bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein arginine N-methyltransferase 1 promotes the proliferation and metastasis of hepatocellular carcinoma cells
Authors: Gou Qing , He ShuJiao , Zhou ZeJian
Published: February 2017

Hepatocellular carcinoma is the most common subtype of liver cancer. Protein arginine N-methyltransferase 1 was shown to be upregulated in various cancers. However, the role of protein arginine N-methyltransferase 1 in hepatocellular carcinoma progression remains incompletely understood. We investigated the clinical and functional significance of protein arginine N-methyltransferase 1 in a series of clinical hepatocellular carcinoma samples and a panel of hepatocellular carcinoma cell lines. We performed suppression analysis of protein arginine N-methyltransferase 1 using small interfering RNA to determine the biological roles of protein arginine N-methyltransferase 1 in hepatocellular carcinoma. In addition, the expression of epithelial-mesenchymal transition indicators was verified by western blotting in hepatocellular carcinoma cell lines after small interfering RNA treatment. Protein arginine N-methyltransferase 1 expression was found to be significantly upregulated in hepatocellular carcinoma cell lines and clinical tissues. Moreover, downregulation of protein arginine N-methyltransferase 1 in hepatocellular carcinoma cells by small interfering RNA could inhibit cell proliferation, migration, and invasion in vitro. These results indicate that protein arginine N-methyltransferase 1 may contribute to hepatocellular carcinoma progression and serves as a promising target for the treatment of hepatocellular carcinoma patients.
Orai1 mediates tumor-promoting store-operated Ca2+ entry in human gastrointestinal stromal tumors via c-KIT and the extracellular signal–regulated kinase pathway
Authors: Wang Lei , Hao Jiaqi , Zhang Yijian , Yang Ziyi , Cao Yang , Lu Wei , Shu Yijun , Jiang Lin , Hu Yunping , Lv Wenjie , Liu Yingbin , Dong Ping
Published: February 2017

Gastrointestinal stromal tumors originate from interstitial cells of Cajal, the pacemaker cells of the gut. Ca2+ regulates the pacemaker activity of interstitial cells of Cajal. Store-operated Ca2+ entry mediates the majority of Ca2+ entry in most cancer cells and may be a factor in regulating intracellular Ca2+ in interstitial cells of Cajal and gastrointestinal stromal tumors. Therefore, a blockade of this mechanism may affect the progression of gastrointestinal stromal tumors. Orai1 is the pore subunit of store-operated Ca2+ channels. Here, we reported that Orai1 was overexpressed in gastrointestinal stromal tumor tissues and was positively correlated with a high-risk grade in gastrointestinal stromal tumor patients. Furthermore, upon Orai1 silencing, the functional store-operated Ca2+ entry in gastrointestinal stromal tumor cells was decreased, indicating that the function of store-operated Ca2+ entry was mediated by Orai1. Inhibition of Orai1-mediated store-operated Ca2+ entry by Orai1 silencing or store-operated Ca2+ entry blockers (SKF-96365 and 2-aminoethyl diphenylborate) induced obvious cell proliferation suppression, cell-cycle distribution, and apoptosis stimulation in GIST-T1 cells. Conversely, Orai1 overexpression increased store-operated Ca2+ entry and cell proliferation in GIST882 cells. In addition, we found that activation of c-KIT and the extracellular signal–regulated kinase pathway participated in the oncogenic functions of Orai1-mediated store-operated Ca2+ entry in gastrointestinal stromal tumor cells. These results revealed that Orai1-mediated store-operated Ca2+ entry is critical for gastrointestinal stromal tumor cell proliferation via c-KIT and ERK signaling pathway activation. Orai1-mediated store-operated Ca2+ entry plays an oncogenic role and may be a novel prognostic factor and therapeutic target for patients with gastrointestinal stromal tumors.
CDK9 is a prognostic marker and therapeutic target in pancreatic cancer
Authors: Kretz Anna-Laura , Schaum Monika , Richter Julia , Kitzig Ella F , Engler Christine C , Leithäuser Frank , Henne-Bruns Doris , Knippschild Uwe , Lemke Johannes
Published: February 2017

Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.
Translation and validation of the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire in French, Italian, Swedish, and Dutch
Authors: Wapenaar Monique , Patel Amit S , Birring Surinder S , Domburg Ron T van , Bakker Eric WP , Vindigni Virginia , Sköld C Magnus , Cottin Vincent , Vancheri Carlo , Wijsenbeek Marlies S
Published: February 2017

No disease-specific instruments exist in Dutch, French, Italian, and Swedish to measure health status in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). The King’s Brief Interstitial Lung Disease (K-BILD) is a 15-item validated questionnaire assessing health status in patients with ILD. The aim of this study was to translate and validate the K-BILD to French, Italian, Swedish, and Dutch versions. The K-BILD was translated following a forward–backward multistep procedure and tested in structured patient interviews. Subsequently, 195 outpatients with ILD were asked to complete K-BILD, St. George’s Respiratory Questionnaire (SGRQ), and Euroqol EQ-5D-5L (EQ5D), twice, 2 weeks apart. Internal consistency, concurrent validity, and repeatability were determined. No major difficulties occurred in the translation processes. The K-BILD was considered comprehensible and relevant by patients. One hundred seventy-six patients (108 IPF and 68 other ILDs) completed the translated K-BILD. Internal consistency was good for all K-BILD modules (Cronbach’s α 0.70–0.93). Concurrent validity of K-BILD was strong compared with SGRQ ( r = −0.86) and EQ5D ( r = 0.68), low with transfer capacity of the lung for carbon monoxide corrected for hemoglobin ( r = 0.33) and with forced vital capacity ( r = 0.35). The K-BILD and its domains were repeatable over 2 weeks; intraclass correlation coefficients were 0.86–0.93 ( n = 159). Known groups validity showed K-BILD was able to discriminate between patients based on severity of disease. K-BILD’s validity and reliability for patients with IPF was similar to that of other ILDs. The French, Italian, Swedish, and Dutch translated K-BILD questionnaires were well-received by patients and demonstrated excellent validity comparable to the original English K-BILD.
How Supreme Court Justices Supervise Ideologically Distant States
Authors: Bryan Amanda Clare , Owens Ryan J.
Published: February 2017

Because the Supreme Court can decide only so many cases per term, justices carefully target which cases they hear and which parties they supervise. We focus on their decisions to hear cases involving states as parties. We believe justices use the agenda power to target states with whom they disagree ideologically. Granting review allows justices to keep an eye on wayward states and to remind them of the ever-present threat of Supreme Court review. The results support our theory. Justices are significantly more likely to grant review to cases involving ideologically unfriendly states—and these results are exacerbated in salient cases. These findings suggest justices are more aggressive agenda setters than commonly believed. In addition, the findings suggest that even the so-called federalism revolution of the Rehnquist Court was driven by policy goals.
Factors Associated to Health Care Service Use among Latino Day Laborers
Authors: Boyas Javier Francisco , Negi Nalini Junko , Valera Pamela
Published: February 2017

Latino day laborers (LDLs) are at elevated risks for disease and injury because of the environments in which they work. Despite this recognition, a comprehensive examination of factors related to LDLs’ health service use remains unexamined. Using the Andersen model, the current exploratory study examined predisposing (age, education level, location of educational training, legal status, and marital status), enabling (income, trust in medical personnel, whether the respondent has someone they consider their personal doctor, and whether their doctor speaks the same language, perceived barriers to care), and need (self-rated health, number of chronic conditions) variables to predict use of health services among a purposive sample of LDLs ( N = 150). Cross-sectional data were collected in 2012 from 4 day laborer sites in Dallas and Arlington, Texas. Regression results suggest that the strongest predictor of health care use was trust in medical providers (β = .41). LDLs who were U.S legal residents (β = .21), reported multiple chronic conditions (β = .16), and had a doctor who spoke their language (β = .15) reported significantly higher levels of health care usage. In terms of barriers, not being able to pay for services (β = −.23), lacking health care insurance coverage (β = −.22), and being embarrassed or having a family member not approve of utilizing services (β = −.18) were significantly associated with lower health care usage among LDLs. These findings suggest that LDLs are faced with a number of predisposing, enabling, and need factors that comprise health care use.
A central pattern generator approach to footstep transition for biped navigation
Authors: Xia Zeyang , Deng Hao , Zhang Xue , Weng Shaokui , Gan Yangzhou , Xiong Jing
Published: February 2017

Existing sampling-based footstep planning method for biped navigation used an intermediate static posture for footstep transition. However, when adopting this approach, the robot is sensitive to modeling error and external environments, and also the transition between different gait patterns is unnatural. This article presents a central pattern generator approach to footstep transition for biped navigation. First, this approach decomposes the biped walking motion into five motion types and designs central pattern generator network for all joints of legs accordingly. Then, the central pattern generator parameters are simplified and the relationship between these parameters and footstep transition is formulated. By modifying the central pattern generator parameters, different walking gaits can be obtained. With sensing feedbacks, self-adaption walking on irregular terrains, such as walking on unknown sloped terrains and flat floor with tiny obstacles, is realized. Experiments were conducted both in simulator and on a physical biped robot. Results have shown that the proposed approach is able to generate gesture transition trajectory for biped robot navigation and realize a self-adaption walking for irregular terrains.
Physiological responses during two climbing tests with different hold types
Authors: Michailov Michail L , Rokowski Robert , Ręgwelski Tomasz , Staszkiewicz Robert , Brown Lee E , Szygula Zbigniew
Published: February 2017

The purpose of this study was to investigate physiological responses to climbing with different hold types. Eight elite climbers (red-point achievements 8a – 9a, French grades) performed two climbing tests to failure which were steady in pace and uniform in wall inclination, distances between holds and hold deepness. Only the hold contact surface inclination was different. Duration of test 1 (111 ± 54 s) was significantly ( P = 0.005) less than test 2 (255 ± 127 s), but peak and average oxygen uptake (V̇O2), heart rate (HR) and post-climbing lactate concentrations were not different ( P > 0.05). Nevertheless, hold type had a greater impact on peak compared to average V̇O2 and HR. Peak V̇O2 and HR in test 1 and 2 were 34.1 ± 4.8 versus 37 ± 2.1 ml/min/kg and 166 ± 16 versus 171 ± 13 bpm, respectively. Average V̇O2 and HR were 28.2 ± 2.7 versus 29.2 ± 2.1 ml/min/kg and 154 ± 15 versus 156 ± 14 bpm. Duration of test 1 and percent lactate clearance were significantly correlated with red-point achievement ( r = 0.94, P = 0.001 and r = 0.75, P = 0.033, respectively). Peak V̇O2 was significantly correlated with duration of test 1 ( r = 0.80, P = 0.017) and average V̇O2 was significantly correlated with duration of test 2 ( r = 0.85, P = 0.008). Different climbing hold types had no influence on either average or maximal V̇O2 and HR or on post-climbing lactate. Therefore, these variables could be used for performance evaluation but not as intensity indicators during training for sport climbing.
Factors influencing compliance to the infection control precautions among nurses and physicians in Jordan: A cross-sectional study
Authors: Nofal Maysa , Subih Maha , Al-Kalaldeh Mahmoud , Al Hussami Mahmoud
Published: February 2017

Background:

Adherence to infection control precautions (ICP) is important to reduce the transmission of healthcare-associated infections (HAIs).

Aims:

To determine nurses and physician’s knowledge, attitude and compliance to ICPs and factors associated with reported compliance.

Methods:

A cross-sectional survey of nurses and physicians recruited from three hospitals at three different healthcare sectors in Jordan. Three instruments were used to assess knowledge, attitudes and compliance to ICPs.

Findings:

A total of 211 professionals completed the survey: 155 nurses and 56 physicians. Both groups had low knowledge scores for ICP but a high positive attitude. Although both groups had high reported compliance scores, nurses scores were higher ( P = 0.04). Participants from the private hospital had higher knowledge and compliance scores. Length of experience, knowledge and attitude were significant predictors of reported compliance to ICPs.

Discussion:

Despite poor knowledge, Jordanian healthcare professionals reported high scores for positive attitudes and compliance with IPCs. Clinical training programmes are required to enhance knowledge and understanding of IPCs.
The ‘strong’ state and the ‘soft’ market in educational reform processes: Management philosophies and their consequences
Authors: Rüsselbæk Hansen Dion , Bøje Jakob Ditlev
Published: February 2017

In contemporary western society, welfare work in general, particularly in education, has been struck by an endless series of policy reforms, discourses and technologies. These have consequences not only for the production of professional identity, but also for the way educational tasks are understood and handled. Inspired by the work of post-structuralist thinkers such as Foucault, Rose, Ball, Alvesson and Willmott, and the psychoanalytical thinker Žižek, the authors describe some of these consequences by analysing two examples which stem from the Danish educational context: upper secondary schools and vocational educational training. The first example shows how a ‘strong’ state logic results in a focus on numbers, which leads to a form of cynical leadership and an undermining of teachers’ professional judgment. The second example shows how leaders and teachers in a vocational training school, with help from critical utopian action researchers, seek to innovate their practices in accordance with ‘soft’ market logic. As a consequence, teachers’ professionalism is ‘hijacked’ by a new form of organizational professionalism.
Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes
Authors: Wendt Sabrina Lyngbye , Ranjan Ajenthen , Møller Jan Kloppenborg , Schmidt Signe , Knudsen Carsten Boye , Holst Jens Juul , Madsbad Sten , Madsen Henrik , Nørgaard Kirsten , Jørgensen John Bagterp
Published: February 2017

Background:

Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon.

Methods:

Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE).

Results:

Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients.

Conclusions:

The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia.
Short- and long-term results of an inpatient programme to manage Complex Regional Pain Syndrome in children and adolescents
Authors: Cucchiaro Giovanni , Craig Kevin , Marks Kerri , Cooley Kristin , Cox Thalitha Kay Black , Schwartz Jennifer
Published: February 2017

The aim of this retrospective study was to determine whether an inpatient approach and the use of regional anaesthesia techniques can accelerate the recovery to normal functions in children with Complex Regional Pain Syndrome (CRPS). This study looked at the data of patients admitted to the rehabilitation unit with a diagnosis of CRPS from January 2010 to April 2015. Variables such as hospital stay, medications administered, regional anaesthesia procedures, changes in functional status prior to treatment and at the time of discharge, psychological evaluation and diagnosis were evaluated. A total of 31 patients (21 females and 10 males) were admitted with a diagnosis of CRPS 1 and 2. In all, 97% of the patients received a peripheral or central nerve catheter for an average of 4 days with pain scores of Verbal Numeric Scale (VNS) score = 1.0 ± 0.7 and an average length of hospital stay of 8.2 ± 2.6 days. The modified Functional Independence Measure for Children (WeeFIM) scores and Canadian Association of Occupational Therapists tests significantly improved at the time of hospital discharge, as well as their pain scores, which decreased from 8.2 ± 2 to 1.6 ± 3. In conclusion, these data suggest that the use of regional anaesthesia techniques and an intensive inpatient rehabilitation programme could accelerate the recovery of children with CRPS.
Screening for prostate cancer in renal transplant candidates: Single-centre experience over 10 years
Authors: Aleckovic-Halilovic Mirna , Zelhof Bachar , Solomon Laurie , Ahmed Aimun , Woywodt Alexander
Published: February 2017

Objectives:

The purpose of this article is to report 10 years of single-centre experience with prostate cancer screening in renal transplant candidates.

Patients and methods:

This is a single-centre retrospective analysis of results of prostate cancer screening as a part of renal pre-transplant workup. We included all male patients suitable for transplant workup over 10 years. Patients with persistently elevated prostate specific antigen were considered for prostate biopsy. Biopsy results, treatment data and short-term outcomes for patients diagnosed with prostate cancer were collected.

Results:

We identified 542 patients with a mean age of 52 years. Thirty-one (5.7%) patients were referred to a urologist. Twenty-three (74%) of those referred were biopsied. Histological findings for 10 biopsies (44%) were normal, three (13%) had prostatic intraepithelial neoplasm and nine patients (39%) had invasive adenocarcinoma. One case (4%) was inconclusive. All patients with a normal biopsy proceeded with pre-transplant workup. Out of nine patients diagnosed with prostate cancer, five were transplant listed, two were receiving treatment and two were subsequently deceased.

Conclusion:

Prostate specific antigen screening with repeat testing and the use of age-adjusted normal values led to the diagnosis of prostate cancer that had major implications for transplant listing. For the majority of cancers the diagnosis did not deny transplant surgery to patients but only delayed listing for transplant.
Quantitative Anatomic Analysis of the Native Ligamentum Teres
Authors: Mikula Jacob D. , Slette Erik L. , Chahla Jorge , Brady Alex W. , Locks Renato , Trindade Christiano A. C. , Rasmussen Matthew T. , LaPrade Robert F. , Philippon Marc J.
Published: February 2017

Background:

While recent studies have addressed the biomechanical function of the ligamentum teres and provided descriptions of ligamentum teres reconstruction techniques, its detailed quantitative anatomy remains relatively undocumented. Moreover, there is a lack of consensus in the literature regarding the number and morphology of the acetabular attachments of the ligamentum teres.

Purpose:

To provide a clinically relevant quantitative anatomic description of the native human ligamentum teres.

Study Design:

Descriptive laboratory study.

Methods:

Ten human cadaveric hemipelvises, complete with femurs (mean age, 59.6 years; range, 47-65 years), were dissected free of all extra-articular soft tissues to isolate the ligamentum teres and its attachments. A coordinate measuring device was used to quantify the attachment areas and their relationships to pertinent open and arthroscopic landmarks on both the acetabulum and the femur. The clock face reference system was utilized to describe acetabular anatomy, and all anatomic relationships were described using the mean and 95% confidence intervals.

Results:

There were 6 distinct attachments to the acetabulum and 1 to the femur. The areas of the acetabular and femoral attachment footprints of the ligamentum teres were 434 mm2 (95% CI, 320-549 mm2) and 84 mm2 (95% CI, 65-104 mm2), respectively. The 6 acetabular clock face locations were as follows: anterior attachment, 4:53 o’clock (95% CI, 4:45-5:02); posterior attachment, 6:33 o’clock (95% CI, 6:23-6:43); ischial attachment, 8:07 o’clock (95% CI, 7:47-8:26); iliac attachment, 1:49 o’clock (95% CI, 1:04-2:34); and a smaller pubic attachment that was located at 3:50 o’clock (95% CI, 3:41-4:00). The ischial attachment possessed the largest cross-sectional attachment area (127.3 mm2; 95% CI, 103.0-151.7 mm2) of all the acetabular attachments of the ligamentum teres.

Conclusion:

The most important finding of this study was that the human ligamentum teres had 6 distinct points of attachment on the acetabulum (transverse, anterior, and posterior margins of the acetabular notch and cotyloid fossa attachments: ilium, ischium, and pubis) and 1 on the femur. On the acetabulum, the anterior attachment was substantially larger than the posterior attachment and was located at a mean clock face position of 4:53 o’clock.

Clinical Relevance:

These quantitative descriptions of the ligamentum teres can be used by clinicians to arthroscopically identify the attachments of the ligamentum teres, guiding arthroscopic surgical interventions designed to address ligamentum teres pathology.
A Bridge to Active Learning: A Summer Bridge Program Helps Students Maximize Their Active-Learning Experiences and the Active-Learning Experiences of Others
Authors: Cooper Katelyn M. , Ashley Michael , Brownell Sara E.
Published: February 2017

National calls to improve student academic success in college have sparked the development of bridge programs designed to help students transition from high school to college. We designed a 2-week Summer Bridge program that taught introductory biology content in an active-learning way. Through a set of exploratory interviews, we unexpectedly identified that Bridge students had developed sophisticated views of active learning, even though this was not an explicit goal of the program. We conducted an additional set of semistructured interviews that focused on active learning and compared the interviews of Bridge students with those from non-Bridge students who had been eligible for but did not participate in the program. We used the constant comparative method to identify themes from the interviews. We found that Bridge students perceived that, because they knew how to approach active learning and viewed it as important, they benefited more from active learning in introductory biology than non-Bridge students. Specifically, Bridge students seemed to be more aware of their own learning gains from participating in active learning. Compared with the majority of non-Bridge students, the majority of Bridge students described using a greater variety of strategies to maximize their experiences in active learning. Finally, in contrast to non-Bridge students, Bridge students indicated that they take an equitable approach to group work. These findings suggest that we may be able to prime students to maximize their own and other’s experiences in active learning.
Constrained electrical resistivity tomography Bayesian inversion using inverse Matérn covariance matrix
Authors: Bouchedda Abderrezak , Bernard Giroux , Gloaguen Erwan
Published: February 2017

Bayesian inversion using maximum a posteriori estimator is a quantitative approach that has been successfully applied to the electrical resistivity tomography inverse problem. In most approaches, model covariance parameters are generally chosen as stationary and isotropic, which assumes a statistical homogeneity of the studied field. However, the statistical properties of resistivity within the earth are, in reality, location dependent due to spatially varying processes that control the bulk resistivity of rocks, such as water content, porosity, clay content, etc. Taking into account the spatial variability of the resistivity field, we use the nonstationary Matérn covariance family, which is defined through linear stochastic partial differential equations. Two types of prior information are considered: structure orientation and spatially increasing the range with increasing depth. The latter is applied successfully on the first synthetic model, which aims at retrieving the depth of bedrock and the shape of the conductive lens. In the second synthetic example, a conductive dike model embedded into four layers is used to study the performance of structure orientation. Finally, the proposed approach is used to invert real data measured over an extensively characterized sandy-to-silty aquifer. First, the structure orientation of this aquifer was determined by applying a structure tensor calculated using gradients of the ground penetrating radar image. The introduction of this information gives a resistivity model that is more compatible with the aquifer structure.
Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802.
Authors: Tester W , Caplan R , Heaney J , Venner P , Whittington R , Byhardt R , True L , Shipley W
Published: February 2017

PURPOSE

This phase II study was designed to evaluate effectiveness and toxicity of a combined chemoradiotherapy program with selective bladder preservation in the management of patients with invasive bladder cancer.

PATIENTS AND METHODS

Ninety-one eligible patients with invasive bladder cancer stages T2M0 to T4AM0 suitable for radical cystectomy received two courses of methotrexate, cisplatin, and vinblastine (MCV regimen) followed by radiotherapy with 39.6 Gy and concurrent cisplatin. After complete urologic evaluation, operable patients who achieved complete response were selected for bladder preservation and treated with consolidation cisplatin-radiotherapy.

RESULTS

Of 91 eligible patients, 85 underwent complete urologic evaluation and 68 (75%; 95% confidence interval [CI], 59% to 84%) had documented complete responses. Fourteen operable patients with residual tumor underwent immediate cystectomy. Of 70 patients treated with consolidation cisplatin-radiotherapy, 36 subsequently developed bladder recurrences, 23 of which were invasive. Patients with invasive recurrence (n = 16), extensive noninvasive recurrence (n = 6), or severe treatment complications (n = 1) underwent salvage cystectomy. Thus, a total of 37 of 91 patients (40%) required cystectomy. The 4-year cumulative risk of invasive local failure (which includes induction failures) was 43% (95% CI, 33% to 53%). The 4-year actuarial risk of distant metastasis was 22% (95% CI, 13% to 31%). The 4-year actuarial survival rate of the entire group was 62% (95% CI, 52% to 72%). The 4-year actuarial rate of survival with bladder intact was 44% (95% CI, 34% to 54%).

CONCLUSION

Initial results of this combined chemoradiotherapy program show that bladder preservation can be achieved in the majority of patients, and that overall survival is similar to that reported with aggressive surgical approaches. Long-term survival and quality-of-life assessments require longer follow-up study.
Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. European Organization for Research and Treatment of Cancer Gastrointestinal Treat Cancer Cooperative Group.
Authors: Conroy T , Etienne P L , Adenis A , Wagener D J , Paillot B , François E , Bedenne L , Jacob J H , Seitz J F , Bleiberg H , Van Pottelsberghe C , Van Glabbeke M , Delgado F M , Merle S , Wils J
Published: February 2017

PURPOSE

To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma.

PATIENTS AND METHODS

Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion.

RESULTS

Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1).

CONCLUSION

These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.
Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.
Authors: Larson R A , Mick R , Spielberger R T , O'Brien S M , Ratain M J
Published: February 2017

PURPOSE

The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions.

PATIENTS AND METHODS

Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each.

RESULTS

Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients.

CONCLUSION

2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.
Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma.
Authors: Sarris A H , Younes A , McLaughlin P , Moore D , Hagemeister F , Swan F , Rodriguez M A , Romaguera J , North L , Mansfield P , Callendar D , Mesina O , Cabanillas F
Published: February 2017

PURPOSE

Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS

Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses.

RESULTS

All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths.

CONCLUSION

Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.
Trade-offs between survival and breast preservation for three initial treatments of ductal carcinoma-in-situ of the breast.
Authors: Hillner B E , Desch C E , Carlson R W , Smith T J , Esserman L , Bear H D
Published: February 2017

PURPOSE

To assess the trade-offs between survival and breast preservation of currently accepted approaches for ductal carcinoma-in-situ (DCIS) of the breast.

PATIENTS AND METHODS

Decision analysis was performed using the Markov model of hypothetical cohorts of 55-year-old white women with nonpalpable mammographic abnormalities found to be DCIS. Strategies were breast-conserving surgery (BCS), BCS with 50-Gy radiation (RT) or initial mastectomy. Recurrence rates were derived from the published literature. Main outcomes were overall, breast cancer-free, and event-free survival plus years of both breasts preserved.

RESULTS

Using the conditions defined in this model, the actuarial survival rates at 10 and 20 years were 91.7% and 74.1% for the initial mastectomy strategy, 91.0% and 72.1% for BCS plus RT, and 89.6% and 68.2% for BCS alone. At 20 years, the initial mastectomy strategy also had a greater breast cancer-free survival rate of 74.5%, compared with 63.3% for BCS plus RT, or 46.8% for BCS alone. However, BCS alone had the highest survival rate with both breasts preserved (64.2%) compared with BCS plus RT (56.0%) or initial mastectomy (0%). Of the breast-conserving strategies at 20 years, the breast event-free survival rate (no invasive cancer or DCIS) was greater for BCS plus RT (47.2%) compared with BCS alone (28.4%). Using just survival as the primary end point, mastectomy is the optimal strategy by a small margin. However, if quality-adjusted survival is at issue, mastectomy is the choice only if the yearly reduction in quality of life due to mastectomy is less than 1%.

CONCLUSION

BCS with or without radiation compared with mastectomy as initial management of DCIS of the breast trades a slight decrease in survival rates for the value of breast preservation. This model should aid clinicians in matching treatments to their patients' preferences.
Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer.
Authors: Canal P , Gay C , Dezeuze A , Douillard J Y , Bugat R , Brunet R , Adenis A , Herait P , Lokiec F , Mathieu-Boue A
Published: February 2017

PURPOSE

A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships.

PATIENTS AND METHODS

Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection.

RESULTS

The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome.

CONCLUSION

Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.
Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.
Authors: Holmes F A , Madden T , Newman R A , Valero V , Theriault R L , Fraschini G , Walters R S , Booser D J , Buzdar A U , Willey J , Hortobagyi G N
Published: February 2017

PURPOSE

To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially.

PATIENTS AND METHODS

Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly.

RESULTS

Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3.

CONCLUSION

When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.
Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group.
Authors: Pritchard K I , Paterson A H , Paul N A , Zee B , Fine S , Pater J
Published: February 2017

PURPOSE AND METHODS

Associations between thromboembolism and malignancy, usually widespread, and between thromboembolism and hormonal and/or chemotherapy have been previously reported. We performed a randomized trial of tamoxifen 30 mg/d for 2 years (T) versus T plus 6 months of intravenous chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) for postmenopausal women with involved axillary nodes and positive estrogen receptor (ER) or progesterone receptor (PgR) status following primary therapy for breast cancer.

RESULTS

We observed one or more thromboembolic events in 48 of 353 women (13.6%) allocated to receive T plus CMF in comparison to five of 352 women (2.6%) randomized to receive T alone (P < .0001). Six women in the T plus CMF arm, but none randomized to receive T alone, suffered two thromboembolic events while an study therapy. There were also significantly more women who developed severe (grade 3 to 5) thromboembolic events in the T plus CMF arm than in the T arm (34 v five; P < .0001). Most thromboembolic events (39 of 54) occurred while women were actually receiving chemotherapy (P < .0001). Thromboembolic complications resulted in more days in hospital and more deaths than any other complication of therapy, including infection, in this trial.

CONCLUSION

Thromboembolism related to the addition of CMF chemotherapy to tamoxifen as adjuvant therapy in this group of women represents a relatively common and serious complication that may outweigh any benefits offered by this additional therapy.
Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan.
Authors: Perez-Soler R , Glisson B S , Lee J S , Fossella F V , Murphy W K , Shin D M , Hong W K
Published: February 2017

PURPOSE

This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with small-cell lung cancer (SCLC) refractory to etoposide.

PATIENTS AND METHODS

Refractoriness to etoposide was defined as lack of response to etoposide-containing frontline therapy, or progression during or within 3 months of the last dose of etoposide-containing frontline or second-line therapy. Other eligibility criteria were presence of measurable disease, Zubrod scale performance status (PS) < or = 2, < or = two prior chemotherapy regimens, and adequate renal and liver function. TPT was administered at a dose of 1.25 mg/m2/d for 5 days over 30 minutes every 21 days.

RESULTS

Thirty-two patients were registered, of whom 28 are fully assessable. All patients had been treated with frontline etoposide and cisplatin. Three patients (11%) achieved a partial remission (PR) (durations, 7, 8, and 19 weeks) and two (7%) achieved a minor response; five patients (17%) had stable disease and 18 (65%) had progressive disease. One of the three patients who achieved a PR had failed to respond to frontline cisplatin and etoposide. The overall median survival duration was 20 weeks. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 70% and 31% of courses administered, respectively. No grade 3 to 4 non-hematological toxicities were observed. Grade 1 or 2 nonhematological toxicities (in percentage of patients) consisted of nausea (41%, 8%) and vomiting (25%, 11%), and alopecia (100%).

CONCLUSION

TPT at the dose and schedule used has modest antitumor activity in SCLC patients refractory to etoposide and cisplatin, which indicates that clinical resistance to the topoisomerase II poison etoposide does not confer cross-sensitivity to the topoisomerase I poison TPT. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.