bluuebunny/crossref_metadata_2025 huggingface dataset:
Terfenadine-Induced Torsade de Pointes: Risk Factors and Mechanisms
Authors: Chan Thomas Yk
Published: July 2017

Objective:

To review the risk factors and mechanisms of terfenadine-induced torsade de pointes and to discuss how this adverse reaction might be avoided.

Data Sources:

Previous reports of terfenadine-induced torsade de pointes and studies of the underlying mechanisms were identified by a MEDLINE search or from the reference lists of pertinent articles.

Study Selection and Data Extraction:

All relevant articles were included in the review. Pertinent information was selected for discussion.

Data Synthesis:

Terfenadine is extensively (99%) metabolized by CYP3A4 to an active acid metabolite (terfenadine carboxylate), and with therapeutic dosages, unchanged terfenadine is usually undetectable in plasma. A review of all the reported cases of torsade de pointes indicated that most patients had one or more factors that would be expected to cause excessively high concentrations of unchanged terfenadine, such as overdose; use of supratherapeutic dosages; concurrent use of CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and troleandomycin; and liver dysfunction. Many patients had one or more factors known to predispose to drug-induced torsade de pointes (e.g., preexisting prolonged QT interval, ischemic heart disease, hypokalemia). Pharmacokinetic studies in healthy volunteers have shown that ketoconazole, itraconazole, erythromycin, and clarithromycin can alter the metabolism of terfenadine and result in the accumulation of unchanged terfenadine, which is associated with significant prolongation of the QT interval. In vitro studies have shown that the proarrhythmic effects of terfenadine are secondary to the blockade of cardiac potassium channels. Terfenadine carboxylate does not have such an effect.

Conclusions:

Supratherapeutic dosages of terfenadine should never be used. The concurrent use of CYP3A4 inhibitors should be avoided. Terfenadine should be avoided in patients with liver dysfunction or factors known to predispose to drug-induced torsade de pointes.
Pharmacy Technician Competencies for Practice in an Oncology Pharmacy
Authors: Waddell J Aubrey , Hannan Lance C , Stephens Marissa R
Published: July 2017

Objective:

To document the additional competencies that a well-trained pharmacy technician, with no previous oncology pharmacy training or experience, needs to practice effectively in an oncology pharmacy; and to develop a form to document the training of oncology pharmacy technicians at our institution.

Design:

From September 1, 1997, to November 1, 1997, the oncology pharmacist and the oncology pharmacy technicians developed a list of pharmacy technician competencies that were believed to be unique to pharmacy technician practice in an oncology pharmacy. Information from MEDLINE searches, drug manufacturer materials, and reference books was used to support the competencies identified.

Setting:

This project was conducted at Brooke Army Medical Center, a 450-bed teaching and research institution of the US Army Medical Department.

Results:

Twenty-five oncology pharmacy technician competencies were documented. This list was made into a form for inclusion in each oncology pharmacy technician's competency-based assessment folder and for use in training of future oncology pharmacy technicians.

Conclusions:

There are a significant number of additional competencies that a well-trained pharmacy technician needs in order to practice effectively in our institution's oncology pharmacy. The identification of these additional competencies facilitated the development of a form to document the training of oncology pharmacy technicians.
Comparison of Dissolution between Regular-Release and Halves of Extended-Release Methylphenidate Tablets
Authors: Erramouspe John , Jarvi Eric J
Published: July 2017

Objective:

To compare the in vitro dissolution of methylphenidate hydrochloride from regular-release tablets to halves of extended-release tablets.

Design:

Regular-release 10-mg methylphenidate tablets and halves of 20-mg extended-release tablets from two manufacturers (MD Pharmaceuticals, Inc., and Ciba Pharmaceutical Company) were dissolved according to the USP method specified for regular-release methylphenidate tablets. Samples were collected at 0.25, 0.5, 0.75, 1, 2, 3, 3.5, 4, 5, 6, and 7 hours. Methylphenidate concentration was determined by HPLC.

Results:

Regular-release methylphenidate tablets had statistically greater cumulative dissolution at all sample collection times of 2 hours or less compared with halves of extended-release tablets. The most dramatic difference occurred in the first 30 minutes, at which time the difference in cumulative dissolution was 63% (generic) and 55% (Ritalin). At 3 hours and thereafter, there was no significant difference in cumulative dissolution.

Conclusions:

Despite being cut in half, extended-release methylphenidate still does not dissolve as fast as regular-release tablets. Halving methylphenidate extended-release tablets may be a clinically acceptable means of achieving a prolonged-acting 10-mg dose.
Worsening Hepatic Encephalopathy Secondary to Zolpidem
Authors: Clark Adam
Published: July 2017

Objective:

To report a case of worsening hepatic encephalopathy secondary to ingestion of Zolpidem.

Case Summary:

A 41-year-old white man had postoperative complications 11 months after liver transplantation. Complications included narrowing of the choledochal anastomosis site, cyclosporine nephrotoxicity, and recurrent hepatitis C. Approximately seven months after transplantation, the patient experienced elevations in liver enzyme concentrations, lethargy, ascites, fever, chills, and nausea. Examination of a biopsy sample revealed recurrent hepatitis C. The patient's condition did not resolve despite administration of interferon alfa-2b, and his mental status began to deteriorate secondary to hepatic encephalopathy. One day before admission, the patient was given Zolpidem 5 mg for sleep; one hour after taking Zolpidem, he awoke in a stupor and was not oriented to place or time. When he became increasingly incoherent and verbally abusive, family members brought him to the emergency department. Although the patient exhibited mental status deterioration before receiving Zolpidem, considering the strong temporal relationship, his rapidly worsening state may be attributable to the drug. The patient subsequently required a second liver transplant in addition to a kidney transplant as a result of cyclosporine nephrotoxicity. The patient was not rechallenged with Zolpidem nor given flumazenil.

Discussion:

One pathophysiologic explanation for hepatic encephalopathy implicates endogenously produced benzodiazepine agonists. In patients with portal-systemic shunting, psychoactive compounds escape metabolism and are subsequently free to cross the blood-brain barrier. This mechanism is supported by reports of successful treatment of patients who have encephalopathy with flumazenil, a benzodiazepine antagonist. Hence, it follows that a benzodiazepine agonist could potentially exacerbate encephalopathic symptomatology. Zolpidem, although structurally unrelated to benzodiazepines, is a benzodiazepine agonist that binds preferentially to the benzodiazepine1 ω1 subtype of the γ-aminobutyric acid (GABAA) receptor complex. Therefore, administration of Zolpidem to patients with encephalopathy may worsen the condition by contributing to the accumulation of benzodiazepine agonists within the central nervous system.

Conclusions:

Although this patient's worsening mental status could be explained by a naturally evolving encephalopathic state, it is possible that Zolpidem exacerbated his decline. Existing evidence supports this view. First, an endogenously produced, benzodiazepine-related mechanism of hepatic encephalopathy is described in the literature. Second, benzodiazepine-like substances have been detected in the serum of patients with encephalopathy who have not received benzodiazepine therapy. Finally, clinical evidence supports the use of flumazenil in encephalopathic patients. Thus, it is likely that administration of Zolpidem hastened the mental decline of this patient.
Neuroleptic Malignant Syndrome Spectrum: A Case Report
Authors: Alao Adekola O , Yolles Jennifer C , Armenta Wendy , Michaels Anne T
Published: July 2017

Objective:

To report a suspected case of subclinical neuroleptic malignant syndrome (NMS) that possibly responded to electroconvulsive therapy.

Case Summary:

A 51-year-old white woman with a history of schizoaffective disorder, depressed type, was admitted to our inpatient unit after presenting with all features of NMS except fever. The patient's symptoms were markedly improved after eight courses of electroconvulsive therapy.

Discussion:

The “spectrum concept” of NMS is increasingly being recognized. More controlled studies are required to understand the components of this syndrome.
Evaluation of Losartan Usage in a Regional Hospital in Hong Kong
Authors: Chang Sophie , Tam Beverly H , Tse Blouie PY , Chan Grace MC , Lee Benjamin SC , Raymond Kenneth , Critchley Julian AJH , Chan Juliana CN
Published: July 2017

Objective:

To determine whether losartan usage follows the hospital's guidelines in terms of indications and reasons for use and to assess the accuracy of physicians in completing the losartan usage monitoring forms.

Design:

Drug utilization survey.

Setting:

A major government hospital in Hong Kong.

Participants:

Inpatients or outpatients prescribed losartan for the first time.

Intervention:

Physicians were to complete a monitoring form with both indications and reasons for losartan use.

Main Outcome Measures:

The appropriateness of losartan prescribing was evaluated in terms of indications (for hypertension with impaired left-ventricular function or hypertension in diabetic patients with persistent proteinuria) and reasons for preferred use (previous intolerance to adverse effects of angiotensin-converting enzyme inhibitors). The accuracy of completed monitoring forms was also assessed.

Results:

Forty-eight patients were prescribed losartan since its addition to the hospital formulary through the end of the study period (September 1997-May 1998). A review of medical records (regardless of the information provided by the physicians on the monitoring forms) revealed that 39 patients (81.3%) were prescribed losartan for appropriate indications and that 22 (45.8%) were given losartan rather than angiotensin-converting enzyme inhibitors for appropriate reasons according to the guidelines. Both appropriate indications and reasons were met in only 15 patients (31.3%). Of the 48 monitoring forms that were collected, three (6.3%) were not completed. The concordance rate of information provided by the doctors and information from case notes was 61.5% for indications and 34.8% for reasons of preferred use.

Conclusions:

Adherence to the hospital's usage guidelines and accuracy of the monitoring forms were suboptimal. Considering the high cost of losartan and its potential for long-term use, more educational activities, better dissemination of information, and more frequent evaluation of the acceptability of recommended usage guidelines are warranted.
The Effect of Coextrusion on Bubble Kinematics, Temperature Distribution and Property Development in the Blown Film Process
Authors: Morris Barry A.
Published: July 2017

The bubble shape, velocity profile and strain history in the region between the die exit and frost line in the blown film process is known to influence film properties. The kinematics in coextrusion is dictated by the material that freezes first. The maximum rate of strain of the remaining layers may occur at a higher temperature, affecting film properties. An example of a HDPE resin extruded alone and coextruded with EVOH is considered.
Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma
Authors: Paludo Jonas , Mikhael Joseph R. , LaPlant Betsy R. , Halvorson Alese E. , Kumar Shaji , Gertz Morie A. , Hayman Suzanne R. , Buadi Francis K. , Dispenzieri Angela , Lust John A. , Kapoor Prashant , Leung Nelson , Russell Stephen J. , Dingli David , Go Ronald S. , Lin Yi , Gonsalves Wilson I. , Fonseca Rafael , Bergsagel P. Leif , Roy Vivek , Sher Taimur , Chanan-Khan Asher A. , Ailawadhi Sikander , Stewart A. Keith , Reeder Craig B. , Richardson Paul G. , Rajkumar S. Vincent , Lacy Martha Q.
Published: July 2017

Key Points

PVD is an active combination in relapsed lenalidomide-refractory MM patients. PVD with weekly bortezomib offers a simpler, more convenient, and well-tolerated regimen option.
Maternal intake of sugar during pregnancy and childhood respiratory and atopic outcomes
Authors: Bédard Annabelle , Northstone Kate , Henderson A. John , Shaheen Seif O.
Published: July 2017

The possible role of maternal consumption of free sugar during pregnancy in the inception of respiratory and atopic diseases has not been studied. We aimed to study the relationship between maternal intake of free sugar during pregnancy and respiratory and atopic outcomes in the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children.

We analysed associations between maternal intake of free sugar in pregnancy (estimated by a food frequency questionnaire), and current doctor-diagnosed asthma, wheezing, hay fever, eczema, atopy, serum total IgE and lung function in children aged 7–9 years (n=8956 with information on maternal diet in pregnancy and at least one outcome of interest).

After controlling for potential confounders, maternal intake of free sugar was positively associated with atopy (OR for highestversuslowest quintile of sugar intake 1.38, 95% CI 1.06–1.78; per quintile p-trend=0.006) and atopic asthma (OR 2.01, 95% CI 1.23–3.29; per quintile p-trend=0.004). These associations were not confounded by intake of sugar in early childhood, which was unrelated to these outcomes.

Our results suggest that a higher maternal intake of free sugar during pregnancy is associated with an increased risk of atopy and atopic asthma in the offspring, independently of sugar intake in early childhood.
The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease
Authors: Burgstaller Gerald , Oehrle Bettina , Gerckens Michael , White Eric S. , Schiller Herbert B. , Eickelberg Oliver
Published: July 2017

The pulmonary extracellular matrix (ECM) determines the tissue architecture of the lung, and provides mechanical stability and elastic recoil, which are essential for physiological lung function. Biochemical and biomechanical signals initiated by the ECM direct cellular function and differentiation, and thus play a decisive role in lung development, tissue remodelling processes and maintenance of adult homeostasis. Recent proteomic studies have demonstrated that at least 150 different ECM proteins, glycosaminoglycans and modifying enzymes are expressed in the lung, and these assemble into intricate composite biomaterials. These highly insoluble assemblies of interacting ECM proteins and their glycan modifications can act as a solid phase-binding interface for hundreds of secreted proteins, which creates an information-rich signalling template for cell function and differentiation. Dynamic changes within the ECM that occur upon injury or with ageing are associated with several chronic lung diseases. In this review, we summarise the available data about the structure and function of the pulmonary ECM, and highlight changes that occur in idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. We discuss potential mechanisms of ECM remodelling and modification, which we believe are relevant for future diagnosis and treatment of chronic lung disease.
A novel immune biomarkerIFI27discriminates between influenza and bacteria in patients with suspected respiratory infection
Authors: Tang Benjamin M. , Shojaei Maryam , Parnell Grant P. , Huang Stephen , Nalos Marek , Teoh Sally , O'Connor Kate , Schibeci Stephen , Phu Amy L. , Kumar Anand , Ho John , Meyers Adrienne F. A. , Keynan Yoav , Ball Terry , Pisipati Amarnath , Kumar Aseem , Moore Elizabeth , Eisen Damon , Lai Kevin , Gillett Mark , Geffers Robert , Luo Hao , Gul Fahad , Schreiber Jens , Riedel Sandra , Booth David , McLean Anthony , Schughart Klaus
Published: July 2017

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.

In this study, we combined an integrated genomic analysis of 1071 individuals within vitroexperiments using well-established infection models.

We identified a single-gene biomarker,IFI27, which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers.In vitrostudies showed thatIFI27was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria.In vivostudies confirmed thatIFI27was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions),IFI27displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections.

IFI27represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection.
A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days
Authors: Wootton Daniel G. , Dickinson Laura , Pertinez Henry , Court Joanne , Eneje Odiri , Keogan Lynne , Macfarlane Laura , Wilks Sarah , Gallagher Jane , Woodhead Mark , Gordon Stephen B. , Diggle Peter J.
Published: July 2017

Our aims were to address three fundamental questions relating to the symptoms of community-acquired pneumonia (CAP): Do patients completely recover from pneumonia symptoms? How long does this recovery take? Which factors influence symptomatic recovery?

We prospectively recruited patients at two hospitals in Liverpool, UK, into a longitudinal, observational cohort study and modelled symptom recovery from CAP. We excluded patients with cancer, immunosuppression or advanced dementia, and those who were intubated or palliated from admission. We derived a statistical model to describe symptom patterns.

We recruited 169 (52% male) adults. Multivariable analysis demonstrated that the time taken to recover to baseline was determined by the initial severity of symptoms. Severity of symptoms was associated with comorbidity and was inversely related to age. The pattern of symptom recovery was exponential and most patients’ symptoms returned to baseline by 10 days.

These results will inform the advice given to patients regarding the resolution of their symptoms. The recovery model described here will facilitate the use of symptom recovery as an outcome measure in future clinical trials.
Chronic pulmonary aspergillosis complicating sarcoidosis
Authors: Uzunhan Yurdagül , Nunes Hilario , Jeny Florence , Lacroix Maxime , Brun Sophie , Brillet Pierre-Yves , Martinod Emmanuel , Carette Marie-France , Bouvry Diane , Charlier Caroline , Lanternier Fanny , Planès Carole , Tazi Abdellatif , Lortholary Olivier , Baughman Robert P. , Valeyre Dominique
Published: July 2017

Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.

This was a retrospective single-centre study on CPA-SA.

In total, 65 patients (44 men), aged 41.4±13.5 and 48.3±11.9 years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8 years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.

CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome.
Complete genome sequence of Microbulbifer sp. CCB-MM1, a halophile isolated from Matang Mangrove Forest, Malaysia
Authors: Moh Tsu Horng , Lau Nyok-Sean , Furusawa Go , Amirul Al-Ashraf Abdullah
Published: July 2017

Microbulbifer sp. CCB-MM1 is a halophile isolated from estuarine sediment of Matang Mangrove Forest, Malaysia. Based on 16S rRNA gene sequence analysis, strain CCB-MM1 is a potentially new species of genus Microbulbifer. Here we describe its features and present its complete genome sequence with annotation. The genome sequence is 3.86 Mb in size with GC content of 58.85%, harbouring 3313 protein coding genes and 92 RNA genes. A total of 71 genes associated with carbohydrate active enzymes were found using dbCAN. Ectoine biosynthetic genes, ectABC operon and ask_ect were detected using antiSMASH 3.0. Cell shape determination genes, mreBCD operon, rodA and rodZ were annotated, congruent with the rod-coccus cell cycle of the strain CCB-MM1. In addition, putative mreBCD operon regulatory gene, bolA was detected, which might be associated with the regulation of rod-coccus cell cycle observed from the strain.
Target-enclosed seismic imaging
Authors: van der Neut Joost , Ravasi Matteo , Liu Yi , Vasconcelos Ivan
Published: July 2017

Seismic reflection data can be redatumed to a specified boundary in the subsurface by solving an inverse (or multidimensional deconvolution) problem. The redatumed data can be interpreted as an extended image of the subsurface at the redatuming boundary, depending on the subsurface offset and time. We retrieve target-enclosed extended images by using two redatuming boundaries, which are selected above and below a specified target volume. As input, we require the upgoing and downgoing wavefields at both redatuming boundaries due to impulsive sources at the earth’s surface. These wavefields can be obtained from actual measurements in the subsurface, they can be numerically modeled, or they can be retrieved by solving a multidimensional Marchenko equation. As output, we retrieved virtual reflection and transmission responses as if sources and receivers were located at the two target-enclosing boundaries. These data contain all orders of reflections inside the target volume but exclude all interactions with the part of the medium outside this volume. The retrieved reflection responses can be used to image the target volume from above or from below. We found that the images from above and below are similar (given that the Marchenko equation is used for wavefield retrieval). If a model with sharp boundaries in the target volume is available, the redatumed data can also be used for two-sided imaging, where the retrieved reflection and transmission responses are exploited. Because multiple reflections are used by this strategy, seismic resolution can be improved significantly. Because target-enclosed extended images are independent on the part of the medium outside the target volume, our methodology is also beneficial to reduce the computational burden of localized inversion, which can now be applied inside the target volume only, without suffering from interactions with other parts of the medium.
Regionalization and Outcomes of Lung Cancer Surgery in Ontario, Canada
Authors: Bendzsak Anna M. , Baxter Nancy N. , Darling Gail E. , Austin Peter C. , Urbach David R.
Published: July 2017

Purpose

Regionalization of complex surgery to high-volume hospitals has been advocated based on cross-sectional volume-outcome studies. In April 2007, the agency overseeing cancer care in Ontario, Canada, implemented a policy to regionalize lung cancer surgery at 14 designated hospitals, enforced by economic incentives and penalties. We studied the effects of implementation of this policy.

Methods

Using administrative health data, we used interrupted time series models to analyze the immediate and delayed effects of implementation of the policy on the distribution of lung cancer surgery among hospitals, surgical outcomes, and health services use.

Results

From 2004 to 2012, 16,641 patients underwent surgery for lung cancer. The proportion of operations performed in designated hospitals increased from 71% to 89% after the policy was implemented. Although operative mortality decreased from 4.1% to 2.9% (adjusted odds ratio, 0.68; 95% CI, 0.58 to 0.81; P < .001), the reduction was due to a preexisting declining trend in mortality. In contrast, in the years after implementation of the policy, length of hospital stay decreased more than expected from the baseline trend by 7% per year (95% CI, 5% to 9%; P < .001), and the distance traveled by all patients to the hospital for surgery increased by 4% per year (95% CI, 0% to 8%; P = .03), neither of which were explained by preexisting trends. Analyses limited to patients ≥ 70 years of age demonstrated a reduction in operative mortality (odds ratio, 0.80 per year after regionalization; 95% CI, 0.67 to 0.95; P = .01).

Conclusion

A policy to regionalize lung cancer surgery in Ontario led to increased centralization of surgery services but was not independently associated with improvements in operative mortality. Improvements in length of stay and in operative mortality among elderly patients suggest areas where regionalization may be beneficial.
Identification of novel fumarate hydratase gene alterations in prostate cancer.
Authors: Millis Sherri Z. , Marsh Sydney , Pecci Cristina , Boddupalli Sai-Sridhar , Ross Jeffrey S. , Stephens Phil , Miller Vincent A. , Ali Siraj Mahamed , Wang Jue
Published: July 2017

11585

Background: Fumarate hydratase (FH), an enzyme involved in the Krebs cycle, plays a crucial role in the generation of energy and oxygenation of cells. Genomic alterations (GAs) of FH, a tumor suppressor gene, have been shown to cause chronic hypoxia that encourages tumor formation and have been linked to hereditary leiomyomatosis and renal cell cancer. Only few reports have associated FH mutations with other cancers, and none in prostate cancer. Methods: Identification of an FH V435M pathogenic alteration, which likely changes fumarate binding kinetics, in a prostate cancer patient, with negative family history for renal cancer and cutaneous leiomyomatosis, led to review of a database of 1781 prostate cancer patients, whose tissue was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified 49 prostate adenocarcinoma patients (3%) with FH gene alterations, 2 of which harbored the V435M GA identified in the original prostate patient. Ten of 40 alterations were H476_k477 insertions, in the C terminus domain, and 14 were amplifications. The rest were variants of unknown significance (VUS). Conclusions: A FH GA, known to impact other cancers, found in a prostate cancer, led to the discovery of a frequency that suggests deregulation of metabolic pathway activation may contribute to prostate cancer pathogenesis for a subset of patients. The somatic FH GA’s are likely to be substantially more common than germline mutations, and identifying metabolic-enzyme mutations that are pathogenic in prostate cancer could lead to pharmacologic manipulations that are more effective and less toxic than existing therapies. No FDA approved therapies currently exist for this patient’s tumor type nor of any other tumor type with FH GA’s. In our case, alterations in the C-terminal binding domain of FH might inform drug development.
A clinical and genomic profile of inflammatory myofibroblastic tumors.
Authors: Daniel Sugganth , Gay Laurie M. , Vergilio Jo-Anne , Ross Jeffrey S.
Published: July 2017

1538

Background: Inflammatory Myofibroblastic Tumors (IMT) are tumors that morphologically traverse the neoplastic and inflammatory realms. With a predilection for children and young adults, many patients present with systemic symptoms and the tumors demonstrate local invasiveness and even metastasis. IMTs are composed of fascicles of myofibroblastic spindle cells with a marked lymphoplasmacytic infiltrate. Methods: Integrated genomic profiling of DNA and RNA from IMTs in 30 patients was performed using a hybrid capture, paired-end NGS sequencing method and customized pipeline analysis. Results: 23 patients were children or young adults ( < 30y), overall the age ranged from 7 months to 72 years. The tumor was clinically aggressive in 10 patients; 3 metastatic, 5 multifocal and 2 locally invasive. Epithelioid morphology was documented in 2 cases, one demonstrated the ALK-RANBP2 fusion. ALK rearrangements were detected in 13 patients, with 7 different fusion partners. ALK IHC or FISH was performed in 23 patients and were all concordant with the genomic results. 22 gene fusions were detected in 21 patients, 4 tumors had ROS1-TFG fusions, 2 had NTRK3-ETV6 fusions. 3 had novel fusions in JAK1-PML, PDGFRB-NOTCH1 and MUTYH-TESK2 respectively. Intact tyrosine kinase domains (TKD) in JAK1 are transposed to the promoter coiled-coil motif in PML, in the rearrangement. While the TKDs are preserved in the PDGRB and TESK2 rearrangements, the functional roles of their partners are yet to be elucidated. The prevalence of rearrangements was higher in patients below 30 years of age (20/23) compared to that above 30y (3/7). All 10 aggressive tumors were detected to have rearrangements. Conclusions: IMTs are seen predominantly in younger age groups. Gene rearrangements are seen more frequently in patients with younger age and also in more aggressive tumors, in a statistically significant manner. Alterations in genes associated with hematopoietic neoplasms such as JAK1 among others, are interesting, given the hematologic component of the lesion, and the presence of novel tyrosine kinase rearrangements warrant further investigations to elucidate mechanistic models.
Comprehensive genomic profiling (CGP) of advanced papillary renal cell carcinoma (PRCC) to reveal distinctions from TCGA dataset.
Authors: Pal Sumanta K. , Geynisman Daniel M. , Ali Siraj Mahamed , Yakirevich Evgeny , Stephens Phil , Ross Jeffrey S. , Miller Vincent A. , Chung Jon , Choueiri Toni K.
Published: July 2017

4517

Background: Biologic characterization of PRCC by TCGA reveals alterations in MET in type 1 disease, and CDKN2Asilencing, SETD2 mutations and TFE3 fusions in type 2 disease. A limitation of TCGA data is that of 161 pts analyzed, 73% and 3% had M0 and M1 disease, respectively. We present the gene alterations (GA) identified in pts with advanced PRCC.Methods: FFPE tissue was obtained from 169 patients with PRCC. Diagnosis and PRCC subtyping was centrally confirmed by 2 board-certified pathologists. DNA was extracted and comprehensive genomic profiling (CGP) was performed (median coverage, 648X) in a CLIA-certified central laboratory. Results: Of 169 pts with advanced PRCC, 39 (23%) were type 1, 108 (64%) were type 2 and 22 (13%) were unclassified. 66 samples (39%) were from a metastatic site biopsy, and 103 were from the kidney (61%). An average of 2.4 GA/tumor were detected. In type 1 pts, commonly altered genes were MET (33%: 8 activating mutations, 5 amplifications), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In type 2 pts, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%) and FH (13%); METGAs (5 mutations, 3 amplifications) were observed in 7.4% of type 2 pts. MET GA was significantly associated with type 1 PRCC (p = 0.0002) and NF2 GA and alterations in SWI/SNF complex genes were both significantly associated with type2 PRCC (p = 0.02 and p = 0.007, respectively). Overall, frequent alterations were found in genes involved in SWI/SNF complexes (25%), chromatin modification (23%) and cell cycle regulation (22%). RAS/RAF pathway (9%) and PI3K/mTOR pathway (8%). Notable differences with TCGA include higher frequencies of MET and NF2 GAs, association of GAs in the SWI/SNF with type 2 PRCC, and frequent CDKN2A/B alteration in both type 1 and type 2 disease. MET alteration was lower in metastases vs primary (type 1: 15% vs 38%; type 2: 4% vs 10%). Conclusions: In a cohort of PRCC patients slightly larger than the TCGA experience, key differences in CRGA frequency were observed. These likely underscore the marked difference in stage distribution between datasets. Results of this study may inform trials of relevant targeted therapy in metastatic PRCC.
NTRK1-3 point mutations in poor prognosis thyroid cancers.
Authors: Iniguez-Ariza Nicole M. , Bible Keith Christopher , Morris John C. , Chintakuntlawar Ashish V. , Shridhar Vijayalakshmi , Smallridge Robert C. , Menefee Michael E. , Hilger Crystal , Severson Eric Allan , Ryder Mabel M
Published: July 2017

6087

Background: NTRK1-3 fusions, identified in pediatric radiation-associated thyroid cancers, are low frequency oncogenic drivers that can trigger constitutive activation of TrK1-3 tyrosine kinase domains with responsively heightened downstream signaling through RAS-MAPK, PI3K-AKT, and/or PLCγ-PKC. NTRK point mutations are rare and of largely uninvestigated oncogenic potential, but some appear oncogenic. Methods: Advanced thyroid cancer (TC) patients (pts) requiring systemic therapy at Mayo Clinic sites underwent tumor genetic interrogation using Foundation One analyses with the goal of informing salvage therapeutic strategies. In this IRB-approved study, data from pts with TCs bearing NTRK point mutations were retrospectively analyzed, as this occurrence was unexpected but potentially of prognostic and/or therapeutic relevance. Results: Five of 55 pts (9%) with advanced TCs subject to Foundation One tumor interrogation had NTRK1-3 point mutations (allele frequency, AF, 15-49%); none had fusions. All 5 tumors had microsatellite stability; 4/5 had low tumor mutation burden (2-5 mutations/megabase). NTRK mutations in 3 anaplastic TC (ATC) pts (15% prevalence) were: NTRK3 I749M (AF 15%; overall survival, OS, 15 mos), NTRK1 R744H (AF not available; OS 9.5 mos), and NTRK1 R583H (AF 20.1%; OS > 4.9 mos); NTRK2 S167Y (AF 49%; OS > 51 mos) or NTRK1 R6W (AF 42%; OS > 60 mos) were found in one papillary (PTC) and one Hürthle cell (HCC) TC pt respectively (summary table below). Conclusions: NTRK point mutations, but not fusions, were unexpectedly identified in 9% of assessed advanced TCs - but remarkably in 15% of ATCs. Mutated NTRKs, along with oncogenic p53 and TERT, may contribute to TC progression, especially in ATC, consequent to downstream activation of MAPK and PI3K-AKT pathways. We posit that NTRK point mutations may have therapeutic implications for treatment of refractory disease. [Table: see text]
Clinical and genomic alterations features of patients with advanced colitis associated cancers (CAC).
Authors: Kelsen David Paul , Miller Vincent A. , Tang Laura H. , Capanu Marinela , Balasubramanian Sohail , Ross Jeffrey S. , Stephens Philip J. , Yaeger Rona
Published: July 2017

e15010

Background: CAC are a catastrophic complication of inflammatory bowel disease. The spectrum of genomic alterations (GA) in CAC is different than that of sporadic colorectal cancer (CRC) (Yaeger et al PMID 27063727). While the prognosis for CAC patients (pts) may be worse than that of sporadic CRC pts, there is little data regarding outcome for metastatic CAC pts treated with standard chemotherapy regimens. We reviewed demographic features and clinical outcome for pts with metastatic CAC in the context of somatic tumor GA. Methods: We identified small and large bowel CAC cases seen at Memorial Sloan Kettering between 2003 and 2015 with tissue available for study. Hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes was used to comprehensively characterize GA. The electronic medical record of each patient was reviewed. Demographic and clinical data was extracted and outcome reviewed in the context of somatic tumor GA. Results: Clinical features for 17 pts with metastatic CAC are shown below. All pts with initial stage III CAC received FOLFOX adjuvant therapy. First-line treatment for metastatic disease included FOLFOX/FOLFIRINOX/FU-LV in 10 previously untreated pts and FOLFIRI after adjuvant therapy. Median duration of survival from time of metastatic disease was 14.8 months, (95% CI 5.7-24.3;range 2-68+ months), substantially less than that expected for pts with Stage IV CRC. Only 4 patients survived for > 24 months. GA were identified in TP53 (87%) and KRAS (33%); potentially targetable alterations were found in 8 pts ( IDH1 (1), EML4-ALK(1), ERBB2 (1); FGFR1/2 (3); BRAF (1); PIK3CA(1). 2 pts received a targeted agent based on GA; 1 partial response to a FGFR inhibitor is ongoing. No patient had a hyper-mutated tumor. Conclusions: Metastatic CAC pts have an exceedingly poor prognosis, with survival well below that expected for sporadic CRC. BRAF mutations associated with poor outcome in sporadic CRC are rare in CAC. 47% of CAC pts had potentially targetable GA. [Table: see text]
Feasibility of collaborative precision medicine oncology between academic- and community-based hospitals.
Authors: Rodriguez-Rodriguez Lorna , Krasna Mark , Hirshfield Kim M. , Rojas Veronica , Riedlinger Gregory , Ali Siraj Mahamed , Miller Vincent A. , Ganesan Shridar
Published: July 2017

e18015

Background: The Rutgers Cancer Institute of New Jersey (CINJ) is conducting an ongoing, prospective, observational clinical trial that is evaluating use of comprehensive genomic profiling (CGP) and molecular tumor board (MTB) review to assist in caring for patients with rare or refractory cancers. As part of this precision medicine approach to cancer care, CINJ has formed a partnership with community hospitals (Meridian Health) to enroll patients in this study, and to actively participate in MTB meetings. The purpose of this cohort analysis is to evaluate the feasibility of using CGP to identify clinically-relevant genomic alterations as an aid to guiding point-of-care management in a community hospital setting. Methods: Meridian Health staff was trained in patient selection, enrollment, and follow-up. CGP was performed by Foundation Medicine, Inc. The patient case’s clinical history, pathology, and CGP results were presented at an MTB meeting. The enrolling physicians (n = 11) were invited to attend the MTB in person or through web-accessible video conferencing. A letter listing MTB consensus recommendations on potential treatment options was sent to the referring physician, and patient follow-up was scheduled at regular intervals. Results: 35 patients were enrolled by Meridian Health. Gyn and GI cancers were the most common types at enrollment (each 26%, 9 out of 35), followed by breast cancer (20%, 7 out of 35). At study enrollment, the mean KPS was 91%, and 23 patients (66%) had stage IV disease. The median duration between study enrollment and MTB presentation was 44 days. 3 patients were excluded because of deteriorated clinical status at the time of the MTB. MTB-based treatment options were implemented in 9 of 32 patients (28%). This result is similar to those reported in published analyses of patients enrolled at CINJ. Conclusions: Collaborations between an academic cancer center and a community hospital is a feasible approach to facilitating access to precision medicine for cancer patients treated in the community. A larger cohort is needed to determine the impact on patient’s outcomes.
Incidence and Prevalence of Cancer in Colombia: The Methodology Used Matters
Authors: Valencia Omaira , Lopes Gilberto , Sánchez Patricia , Acuña Lizbeth , Uribe Daniel , González Jaime
Published: July 2017

Purpose

Incidence and prevalence are important factors in policy making and planning in health care systems. The aim of this study was to compare two different estimates of the incidence and prevalence of cancer in Colombia—real-world data from the health care system and estimates from cancer registries.

Materials and Methods

Data from all providers were aggregated by the High-Cost Diseases Office (Cuenta de Alto Costo [CAC]). The real-world, age-standardized observed incidence (OI) and observed prevalence (OP) rates were calculated using the number of patients with a diagnosis of cancer who were cared for in the national health system between 2014 and 2015. The registry estimated incidence (EI) and estimated prevalence (EP) were extracted from GLOBOCAN population fact sheets for 2012, which use data from four Colombian city-based registries and extrapolate survival using the average for Asian countries, together with registries from Uganda and Zimbabwe.

Results

A total of 130,441 patients were analyzed. The OI of cancer in Colombia was 69.2 and the OP was 479 (per 100,000 people) in early 2015, whereas the EI was 175.2 and the 5-year EP was 501.2 (per 100,000 people), showing a higher estimate from GLOBOCAN data for 2012 than was observed in early 2015 by the CAC. Some differences were higher in specific cancers.

Conclusion

Because of differences in methodology, the EI and the EP are not comparable to the OI and the OP. Policymakers need robust and current information to prioritize disease prevention and control programs. In Colombia, the OI and the OP—calculated by the CAC with data from the whole country—offer an opportunity for a more precise real-world estimation of patients with cancer in Colombia.
Verapamil Use Is Associated With Reduction of Newly Diagnosed Diabetes Mellitus
Authors: Yin Ti , Kuo Shu-Chen , Chang Yea-Yuan , Chen Yung-Tai , Wang Kai-Wei Katherine
Published: July 2017

Objective:

The mechanism of the beneficial effect of calcium-channel blockers (CCBs), especially verapamil, on the development of type 2 diabetes mellitus (T2DM) has been described. This study compared the incidence of T2DM in adults prescribed oral verapamil and propensity score–matched adults prescribed other oral CCBs.

Methods:

This retrospective population-based cohort study used Taiwan’s National Health Insurance Research Database from 2000 to 2011. T2DM was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification.

Results:

During follow-up periods of 41,958 and 42,118 person-years, 269 of 4930 patients in the verapamil cohort and 340 of 4930 patients in the matched cohort, respectively, developed T2DM. The incidence rates were 6.41 and 8.07 per 1000 population per year among verapamil and other CCB users, respectively. The adjusted hazard ratio (HR) for T2DM associated with use of verapamil (vs. other CCBs) was 0.80 [95% confidence interval (CI), 0.68 to 0.94; P = 0.006]. After exclusion of patients followed for <180 days or <365 days (to avoid bias derived from delayed diagnosis), adjusted HRs remained significant [0.79 (95% CI, 0.67 to 0.93; P = 0.005) and 0.77 (95% CI, 0.65 to 0.91; P = 0.002), respectively]. Only the interaction term for age was significant (P = 0.009). Verapamil had a more prominent effect on patients aged older than 65 years (P < 0.001).

Conclusions:

In patients with no known history of diabetes mellitus, oral verapamil use was associated with a decreased incidence of T2DM compared with other CCBs.
Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding–Mediated Analgesic Effects in Complete Freund’s Adjuvant-Induced Inflammatory Pain
Authors: Du Kairong , Wang Xue , Chi Laiting , Li Wenzhi
Published: July 2017

BACKGROUND:

The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia.

METHODS:

Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral “Kunlun” (BL60), “Zusanli” (ST36), and “Sanyinjiao” (SP6) acupoints in the rat model of inflammatory pain (complete Freund’s adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection.

RESULTS:

ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression.

CONCLUSIONS:

The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.