30% of single-biomarker tests for EGFR, ALK, and ROS1. CGP accuracy was supported by clinical outcomes. For example, 5 patients with prior negative ALK-fusion testing began ALK-directed therapy after positive CGP results. All 5 exhibited at least a partial response as recorded in the EHR by treating clinicians. Immunotherapy was used in 22% of patients (n = 353). TMB predicted response to nivolumab, including in PD-L1 negative populations. We recapitulated known associations with smoking, histology, and driver mutations. Conclusions: We present and validate a new paradigm for rapidly generating large, research-grade, longitudinal clinico-genomic databases by linking genomic data with EHR clinical annotation. This method offers a powerful tool for understanding cancer genomics and advancing precision medicine.
Targeted therapy for HER2 driven colorectal cancer.
Authors: Ross Jeffrey S. , Ali Siraj Mahamed , Elvin Julia Andrea , Schrock Alexa Betzig , Suh James , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Philip J. , Gay Laurie M.
Published: July 2017

3583

Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with pancreatic ductal adenocarcinoma (PDA).
Authors: Bahary Nathan , He Jie , Bailey Mark , Zhong Shan , Li Gerald , Young Lauren , Singhi Aatur D. , Stephens Phil , Ali Siraj Mahamed , Singal Gaurav , Schrock Alexa Betzig , Chung Jon , Ross Jeffrey S. , Miller Vincent A. , George Ben
Published: July 2017

4128

Background: PDA is a lethal and increasingly common malignancy and tissue samples for genomic characterization may be limited. As PDA has a high and consistent frequency of KRAS, p53 and CDKN2A mutations it serves as a robust indication to test the utility of ctDNA in accurately characterizing genomic alterations (GA). A prior study suggested significant differences between ctDNA and tissue base profiling but assays were not conducted on the same platform (PMID27833075). We undertook this study to see whether ctDNA could recapitulate the known genomic hallmarks of tumor based profiling. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 78 pts with advanced PDA with samples received in the course of clinical care. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Frequencies of alterations in these common drivers were then compared to those seen in tumors of pts who underwent comprehensive genomic profiling (CGP) tissue testing performed on the same core platform, FoundationOne, and The Cancer Genome Atlas (TCGA). Results: Pt characteristics: Median age 65 (range, 47-88); Female (33) /Male (45). FoundationACT results show that 53/78 (68%) cases had MSAF >0 (56%-78%%, 95% CI). ≥1 GA was reported in 81% of the cases with evidence of ctDNA in the blood. The most common GA detected by FoundationACT (based on cases with evidence of ctDNA in blood) vs FoundationOne were in KRAS (59% vs 89%, p< 0.0001), TP53 (69% vs.74%, p=0.19), and CDKN2A (14% vs.45%). Other detected clinically relevant GA detected by FoundationACT included: BRCA1, ERBB2, NF1, PIK3CA. Conclusions: This study demonstrates significant differences between the established driver oncogenic alterations for PDA, as assessed by ct DNA and tissue based genomic profiling which are unlikely to be explained by differences in assay, but rather novel cancer biology. At present use of ctDNA genomic profiling in PDA should not routinely replace tissue based genomic characterization. [Table: see text]
Comprehensive genomic profiling (CGP) versus conventional molecular diagnostic testing of patients with advanced non-small cell lung cancer (NSCLC): Overall survival (OS) and cost in a U.S. health plan population.
Authors: Signorovitch James , Zhou Zhou , Ryan Jason , Chawla Anita
Published: July 2017

6599

Background: Molecular diagnostic testing options in NSCLC include conventional testing (specific alterations in single genes or multi-gene panels), and CGP (all classes of genomic alterations—base pair substitutions, copy number, insertions/deletions, and rearrangements in multi-gene panels). Guidelines recommend broad molecular profiling to enable genomic matching with available compendia-based and investigational treatment options. This study estimated the incremental benefits and costs of CGP versus conventional testing of patients with advanced NSCLC. Methods: The impacts of increased use of CGP (via FoundationOne) versus conventional molecular testing on OS and on a commercial US health plan budget were estimated using a decision-analytic model. The number of patients needed to test with CGP to add 1 life year was also estimated. Model inputs were based on published literature (incidence rates, OS associated with drugs indicated for advanced NSCLC), real-world data (testing rates, and biopsy, conventional testing, and medical service costs from administrative claims data analyses), list price of FoundationOne, and assumptions for clinical trial participation. Results: Among 2 million covered lives, an estimated 532 had advanced NSCLC and 266 received molecular diagnostic testing. An increase in CGP use from 2% to 10% (+21 patients receiving CGP) was associated with +2 years in population OS and a budget impact of $0.018 per member per month (PMPM). The budget impact was primarily attributable to changes in drug use, longer treatment, and longer survival (collectively $0.013 PMPM) with the remainder due to CGP cost ($0.005 PMPM). Approximately 11 patients need to be tested with CGP versus conventional molecular diagnostic testing to add 1 life year. Conclusions: An increase in molecular diagnostic testing with CGP versus conventional testing to inform treatment decisions in patients with advanced NSCLC was associated with a gain in OS and a modest health plan budget impact, with most of the added costs attributable to increased use of effective treatments and prolonged survival.
Estimated cost of anticancer therapy directed by comprehensive genomic profiling (CGP) in a single-center study.
Authors: Signorovitch James , Janku Filip , Wheler Jennifer J. , Miller Vincent A. , Ryan Jason , Zhou Zhou , Chawla Anita
Published: July 2017

6605

Background: Accumulating evidence supports the clinical benefit of targeted therapies matched to cancer patients based on genomic alterations. CGP, which detects all classes of alterations (base pair substitutions, copy number, insertions/deletions, and rearrangements), can match more patients with available and investigational therapies. This study estimated anti-cancer drug costs and overall survival (OS) for matched vs. unmatched therapy. Methods: Costs were estimated for patients with complete data (N = 188/500) from a prospective, nonrandomized, phase I oncology center study of patients with diverse refractory cancers who underwent CGP and were treated with matched or unmatched therapy (PMID: 27197177). Average time to treatment failure and average OS were assessed during the observation period. Patient-specific drug and administration costs were imputed for the first regimen after CGP based on drug classes, unit costs, and times to treatment failure. Results: Patients onmatched (N = 122) vs. unmatched (N = 66) therapy had, on average, longer time on treatment (+1.5 mos), longer observed survival (+2.4 mos), and higher anti-cancer drug costs (+$38K) (all p < 0.01); 66% of increased drug costs were attributable to longer time on treatment as opposed to higher monthly drug costs. Combination therapy was used for 71% of matched and 53% of unmatched patients. Those undergoing CGP in earlier-line (1-3; N = 58) vs. later-line (4+; N = 130) therapy had numerically larger incremental increases in average times on treatment (+1.9 vs. +1.2 mos) and survival (+2.5 vs. +2.1 mos), and numerically lower incremental drug costs (+$27K vs. +$43K), with matched vs. unmatched therapy. Conclusions: For patients cared for in a phase I clinic, matched vs. unmatched therapy was associated with longer treatment durations, longer survival times, and manageable incremental costs. Despite frequent use of combination therapy, most of the increased costs of matched therapy were due to longer treatment times rather than higher monthly drug costs. Benefits of matching were numerically greater in earlier- vs. later-lines, consistent with the value of earlier-line use of CGP to guide treatment.
Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP).
Authors: Chae Young Kwang , Tamragouri Keerthi , Chung Jon , Schrock Alexa Betzig , Kolla Bhaskar , Ganesan Shridar , Suh James , Velcheti Vamsidhar , Bivona Trever Grant , Ross Jeffrey S. , Stephens Phil , Miller Vincent A. , Patel Manish , Giles Francis J. , Ali Siraj Mahamed , Ou Sai-Hong Ignatius , Wang Victoria
Published: July 2017

8517

Background: SCLC and L-LCNEC are aggressive neoplasms that are both associated with smoking history and are thought to overlap in clinical, histogenetic, and genomic features. We reviewed the genomic profiles of >1187 patients to assess the genomic similarities of these diseases. Methods: Comprehensive genomic profiling (CGP) of tumors from 300 L-LCNEC and 887 SCLC patients in the course of clinical care was performed to suggest pathways to benefit from therapy. Results: Commonly altered genes in both diseases included TP53, RB1, MYC/MYCL1, MLL2, LRP1B and PTEN; alterations in other genes occurred at somewhat differing frequencies (table). For both diseases, RB1 mutation significantly co-occurred with TP53 mutations (p<0.001), but occurred in a mutually exclusive fashion to STK11 and CDKN2A (p<0.001). RB1 was mutually exclusive with KRAS for L-LCNEC but not for SCLC. The interquartile range for SCLC and L-LCNEC TMB is 7.9 and 12.6 with the 75% quartile being 14.4 and 17.1 respectively. Cases of both diseases will be presented with radiographic response to genomically matched targeted therapy and immunotherapy, particularly in cases of high TMB. Conclusions: Given the similar overall genomic profiles and clinical behavior of a subset of these diseases, they could be conceived of as a single disease to be further classified by genomically defined classes such as SCLC-type ( TP53/ RB1mutated) and NSCLC-like (wild type for one or both). By analogy to NSLC and melanoma, benefit from immunotherapy appears most likely for only the upper quartile of cases in TMB. [Table: see text]
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Dagogo-Jack Ibiayi , Bernicker Eric , Li Tianhong , Wang Victoria , Ross Jeffrey S. , Young Lauren , Stephens Philip J. , Chung Jon , Shaw Alice Tsang , Ali Siraj Mahamed , Miller Vincent A. , Schrock Alexa Betzig , Spigel David R. , Ou Sai-Hong Ignatius
Published: July 2017

9025

Background: Tissue biopsy is the gold standard for detection of genomic alterations (GA) and selection of matched targeted therapies in NSCLC, but ctDNA assay provides a possible complementary approach for some pts. Methods: Hybrid-capture based genomic profiling of 62 genes using a ctDNA assay (FoundationACT™) was performed on blood samples from 1,019 consecutive NSCLC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: Pt characteristics: Median age 69 years (range 8-94); 54% were female. Histologies included adenocarcinoma (n = 720), NSCLC not otherwise specified (NSCLC NOS; n = 179), squamous cell (n = 57), LC NOS (n = 51), large cell (n = 6), and sarcomatoid (n = 6). ≥1 reportable GA was detected in 71% of all cases and in 83% of cases with evidence of ctDNA in the blood (MSAF > 0). For 22 pts with paired blood and tissue samples collected within 30 days and MSAF > 0, 33/64 (52%) GA detected in tissue were also detected in ctDNA. In 55 pts for whom tissue was insufficient for analysis, ≥1 GA was detected in ctDNA in 43 (78%) cases. For 856 cases with MSAF > 0, an average of 1.8 GA/sample were reported. GA were most frequently detected in TP53 (57%), EGFR (23%) and KRAS (17%). Comparative analysis with the tissue-based FoundationCORE™ database (n = 19,264) showed similar frequencies of GA per gene, although KRAS mutation was more frequent in tissue than ctDNA (27% vs 17%, P < 0.0001), and EGFR T790M was more frequent in ctDNA than tissue (7% vs 2%, P < 0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy .Kinase fusions ( ALK, ROS1, RET, FGFR3, PDGFRA) were identified in 5% (39/856) of cases. Diverse and novel mechanisms of acquired resistance (AR) were detected in ctDNA including MET Y1230C and EGFR amplification post-crizotinib, FGFR3-TACC3 fusion post-EGFR inhibitor, and multiple EGFRAR mutations post-osimertinib. Conclusions: In this series, use of a rigorously validated capture-based assay revealed evidence of ctDNA in the blood in 84% of cases. Our results provide clinical support for use of this assay as a complementary technology to tissue-based genomic testing in a subset of pts with NSCLC.
Landscape of genomic alterations (GA) and tumor mutational burden (TMB) in different metastatic melanoma (MM) subtypes.
Authors: Johnson Douglas Buckner , Carlson J. Andrew , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Ali Siraj Mahamed , Schrock Alexa Betzig , Cho Byoung Chul , Gibney Geoffrey Thomas , Chmielowski Bartosz , Ganesan Shridar , Mehnert Janice M. , Miller Vincent A. , Stephens Phil , Gay Laurie M. , Ross Jeffrey S.
Published: July 2017

9536

Background: MM is a highly targetable malignancy, with both kinase inhibitors and immunotherapies providing meaningful survival benefit. Different subtypes of mm harbor distinct GA that suggest targeted and immunotherapy options. Methods: Comprehensive genomic profiling was performed in 2,197 MMs for up to 315 cancer-related genes plus introns from 28 genes commonly rearranged in cancer on hybrid-capture, adaptor ligation-based libraries (mean coverage depth > 600X). TMB was calculated from ≥1.11 Mb sequenced DNA. We assessed base substitutions, insertions and deletions (short variants; SV), rearrangements, and copy number changes. Results: We assessed 6 subtypes: routine cutaneous (CT; 90%), desmoplastic (DM: 1%), acral lentiginous (AL; 1%), Spitzoid (SP; 1%), mucosal (MC; 2%) and ocular (OC; 5%). Each group harbored characteristic genomic signatures (Table). BRAFwas mutated in 38% of CT of which 92% were SV GA and 8% were amplifications, fusions or cases with > 1 BRAF GA. High TMB in CT and DM is highly prevalent (42% and 83% with > 20 mut/Mb). BRAFGA were less common in AL (18%), MC (15%), and OC (2%). SP GA were dominated by fusions in BRAF (60%) and other kinases. KIT GA were prominent in MC and AL. TMB for MC and OC mm were very low. Key findings include novel drivers of BRAF inhibitor resistance including BRAFinternal rearrangements and kinase domain duplications. Conclusions: In the largest cohort of mm with NGS to date, genomic profiles and TMB differ across mm subtypes. Highly prevalent BRAF GA (including in the SP variant) and high TMB in CT and DM mm permit effective use of targeted and immunotherapies. Although MC and OC have lower BRAF GA frequency and lower TMB, targetable GA can be present. Novel BRAF inhibitor resistance mechanisms were observed. [Table: see text]
Comprehensive genomic profiling to identify tumor mutational burden (TMB) as an independent predictor of response to immunotherapy in diverse cancers.
Authors: Goodman Aaron , Kato Shumei , Bazhenova Lyudmila , Patel Sandip Pravin , Frampton Garrett Michael , Miller Vincent A. , Stephens Phil , Kurzrock Razelle
Published: July 2017

e14508

Background: Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. Methods: We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Results: Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036) (Table). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Comparable data was observed when patients with melanoma (N = 52) and NSCLC (N = 36) were excluded (N = 63 patients; 19 tumor types). Interestingly, anti-CTLA4/anti-PD-1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Conclusions: Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. [Table: see text]
Frequency of genetic homologous recombination (HR) alterations in metastatic cutaneous melanoma.
Authors: Kim Kevin , Leong Stanley P. L. , Singer Mark I. , Parrett Brian M , Moretto John , Minor David R. , Vosoughi Elham , Millis Sherri Z. , Ross Jeffrey S. , Kashani-Sabet Mohammed
Published: July 2017

e21033

Background: In various cancer types, cells with “BRCA-like” or HR mutations/alterations have been shown to be sensitive to PARP inhibitors in preclinical studies. In ovarian cancer, PARP inhibitors have shown improved response rate and progression-free survival in clinical studies. We investigated the frequency of HR mutations/alterations in melanoma. Methods: Comprehensive genomic profiling, (next-generation sequencing [NGS]) that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded tumor samples. The patient and tumor characteristics were obtained from electronic health records. Results: At our institution (CPMC), 59 patients underwent NGS analysis of melanoma specimens. Eighteen (30.5%) harbored a mutation in at least 1 of the HR genes in their tumor. The patient characteristics are: median age 69, male (83%), primary head and neck melanoma (61%), absence of ulceration at the primary site (86%) and mitotic rate >1 mm/m2 (86%). Tumor mutation burden was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly altered gene was ARID2 (11.9%), followed by ARID1A, FANCA, ATM, BRCA1 (3.4% each). Three patients had multiple HR alterations: one with mutations in ARID1A, BRCA1 and MRE11A, one with mutations in ARID2 and ATM, and one with mutations in ARID2 and CHEK2. Among the 18 patients with HR mutation(s), concurrent NF1, NRAS, BRAF (V600), and KIT mutations were found in 7 (39%), 6 (33%), 5 (28%) and 1 (6%) patients, respectively. A larger dataset analyzed by Foundation Medicine (FM) (n=1,986) showed a similar pattern: The most common mutations/alterations were ARID2, followed by ARID1A, ATM, ATRX, BRCA2, ATR, BRCA1, BRIP1 and FANCA (Table). Conclusions: HR mutations / alterations are frequently observed in metastatic melanoma. Melanomas with these alterations may represent a unique subset of patients who could potentially benefit from PARP inhibitors. [Table: see text]