bluuebunny/crossref_metadata_2025 huggingface dataset:
Back pain and scoliosis in children: When to image, what to consider
Authors: Calloni Sonia F , Huisman Thierry AGM , Poretti Andrea , Soares Bruno P
Published: March 2017

Back pain and scoliosis in children most commonly present as benign and self-limited entities. However, persistent back pain and/or progressive scoliosis should always be taken seriously in children. Dedicated diagnostic work-up should exclude etiologies that may result in significant morbidity. Clinical evaluation and management require a comprehensive history and physical and neurological examination. A correct imaging approach is important to define a clear diagnosis and should be reserved for children with persistent symptoms or concerning clinical and laboratory findings. This article reviews the role of different imaging techniques in the diagnostic approach to back pain and scoliosis, and offers a comprehensive review of the main imaging findings associated with common and uncommon causes of back pain and scoliosis in the pediatric population.
Circulatory power and ventilatory power over time under goal‐oriented sequential combination therapy for pulmonary arterial hypertension
Authors: Hirashiki Akihiro , Adachi Shiro , Nakano Yoshihisa , Kamimura Yoshihiro , Shimokata Shigetake , Takeshita Kyosuke , Shimizu Atsuya , Toba Kenji , Murohara Toyoaki , Kondo Takahisa
Published: March 2017

Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2 cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal‐oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first‐line treatment, with phosphodiesterase type 5 inhibitors (PDE‐5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O2 uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation–CO2 production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE‐5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg·min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline (P = 0.047); VP was greater after three months than at baseline (P = 0.019) and further improved at six months compared with three months (P = 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal‐oriented treatment for PAH.
Simulation games on the European Union in civics: Effects on secondary school pupils’ political competence
Authors: Oberle Monika , Leunig Johanna
Published: March 2017

Civics courses strive to promote students’ political competencies, which according to the model of Detjen et al. incorporate content knowledge, abilities to make political judgements and take political action, as well as motivational skills and attitudes. For achieving these goals, high hopes are placed on active learning tools such as political simulations. Looking at positive expectations generally placed on simulation games, they seem very suitable for addressing key problems of teaching about European Union identified earlier. However, simulation games have also been regarded as demanding and time-consuming, with the ‘fun-factor’ outweighing the ‘learning factor’. There is a profound lack of systematically won empirical evidence for such positive and negative expectations. This study addresses this research deficit, focusing on the effects of short European Union simulation games of the decision-making of the European Parliament on pupils and their political competence controlling for different background variables (e.g. gender, cultural capital, pre-knowledge, political interest). Data were collected from 2013 to 2016 in secondary schools of Lower Saxony and North Rhine-Westphalia (N = 308; average age = 16.75 years) using partly standardised questionnaires accompanied by interviews. The intervention study (pre–post design) focuses on the competency dimensions content knowledge, motivation (political interest, self-efficacy), volition (willingness to participate politically) and attitudes (e.g., perceived responsiveness of European Union and perceived relevance of European Union for everyday life).
Strengthening Institutional Isomorphism in Development NGOs? Program Mechanisms in an Organizational Intervention
Authors: Kontinen Tiina , Onali Anja
Published: March 2017

Nongovernmental organizations (NGOs) in international development struggle between being actors in the mainstream or representatives of alternatives to it. However, many NGOs all over the world align with the mainstream and are increasingly similar to each other. This homogenization results from institutional isomorphism, which is affected by their aspirations to be legitimate vis-á-vis the international field. Consultancies are among the main practices to promote normative isomorphism, but little is known about their micro-level dynamics. Drawing on the notion of program mechanisms in realistic evaluation, we scrutinize how external facilitators in organizational development processes enable normative isomorphism. As a result of analysis of interventions in three Finnish development NGOs, we identify program mechanisms of convincing, embedding, and consolidating. Our findings show how organizational development activities contribute to the direction of change toward normative isomorphism and argue that a detailed analysis of intervention mechanisms would be useful for self-reflection in any field of activity.
Reflections on Hip Fracture Recovery From Older Adults Enrolled in a Clinical Trial
Authors: Stott-Eveneshen Sarah , Sims-Gould Joanie , McAllister Megan M. , Fleig Lena , Hanson Heather M. , Cook Wendy L. , Ashe Maureen C.
Published: March 2017

This study describes patients’ perspectives on recovery during participation in a randomized controlled trial that tested a postoperative hip fracture management program (B4 Clinic), compared with usual care, on mobility. Semistructured qualitative interviews were conducted with 50 older adults with hip fracture (from both groups) twice over 12 months. A total of 32 women (64%) and 18 men (36%) participated in the study with a mean age at baseline of 82 (range = 65-98) years. A total of 40 participants reported recovery goals at some point during their recovery from hip fracture but only 18 participants realized their goals within 12 months. Recovering mobility, returning to prefracture activities, and obtaining stable health were the most commonly reported goals. Participants described good social support, access to physiotherapy, and positive perspective as most important to recovery. These factors were influenced by participants’ knowledge, resources, and monthly contact with study staff (perceived as a form of social support). The most frequently reported barriers to participants’ recovery were the onset of complications, pain, and limited access to physiotherapy. Potential implications of these findings include design and modification of new or preexisting fracture programs, prioritizing patient engagement and enhanced knowledge for future clinical research in hip fracture recovery.
Patient Perceptions of Clinician’s Empathy
Authors: Hojat Mohammadreza , DeSantis Jennifer , Gonnella Joseph S
Published: March 2017

The prominence of reciprocal understanding in patient–doctor empathic engagement implies that patient perception of clinician’s empathy has an important role in the assessment of the patient–clinician relationship. In response to a need for an assessment tool to measure patient’s views of clinician empathy, we developed a brief (5-item) instrument, the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE). This review article reports evidence in support of the validity and reliability of the JSPPPE.
Discordance in investigator-reported and adjudicated sudden death in TIOSPIR
Authors: Wise Robert A. , Kowey Peter R. , Austen George , Mueller Achim , Metzdorf Norbert , Fowler Andy , McGarvey Lorcan P.
Published: March 2017

Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD) patients. TIOSPIR (N=17 135) compared the safety and efficacy of tiotropium Respimat 5/2.5 µg with HandiHaler 18 µg in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC) assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death.

The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302) and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables).

There was agreement between investigator-reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC) and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC). Reasons for discrepancies included investigator attribution to the immediate (e.g.myocardial infarction (MI)) over the underlying cause of death (e.g.COPD) and insufficient information for a definitive cause.

Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence.
Psychological profile of individuals presenting with chronic cough
Authors: Hulme Katrin , Deary Vincent , Dogan Sian , Parker Sean M.
Published: March 2017

Chronic refractory cough (CRC) is a common problem in respiratory clinics. Adverse effects on quality of life are documented in the literature, but relatively little is known about the underlying psychological factors in this patient population. We aimed to investigate the association of psychological factors with chronic cough, comparing CRC to explained cough and non-cough groups.

67 patients attending a specialist cough clinic (CRC, n=25; explained cough, n=42) and 22 non-cough individuals participated. All participants completed the Hospital Anxiety & Depression Scale, Big Five Inventory (Personality), Chalder Fatigue Scale and Patient Health Questionnaire-15. Cough patients also completed the Illness Perception Questionnaire-Revised. Appropriate statistical analyses were used to compare participant groups.

Chronic refractory coughers displayed significantly higher levels of anxiety, depression, fatigue and somatic physical symptoms than non-cough participants. Compared to explained coughers, there were higher depression and fatigue scores and significantly more negative illness representations (specifically, strong beliefs regarding negative consequences, lower illness coherence and higher emotional representations). “Explained” coughers reported significantly increased fatigue and somatic symptoms in comparison to non-coughers.

The prevalence of fatigue, low mood, negative illness beliefs and increased physical symptom reporting should be considered in consultations and in developing novel interventions for CRC patients.
Stuck between a rock and a reflection: A tutorial on low-frequency models for seismic inversion
Authors: Sams Mark , Carter David
Published: March 2017

Predicting the low-frequency component to be used for seismic inversion to absolute elastic rock properties is often problematic. The most common technique is to interpolate well data within a structural framework. This workflow is very often not appropriate because it is too dependent on the number and distribution of wells and the interpolation algorithm chosen. The inclusion of seismic velocity information can reduce prediction error, but it more often introduces additional uncertainties because seismic velocities are often unreliable and require conditioning, calibration to wells, and conversion to S-velocity and density. Alternative techniques exist that rely on the information from within the seismic bandwidth to predict the variations below the seismic bandwidth; for example, using an interpretation of relative properties to update the low-frequency model. Such methods can provide improved predictions, especially when constrained by a conceptual geologic model and known rock-physics relationships, but they clearly have limitations. On the other hand, interpretation of relative elastic properties can be equally challenging and therefore interpreters may find themselves stuck — unsure how to interpret relative properties and seemingly unable to construct a useful low-frequency model. There is no immediate solution to this dilemma; however, it is clear that low-frequency models should not be a fixed input to seismic inversion, but low-frequency model building should be considered as a means to interpret relative elastic properties from inversion.
Survival results of a multicenter phase II study of trastuzumab with S-1 alone in elderly patients with HER-2 positive advanced gastric cancer (JACCRO GC-06).
Authors: Nishikawa Kazuhiro , Kimura Yutaka , Masuishi Toshiki , Kunisaki Chikara , Matsusaka Satoshi , Segawa Yoshihiko , Nakamura Masato , Sasaki Kinro , Nagao Narutoshi , Hatachi Yukimasa , Yuasa Yasuhiro , Asami Shinya , Takeuchi Masahiro , Furukawa Hiroshi , Fujii Masashi , Nakajima Toshifusa
Published: March 2017

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Background: S-1 plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in Japan. In patients with HER-2 positive AGC, combined administration of fluoropyrimidine plus cisplatin and trastuzumab is the standard treatment. However, cisplatin has several important drawbacks, including nausea, vomiting, and renal toxicity. Especially, these disadvantages of cisplatin are noticeable in elderly patients. We have already reported the results of the efficacy and safety of trastuzumab combined with S-1 alone in elderly patients with HER-2 positive AGC. In this time, we report the survival results of this study. Methods: Patients, 65 years or older, with HER-2 positive AGC received S-1 (80-120mg per day) orally on days 1-28 of a 42-day cycle and trastuzumab (first time: 8 mg/kg, from 2nd onward: 6 mg /kg) intravenously on day 1 of a 21-day cycle. Results: A total of 51 patients were enrolled. One patient was ineligible, one patient did not receive study treatment, therefore in the full analysis set of 49 patients, the median age was 71 years (range: 65-85) and ECOG PS was 0/1/2: 32/14/3. The confirmed RR (CR/PR/SD/PD: 2/18/21/8) was 40.8% (80% confidence interval (CI): 31.8-49.8%, 95% CI: 27.1-54.6%), and the null hypothesis was rejected. Median follow up period was 10.6 months. Median OS was 15.8 months (95%CI: 9.13-20.37). Median PFS was 5.1 months (95%CI: 3.78-5.55), and TTF was 4.0 months (95%CI: 3.09-5.39). Major grade 3 or 4 adverse events included neutropenia (12.0%), anemia (24.0%), diarrhea (10.0%) and anorexia (12.0%). There was one treatment-related death. Conclusions: Trastuzumab in combination with S-1 alone demonstrated promising antitumor activity and manageable toxic effects, as well as promising survival results in elderly patients with HER-2 positive AGC. Clinical trial information: 000007368.
Interim safety and clinical activity in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase 1 study of ramucirumab (R) plus pembrolizumab (P).
Authors: Chau Ian , Bendell Johanna C. , Calvo Emiliano , Santana-Davila Rafael , Rodon Ahnert Jordi , Penel Nicolas , Arkenau Hendrik-Tobias , Yang Jing , Rege Jessicca , Mi Gu , Ferry David , Herbst Roy S. , Fuchs Charles S.
Published: March 2017

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Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Two dosing regimens were evaluated, Cohort A (R 8 mg/kg on Days 1&8) and Cohort B (R 10 mg/kg on Day 1), given with P 200 mg on Day 1 q3W. The primary objective was to assess safety and tolerability of adding R to P; preliminary efficacy will be examined. Results: As of 23-Jun-2016, 40 G/GEJ pts have been enrolled (Cohort A: n=23; Cohort B: n=17). First pt treated in Cohorts A and B were on 29-Feb-2016 and 26-Oct-2015, respectively. The median age was 59 y, 75% were male, 65% had ECOG PS of 1, 48% were PD-L1 positive, and 70% received study treatment as third or subsequent regimen. Median duration of treatment was 2.1 mo and 4.1 mo for Cohort A and B, respectively. All grades treatment-related AEs (TRAE) occurred in 31 (78%) pts and similar between cohorts; TRAEs in ≥10% of pts were fatigue (30%), infusion related reaction (12.5%), decreased appetite (12.5%), pruritus (10%), maculopapular rash (10%), and hypertension (10%). Ten (25%) pts had grade 3-4 TRAEs, most commonly colitis (7.5%) and hypertension (7.5%). One treatment-related death occurred (pneumocystis pneumonia and pulmonary sepsis). Preliminary efficacy data showed 3 of 40 (7.5%) pts (PD-L1 negative, n=1; PD-L1 positive, n=2) have responded (1 confirmed and 2 unconfirmed PR) to treatment with a 45% disease control rate. Median PFS was 2.10 mo (95% CI, 1.18 to 4.04) and 2.60 mo (1.38, NR) for Cohorts A and B, respectively. Fifteen (37.5%) pts, including all responders, remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.
Upfront surgery, neoadjuvant, and definitive chemoradiation for clinical T2N0 esophageal adenocarcinoma: A propensity score matched analysis from the National Cancer Database analysis.
Authors: Shridhar Ravi , Huston Jamie , Meredith Kenneth L
Published: March 2017

103

Background: To compare overall survival (OS) of T2N0 esophageal adenocarcinomas treated with either upfront surgery (US), neoadjuvant chemoradiation (NCR), or definitive chemoradiation (DCR) from the National Cancer Database (NCDB). Methods: The NCDB was accessed to identify patients with T2N0 esophageal adenocarcinoma treated between 2004-2013 with either US, NCR, or DCR. NCR and DCR patients were included if they were treated with a radiation dose between 45-50.4 Gy and received chemotherapy. Propensity score matching (PSM) was performed against age and tumor length. Results: After PSM, 446 patients (US 98; NCR 203; DCR 145) were included in the analysis. There was no difference in age, tumor length, and grade. Clinical staging in US patients was accurate pathologically in 32.6% of patients. Median and 5 year OS for US, NCR, and DCR patients was 42.5 months and 40%, 48.5 months and 48%, and 22.9 months and 20%, respectively (p<0.001). There was no difference in OS based on response to NCR compared to US. NCR was associated with improved OS in patients with tumors >3 cm compared to US (median OS 43.8 versus 36.4 months; p=0.01). There was a trend toward improved OS with NCR in high grade tumors compared to US. UVA and MVA of OS revealed that DCR was associated with worse survival. Conclusions: Clinical staging for T2N0 esophageal adenocarcinoma continues to remain highly inaccurate. There was no difference in OS between US and NCR, however, improved OS was seen in NCR patients with tumors >3 cm.
Risk of peritoneal carcinomatosis in localized gastric adenocarcinoma patients who undergo preoperative therapy and attempted surgery.
Authors: Mizrak Kaya Dilsa , Nogueras-Gonzalez Graciela M. , Harada Kazuto , Blum Murphy Mariela A. , Das Prajnan , Minsky Bruce D. , Estrella Jeannelyn , Lin Quan , Ghazanfari Amlashi Fatemeh , Lee Jeffrey H , Weston Brian , Bhutani Manoop S. , Wu Carol C , Matamoros Aurelio , Sagebiel Tara L. , Mansfield Paul F. , Badgwell Brian D. , Ajani Jaffer A.
Published: March 2017

104

Background: Positive peritoneal cytology (+PCyt) or gross peritoneal carcinomatosis (GPC) carries a poor prognosis. Laparoscopic staging to detect +PCyt/GPC is recommended for all ≥T1b GACs. The natural history of GAC patients who have baseline –PCyt and then undergo multimodality therapy is not well documented, particularly for the risk of subsequent GPC. Methods: We analyzed 178 GAC patients with -PCyt at baseline who were followed postoperatively. Results: Of 178 patients who went to surgery after preoperative therapy, surgery in 14 patients (7.9%) was aborted due to GPC in 13 patients, and liver metastases in 1. We then analyzed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (0.6-18) years. The rate of subsequent GPC was 13.4%, (22/164 patients) and the median time to GPC was 15.6 months. The median overall survival (OS) after GPC was only 7.1 months (95% CI: 0.4-17.9 months). Various clinical variables were related with GPC after an R0 resection (Table 1). The 5-year OS rate for patients without subsequent GPC was 75%. Conclusions: Even with baseline –PCyt, subsequent risk for GPC is ~20% in the best group of localized GAC patients. Patients who do not develop GPC have an excellent (75%) OS rate. Further research is warranted to identify patients at high risk of subsequent GPC. [Table: see text]
New tyrosine kinase inhibitors in the treatment of imatinib resistant GIST: An updated meta-analysis.
Authors: Pendola Fiorella , Guirguis John , Ripat Caroline , Yakoub Danny , Hoffman James Edward , Dabage Nemer
Published: March 2017

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Background: Primary or secondary resistance to Imatinib, convolutes the control of Gastrointestinal Stromal Tumors (GIST). We aimed to evaluate clinical outcomes of new tyrosine kinase inhibitors (TKIs) in the treatment of Imatinib resistant GIST. Methods: Online database search of PubMed, MEDLINE, EMBASE, SCOPUS, COCHRANE, and GOOGLE SCHOLAR was performed (2000– Present); key bibliographies were reviewed. Studies comparing patients with Imatinib resistant GIST who were treated with placebo versus new generation TKIs (Regorafenib, Sunitinib, Nilotinib). Primary outcomes were overall and progression free survival (OS, PFS), secondary outcomes include the most common side effects described in trials using new TKIs. Meta-analysis was conducted using Statistical Analysis System (SAS) software. Relative risks with the corresponding 95% confidence intervals (CI) by random effects models of pooled data were calculated. Study quality was assessed using JADAD scoring system. Results: Out of 16 studies, 4 studies met our selection criteria including 825 patients in total; 553 treated with new TKIs and 272 were given placebo (control group). Median age was 57.85 years. Meta-analysis of included data showed significantly improved PFS in the new TKIs group (HR = 0.336, 95% CI 0.208-0.542, p < 0.001.) Similar trend but without statistically significant difference was seen in OS (HR = 0.836, 95% CI 0.682-1.026, p = 0.086). Incidence of hypertension was found to be significantly higher in the new TKIs group (RR = 2.903, 95% CI 1.800-4.681, p < 0.001); the same effect was observed in development of hand foot syndrome (RR = 4.818, 95% CI 2.723-8.525, p < 0.001) and diarrhea (RR = 5.341, 95% CI 3.074-9.281, p < 0.001). Conclusions: New generation of TKIs significantly improved PFS compared with placebo in patients with Imatinib resistant GIST. However new TKIs have increased secondary side effects. Randomized controlled trials are needed to evaluate longer term outcomes of these treatments.
Phase II study of S-1 plus oxaliplatin (OX) at dose of 130 mg/m2 (SOX130) in Japanese patients (pts) with advanced gastric cancer (AGC).
Authors: Kito Yosuke , Machida Nozomu , Hamauchi Satoshi , Tsushima Takahiro , Todaka Akiko , Yokota Tomoya , Yamazaki Kentaro , Fukutomi Akira , Onozawa Yusuke , Tsuji Kunihiro , Doyama Hisashi , Haraguchi Yutaka , Nakashima Koji , Kunieda Kenji , Taku Keisei , Mori Keita , Yasui Hirofumi
Published: March 2017

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Background: The phase III G-SOX trial had adopted SOX100 due to high incidence of thrombocytopenia in the previous phase I/II study, and failed to demonstrate the non-inferiority of SOX100 to S-1 plus cisplatin in chemotherapy-naïve Japanese pts with AGC. However, OX 130 mg/m2 has been approved for AGC in Japan since Sep 2014 on the evidence of the REAL-2 trial. Therefore, we conducted a study to evaluate the feasibility of SOX130 in Japanese AGC pts. Methods: This is a single-arm, open-label, multicenter, phase II study. Pts with unresectable or recurrent adenocarcinoma of stomach, no prior chemotherapy and ECOG PS 0 or 1 were treated with SOX130 (S-1 80-120 mg/day according to BSA for 2 weeks, OX 130 mg/m2 on day 1, every 3 weeks). The primary endpoint was the 3-cycle completion rate, defined as the proportion of pts who receive at least 80% of the planned OX dose for the first 3-cycle. We set the threshold 3-cycle completion rate at 50% and the expected rate at 75%. A sample size of 23 pts was needed with 80% power at a 5% α-level (one-sided). Results: From April 2015 to June 2016, 25 pts were enrolled. Pts’ characteristics were as follows: median age 64.5 years (range, 32-76), male/female 21/4, PS 0/1 15/10, unresectable/recurrent 21/4, and intestinal/diffuse 7/18. The 3-cycle completion rate was 72.0% (90% CI 53.8-86.1%). Among the 12 pts with measurable lesions, objective response rate and disease control rate were 58.3% and 83.3%, respectively. With a median follow-up period of 5.2 months, median progression-free survival was 7.5 months. Grade 3 adverse events were anorexia (n = 5), anemia (n = 3), thrombocytopenia (n = 2), neutropenia (n = 1) and nausea (n = 1). No treatment-related death was observed. Conclusions: SOX130 could be a first-line treatment option even in Japanese AGC pts. Clinical trial information: UMIN000016973.
Outcomes of definitive radiotherapy (dRT) and chemo-radiotherapy (dCRT) for loco-regionally confined (LRC) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ).
Authors: Karivedu Vidhya , McNamara Michael J. , Rybicki Lisa A. , Al taii Haider , Sohal Davendra , Rodriguez Cristina P. , Videtic Gregory M.M. , Stephans Kevin L. , Ives Denise I. , Bodmann Joanna , Adelstein David J.
Published: March 2017

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Background: Surgery is the cornerstone of curative intent therapy for patients with ACA of the E/GEJ. Many patients (pts) with LRC disease are medically unsuitable for resection, and thus alternative treatment strategies are required. Definitive CRT is a standard of care for esophageal squamous cell carcinoma, but less is known regarding the outcomes for ACA of the E/GEJ. Methods: Through the Cleveland Clinic tumor registry, and under an IRB approved protocol, pts with LRC (clinical stage I-III, AJCC 7th) ACA of the E/GEJ treated with either dRT or dCRT between 7/04 and 12/14 were identified. Overall survival (OS) from the date of diagnosis was the primary endpoint. In univariate analysis, Cox proportional hazard analysis was used to identify risk factors for mortality. On multivariable analysis, stepwise Cox proportional hazard analysis with variable entry criterion p≤0.10 and variable retention criteria p≤0.05 was used to identify risk factors for mortality. Results: From 7/04 to 12/14, 155 pts received definitive non-operative treatment (103 dCRT, 52 dRT). Clinical stage I disease was present in 20 (13.2%); stage II in 40 (26.5%) and stage III in 91 (60.3%) of the pts. Pts who received dCRT were younger (67 v 74 years, p<0.001) and had more advanced clinical stage (p=0.026). Loco-regional recurrence / persistence was the predominant form of treatment failure occurring in 60% of pts (dCRT 54.3%, dRT 71.2%, p=0.044). With a median follow-up of 34.9 months (range 2.0-107.1), the median OS was 17.3 months (15.6m dCRT, 19.8m dRT, p=0.40) and the projected 5 year OS was 11.5% (16.1% dCRT, 4.0% dRT, p = 0.030). On univariable and multivariable analysis, a worse ECOG performance status, increasing clinical T descriptor, and increasing clinical N descriptor were prognostic for a worse OS. After adjusting for these variables, dRT was associated with a worse OS [dRT/dCRT HR 1.79 (1.20-2.68) p=0.005]. Conclusions: Definitive RT/CRT for LRC ACA of the E/GEJ is associated with poor OS. Long-term survival is nonetheless possible in a small number of pts and appears more likely after dCRT.
Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal malignancy patients.
Authors: Kamiya Mariko , Aoyama Toru , Sugano Nobuhiro , Sato Tsutomu , Yamamoto Naoto , Taguri Masataka , Yamanaka Takeharu , Oshima Takashi , Yukawa Norio , Rino Yasushi , Masuda Munetaka
Published: March 2017

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Background: Delirium is one of the common postoperative complications. When postoperative delirium occurred, the patient management becomes much more difficult, leading to functional recovery delay, and is also associated with postoperative mortality and morbidity. Although many attempts to prevent and treat delirium have been developed, a higher level of evidence is needed. In the present study, we evaluated the efficacy and safety of TJ-54 (Yokukansan; one of the traditional Japanese medicines, Kampo) for the prevention and/or treatment of postoperative delirium in a randomized phase III trial for the patients receiving surgery for gastrointestinal malignancy. Methods: Patients 70 years of age or older, who were received surgery for gastrointestinal malignancy were eligible in this study. The 167 eligible patients were randomly assigned on a 1:1 ratio to receive TJ-54 or control during their perioperative care (between day 7 before surgery and day 4 after surgery). The signs and symptoms of delirium were assessed with using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV by the investigator during perioperative period. Results: We analyzed 167 eligible gastrointestinal malignancy patients (TJ-54; 83, control; 84). There were no disparities between the two PPS randomized groups. The incidence of delirium was 7.2% (6 patients) in the TJ-54 group and 10.7% (9 patients) in the control group with no significant difference (p=0.431), also no significant difference was observed in duration of delirium between the two groups (p=0.477). The ratio of patients who needed some kind of the medication which including treatment of delirium were significantly less in the TJ-54 group than in the control group (p=0.037). Conclusions: In this study, TJ-54 did not demonstrate the contribution to prevention of occurring delirium in the patients receiving surgery for gastrointestinal malignancy. However, TJ-54 might be effective in reducing the medication for treating delirium after surgery for gastrointestinal malignancy. Clinical trial information: 000005423.
Recurrence patterns of gastric cancer in the era of preoperative therapy.
Authors: Ikoma Naruhiko , Chen Hsiang-Chun , Wang Xuemei , Blum Murphy Mariela A. , Estrella Jeannelyn , Fournier Keith F. , Mansfield Paul F. , Ajani Jaffer A. , Badgwell Brian D.
Published: March 2017

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Background: The purpose of this study was to determine the disease sites and survival durations of patients who developed a recurrence after undergoing gastrectomy for adenocarcinoma. Methods: We collected data from a prospectively maintained database of gastric cancer patients who underwent potentially curative resection of gastric or gastroesophageal cancer at our institution from 1995-2014. Univariate and multivariate analyses were performed to determine the associations between clinicopathologic factors and treatment outcomes. Results: We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (IQR, 53-71 years), and 60% were male. The most common EUS stages were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. The majority (76%) of patients underwent extended (D1+/D2) lymphadenectomy, and the median number of examined lymph nodes was 21 (IQR, 14-29). Of the 488 patients, 125 (26%) experienced recurrence during follow up. The sites of recurrence were locoregional (n = 19 [15%]), peritoneal (n = 61 [49%]), and non-peritoneal distant at any site (n = 67 [53.6%]). The site of recurrence was not associated with neoadjuvant therapy (p = 0.35). The median time from the primary resection to recurrence was 2.7 years (95% CI, 0.8-3.2 years) for locoregional, 1.3 (0.7-1.7) for peritoneum, and 0.6 (0.5-0.9) for distant disease (p = 0.01). The median overall survival time from recurrence was 1.0 year (95% CI, 0.5-3.1 years) for locoregional, 0.6 (0.4-0.9) for peritoneum, and 0.8 (0.5-1.0) for distant recurrence (p = 0.05). A multivariate analysis revealed that age ≥ 65 years (HR, 1.52 [95% CI, 1.12-2.05 years]; p = 0.01) and advanced EUS T stage (3.06 [2.10-4.46]; p < 0.001) were associated with a shorter recurrence-free survival duration. Conclusions: Peritoneal carcinomatosis was the most common site of recurrence after curative resection of gastric cancer, with associated poor survival, and was not associated with the use of neoadjuvant therapy. Future trials should focus on treatment of the peritoneum, which may improve the survival of patients with advanced gastric cancer.
Central validation of HER2 status to determine heterogeneity of marker expression in HER2-positive gastric cancer (GC).
Authors: Haffner Ivonne , Luber Birgit , Maier Dieter , Kretzschmar Albrecht , Fischer von Weikersthal Ludwig , Ahlborn Miriam , Riera-Knorrenschild Jorge , Rau Beate , Weissinger Florian , Fuxius Stefan , Neumann Steffen , Decker Thomas , Schierle Katrin , Wittekind Christian , Lordick Florian
Published: March 2017

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Background: 10-20% of GC overexpress HER2, a membrane-bound receptor tyrosine kinase (RTK) which belongs to the epidermal growth factor receptor (EGFR) family. Drugs directed against HER2 have shown mixed success in the treatment of advanced GC. While trastuzumab, a monoclonal antibody addressing HER2 has been approved for 1st-line treatment of stage IV HER2+ GC, trastuzumab-emtansine failed to improve outcomes in 2nd-line and lapatinib, a small molecular RTK inhibitor of HER2 and EGFR was not effective in 1st- and 2nd-line. Until now, primary and secondary resistance against HER2-directed treatment of GC is not well understood. The VARIANZ study aims to assess mechanisms influencing efficacy of trastuzumab in HER2+ GC. Methods: In this multicenter study, patients who receive medical treatment for advanced GC are recruited in 31 sites. The HER2 status is verified centrally by two dedicated GI pathologists using immunohistochemistry (IHC, DCS, HI608C0I) and chromogenic-in-situ hybridization (CISH, Zytomed Systems, C-3022-40). Results: From May 2014 to August 2016, we have enrolled 316 patients in this ongoing project (72% male, median age 64 years). At present, 281 samples were fully characterized for the HER2 status. According to criteria from the Trastuzumab for Gastric Cancer (ToGA) study, 53 of 281 samples were characterized HER2+ by central testing. In 38 samples that were diagnosed as HER2+ by local pathologists the HER2 status could not be verified centrally. 7 HER2- probes in local testing were characterized as HER2+ by central testing. The overall deviation rate between local and central testing is 27%. HER2 gene amplification in HER2+ tumors with deviating local report (mean HER2/CEP17: 2.8 ± 0.9, range between 1.9 and 4.5) is lower compared to HER2+ tumors and confirmed local report (mean HER2/CEP17: 5.5 ± 2.6; range between 2.2 and 11.0; p = 0.014). Conclusions: HER2-expression in GC is heterogeneous and still not easy to assess. Variability between local and central HER2 assessment is significant. Robust biomarkers predicting response or resistance to HER2 and other target therapies are needed. Clinical trial information: NCT02305043.
Standard personalized medicine platform integrating clinical genomics and patient-derived xenograft models for gastric cancer.
Authors: Yang Han-Kwang , Lee Hyuk-Joon , Suh Yun-Suhk , Kim Min Jung , Kim Woo Ho , Na Deukchae , Park Hansoo , Kim Jong-Il , Lee Charles
Published: March 2017

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Background: Research and development of patient-derived tumor xenograft (PDX) model has gradually increased for preclinical study as well as tailored treatment of patient individual. We report our experience of development and application of gastric cancer PDX model using NSG mouse. Methods: From May 2014, primary tumor tissue and corresponding normal mucosa were sampled immediately after gastrectomy to reduce ischemic time. Corresponding normal mucosa was obtained as far as possible from tumor. Size of samples for implantation is 2x2x1mm/unit. After harvest, these tissue were injected at both flank of NSG mouse (2 times of injection per each mouse). If engrafted primary tissue (P0) would not grow after 90 days of engraftment or grow up to 2,000mm3/unit, model was considered as graduated. Genomic profiles from exome and RNA sequencing was analyzed between human primary tumor and P0. Results: We implanted gastric cancer tissue from 341 patients, and identified 135 P0 cases as tumor growth models (124 cases of primary tumor, 5 cases of metastatic nodes, and 6 cases of paired primary tumor and metastatic nodules). The mean time between fresh tissue sample and reposition at refrigerator was 18 min. The success rate of implantation was 39.6% (135/341). Out of P0 tumor growth models, 51 cases were diagnosed as adenocarcinoma, and 49 cases as lymphoid proliferation pathologically. Compaing pathologic and genomic data between primary tumors and P0 tumors identified as adenocarcinomas, we observed a similar frequency of genome-wide copy number (gain/loss) across overall cases. Moreover, genomic variations between each primary and P0 sample was also similar as shown in a Circos plot indicating somatic mutations, loss of heterozygosity and copy number variations. Relative high expression levels of cancer-related genes including MET and ERBB2 of primary tumors maintained in corresponding P0, when compared to expression levels in normal tissues. Conclusions: We successfully established gastric cancer PDX model which will be a useful tool for tumor biology study and the preclinical study in gastric cancer.
ARDS in the setting of FOLFOX/cetuximab based chemoradiotherapy for locally advanced esophageal adenocarcinoma (E2205).
Authors: Kasozi Ramla NAMISANGO , Choudhary Anita , Gibson Michael K. , Catalano Paul J. , Kleinberg Lawrence , Staley Charles A. , Sokoll Lori J. , Song Wei , Mulcahy Mary Frances , Leichman Lawrence P. , Benson Al Bowen
Published: March 2017

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Background: E2205 was a single-arm, phase II trial that added an epidermal growth factor receptor (EGF-R) inhibitor, cetuximab (C), to CRT. The trial was closed early due to pulmonary toxicity. We investigated the potential role of cetuximab and type of radiation (IMRT vs conventional). Methods: Patients were treated with CRT: Oxaliplatin (OX) 85mg/m2 days 1,15,29; infusional 5-fluorouracil (5-FU) 180mg/m2/24hours x 35 days; C 400mg/m2 day 1 then 250mg/m2days 8,15,22,29 and radiation (IMRT allowed) 180cGy/day x 25 fractions (Monday-Friday), followed by esophagectomy. Results: Of 21 eligible patients enrolled, 17 had surgery (died pulmonary embolism 4 days after CRT, died G3 diarrhea/PD during CRT, died sepsis/hypoxia during CRT). pCR = 7/17. Four post-op deaths from acute respiratory distress syndrome (ARDS) resulted in 7 total study-related deaths. None of the patients who received IMRT died (0/3). 1/6 had ARDS if more than 4 fields with conventional or 3D planning was used. 3 of 15 treated with RT that met the criteria of E1201 guidelines (no more than 3-4 RT fields, normal lung more than 2 cm outside the target volume < 40 Gy, no IMRT). Overall, there was no demonstrable association of ARDS to radiation technique: 4/22 overall, 0/3 if IMRT was used. Conclusions: This regimen is not recommended. There is no clear association between use of IMRT and ARDS. The cause of ARDS remains undetermined. Cetuximab may have played a role. Clinical trial information: NCT00551759.
Short and long term outcomes with robotic assisted esophagectomy.
Authors: Meredith Kenneth L , Huston Jamie , Briceno Pedro , Shridhar Ravi
Published: March 2017

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Background: Surgical resection remains piviotal in the management of patients with esophageal cancer. Minimally invasive esophagectomy(MIE) has demonstrated superior operative outcomes compared to the open approaches. Robotic assistance has potential to further improve outcomes, however the long-term follow with this technique is lacking. Methods: Utilizing the National Cancer Database we identified patients who underwent esophagectomy and stratified by approach: open (OE), laparoscopic (LE) or robotic (RE). Baseline comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis as appropriate. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was performed using the Kaplan-Meier method comparing survival curves with the log-rank test. All statistical tests were two-sided and α (type I) error < 0.05 was considered significant. Results: We identified 18,869 patients who underwent esophagectomy with a mean age of 65 ± 10 years. There were 10,882 (57.7%) OE, 7,102 (37.6%) LE, and 885 (4.6%) RE. There was no difference in T stage or N stage among groups. Thirty and 90-day mortality was 3.2% and 6.9% and was lower in the MIE groups compared to open 6.2% vs 7.9% p < 0.001. Median length of hospitalization in RE, LE and OE was comparable at 9, 10, and 10 days respectively, p = 0.06. Neoadjuvant therapy was administered in 9,118 (48.3%) patients and was more frequent in the RE 66.0% vs 57.5% OE vs LE 32% p < 0.001. Oncologic quality as indicated by R0 resections and median lymph node harvested were improved in patients undergoing RE: 836 (94.9%) and 16, LE: 5,322 (86.7%) and 4, and OE: 9,631 (91.1%) and 12, p < 0.001. The median and 5-year survival by approach: RE, LE and OE was 54.4 months and 47.7%, 55.6 months and 50.3%, and 47.4 months and 43.7%, p < 0.001. MVA demonstrated that age, location, neoadjuvant therapy, T-stage, N-stage, hospital volume, MIE, and R0 resections were predictive of survival. Conclusions: Short and long-term outcomes with robotic assisted esophagectomy demonstrates low mortality with superior R0 resections and lymph node harvest. Overall survival is benefited in patients undergoing MIE.
A Phase I/II trial of fruquintinib in combination with paclitaxel for second-line treatment in patients with advanced gastric cancer.
Authors: Xu Rui-hua , Zhang Dongsheng , Shen Lin , LI Jin , Huang Jing , Gong Jifang , Guo Weijian , Zhang Yang , Fan Songhua , Li Ke , Hua Ye , Su Weiguo
Published: March 2017

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Background: Advanced gastric cancer (AGC) is a major problem particularly in Asian countries. The treatment options are limited after standard first line chemotherapy. This phase I/II study aimed to evaluate the tolerability, pharmacokinetics and preliminary efficacy of fruquintinib, a selective oral VEGFR inhibitor, combined with paclitaxel as second-line therapy in Chinese patients with AGC. Methods: This open arm phase I/II trial (NCT02415023) consisted of dose finding and dose expansion stages. In the dose finding stage, 3 dose levels of fruquintinib (2, 3, 4 mg; once daily for 3 weeks) were evaluated in combination with standard 80 mg/m2 paclitaxel (once weekly on Days 1, 8 and 15) in a 28-day cycle until the maximum tolerated dose or recommended phase II dose (RP2D) was reached. Additional patients were enrolled at the RP2D to further assess the efficacy, safety and pharmacokinetic profile. Results: As of Sept. 10, 2016, a total of 32 patients were enrolled including 15 during dose escalation. The RP2D regimen was determined to be fruquintinib 4mg daily combined with paclitaxel 80mg/m2 weekly for 3 weeks followed by 1 week off in a 4 week cycle. Two patients at 4mg experienced dose-limiting toxicity, both with febrile neutropenia. The grade 3 or 4 treatment emergent adverse events were neutropenia (40.6%), leukopenia (28.1%), decreased hemoglobin (6.25%), hand-foot skin reaction (6.25%), neurophlegmon (6.25%), and hypertension (6.25%), more frequent in the 4mg cohort. At steady state, Fruquintinib AUC (AUCss) increased dose-proportionally and within the historic range as a single agent, while paclitaxel exposure, at the RP2D regimen, increased by approximately 30% compared to the AUC prior to fruqintinib dosing. Twenty-eight of 32 patients were evaluable for response, and of these, 10 patients had partial response (Objective Response Rate = 35.7%), 9 patients experienced stable disease for at least 8 weeks (Disease Control Rate = 67.9%). At RP2D, ≥ 16w-PFS = 50% and ≥ 7m-OS = 50%. Conclusions: Combination of fruquintinb and paclitaxel appeared to be generally well-tolerated with promising tumor response. Further evaluation in a controlled phase II study is warranted. Clinical trial information: NCT02415023.
Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in oesphageal squamous cell carcinoma.
Authors: Jiang Yu-Bo , Xu Jian-Ming , Lo Anthony W.I. , Wong Angela , Chen Wen-Feng , Wang Yan , Lin Li
Published: March 2017

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Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression and tumor-infiltrating immune cells (TILs) in tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 428 archival formalin-fixed, paraffin-embedded (FFPE) ESCC samples were collected between 2004 and 2014 from treatment naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy. Expression of PD-L1 was assessed by IHC. The degree of TILs infiltration was evaluated by examining the H&E-stained specimens. Associations of PD-L1 expression and TILs with clinicopathological features were evaluated by non-zero correlation test. Survival distribution was compared by Kaplan-Meier and a log-rank test. The median follow-up time was 34.4 months(0.3-147.1 m). Changes of PD-L1 expression between paired tumor samples, which were collected before and after chemotherapy (2 cycles and 4 cycles or more), were also evaluated. Results: In the entire cohort, 79.7% (341/428) of specimens were PD-L1+ (defined as having ≥ 1% of tumor cell membranes showing ≥ 1+ intensity). In the intent-to-treat group (patients received curative esophagectomy or definitive chemoradiation therapy), PD-L1 positivity was associated with a significantly poorer DFS and OS. Neither PFS nor OS in palliative chemotherapy group presented a significant difference corresponding to PD-L1 expression. Furthermore, PD-L1 expression was positively associated with TIL density. Changes in PD-L1 expression was examined in 17 paired tumor tissues collected before and after treatments. Results showed that an increase in PD-L1 expression was associated with disease progression, a decrease in PD-L1 expression was associated with satisfactory chemotherapy treatment response. Conclusions: PositivePD-L1 expression was associated with a significantly worse prognosis in ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.