bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a combined diet plus exercise intervention on weight loss, physical fitness, and cancer-related fatigue among Japanese women with breast cancer.
Authors: Okumatsu Koki , Tsujimoto Takehiko , Seki Akina , Yamauchi Teruo , Yamauchi Hideko , Tanaka Kiyoji
Published: September 2018

e21658

Background: Weight gain, deterioration of physical fitness, and cancer-related fatigue often occur in the breast cancer patients mainly due to endocrine therapy. A number of previous studies have reported that obesity increases the risk of breast cancer recurrence and death, while exercise habituation improves physical fitness and fatigue among breast cancer patients. However, almost all studies have been conducted in the Western community and there are few studies focused on Asian women who may have lower BMI compared with the Western ones. Therefore, we investigated whether a combined diet plus exercise program affects weight loss, physical fitness and fatigue indices among Japanese breast cancer patients undergoing endocrine therapies. Methods: Thirty-two Japanese women with breast cancer undergoing endocrine therapy (age; 50±6 years, body weight; 57±10 kg) were voluntarily assigned to either intervention group (n = 21) or control group (n = 11). The intervention group completed a 12-week combined diet plus exercise program, consisting of weekly diet instruction classes aimed at maintaining a nutritionally well-balanced 1,200 kcal/d diet and a weekly 90-min exercise session. Anthropometric indices, physical fitness, blood sample and cancer-related fatigue were measured at baseline and after the 12-week program. Results: All of the 21 women completed the 12-week program. Mean weight loss was 8.7% of the initial weight in the intervention group and 0.1% in the control group ( P < . 001). Significant improvements were observed in cardiorespiratory fitness ( P < .01), flexibility ( P < .01) and agility ( P < .01) in the intervention group. Cancer related-fatigue scores decreased by 7.9 points (39%) among the intervention group ( P < .001), while it remained essentially unchanged among the control group. No adverse events were reported in the intervention group. Conclusions: A combined diet plus exercise program may contribute to a decrease in body weight and improvement in physical fitness and cancer-related fatigue. Further study is needed to help reduce side effects due to endocrine therapy and enhance quality of life among Asian breast cancer patients. Clinical trial information: UMIN000025890.
Prognostic factors of mortality and recurrence of malignant pleural effusion in high-risk tumors according to the LENT Score.
Authors: Abrao Fernando , de Oliveira Mariana Campello , Abreu Igor , Garcia Geisa , D'Alpino Renata D'Alpino , Marciano Carolina , Toledo Mariana Belaunde , Younes Riad N.
Published: September 2018

e21666

Background: The aim of this study was to identify predictors of overall survival (OS) and recurrence after palliative pleural procedures in patients with malignant pleural effusion (MPE) and high-risk tumors according to the LENT Score. Methods: Data was collected from our database between January 2013 and December 2015 of patients with MPE and high-risk tumors according to the LENT Score. All patients were followed-up for at least 30 days after the pleural procedure. We evaluated radiological aspects, biochemical and hematologic parameters as well as clinical features. For OS analysis, patients were divided into two groups. Group I included OS < 30 days and group II included OS > 30 days. Prognostic factors for pleural recurrence and OS were identified by univariate analysis, using Fisher's exact and Student's t-test. Subsequently, significant variables were entered into a multivariate logistic regression analysis ( p < 0.05). Results: A total of 134 patients were included. Median follow-up time for surviving patients was 56 (range: 2-623) days. High-risk primary tumors included lung (66.4%), gastrointestinal (24.6%) , sarcoma (3.7%), urologic (3.7%) and others (1.5%). Forty-four patients in Group I had OS < 30 days while 22 patients had MPE recurrence. Factors affecting OS in univariate analysis were: type of procedure, ECOG, albumin, leukocytes, neutrophil to lymphocyte ratio( NRL) and hemoglobin. Factors affecting recurrence were: type of procedure, chemotherapy line (CT), albumin and platelets. In multivariate analysis for Group I, type of procedure (therapeutic pleural aspiration – TPA) ( p= 0.011), ECOG 3/4 ( p= 0.004), NLR > 5 ( p= 0.037) and leukocytes > 8000 ( p= 0.042) were identified as independent predictors of OS. In terms of recurrence, only CT beyond first line ( p = 0.042) was identified as an independent prognostic factor. Conclusions: Patients with MPE who underwent TPA, had ECOG 3/4, leukocytes > 8000, and NLR > 5 were significantly associated with shorter OS,. CT beyond first line was associated with recurrence. The identification of these prognostic factors may assist physicians in choosing the optimal palliative technique.
Developing and piloting an electronic telephone triage application.
Authors: Ellis Peter G. , Carlisle Christine , Ford Colleen F. , Nikolajski Peggy , Reidmiller Carol , Stewart Leslie , Rushford Justin S. , Barry Amanda , Krebs Melinda
Published: September 2018

e21680

Background: With the shift of cancer care to the outpatient setting, telephone triage is a vital part of today’s oncology practice. UPMC CancerCenter (UPMC) desires to streamline the current telephone triage process across its 31 outpatient clinics. UPMC and Via Oncology collaborated to develop and pilot a prototype of an electronic telephone triage application. The key components of the prototype were defined as decision support, EHR integration, reporting, and workflow management. Methods: A prototype application, Symptom Manager (SM), was developed and piloted with 4 nurses at 3 outpatient clinics. Front office staff registered inbound calls in SM, which populated a phone triage queue. The nurse was prompted to enter information about the call. Decision support materials were displayed for reference, including algorithms for symptom assessment, adjudication, and treatment. The output was a structured summary of the encounter that was copied to the patient’s chart. From the queue, the nurse was also prompted to make outbound calls for symptom reassessment. A feedback session with the nurse users and institution leadership was held following the pilot. Results: A total of 235 inbound calls were captured in the application, of which 74 (31.5%) were symptom-related. Additional data fields collected during the pilot included symptom, adjudication, time elapsed for callback, and symptom status at follow up. The ability to extract and report on data of this type was viewed as valuable for quality and process improvement. The nurse users praised SM’s ease of use, but prototype performance issues shortened the pilot. They indicated that the standardized documentation increased efficiency. Requests for future enhancements included deeper EHR integration and additional fields for data capture. Conclusions: This pilot provided the feedback necessary to develop the latest version of SM which begins roll out across UPMC in November 2016 and includes EMR integration. An update on the software and additional data captured during the pilot will be provided at presentation.
Correlation between immunoglobulin dose and incidence of severe and serious infections in secondary immunodeficiencies.
Authors: Ehlers Hans-Ulrich , Otremba Burkhard Joerg , Plath Margarete , Slawik Hans R. , Innig Georg , Pfruender Dietmar
Published: September 2018

e21686

Background: In an interim analysis of an ongoing multicenter observational study on the efficacy and safety of the polyvalent i.v. immunoglobulin product (IVIG) Privigen, we investigated a possible correlation between the two mostly used treatment regimens in Germany - 10 g or 20 g once a month - and the incidence of severe and serious infections in secondary immunodeficiencies (SID). Methods: All patients fulfilling the following criteria were included in this analysis: 1) SID; 2) observation period ≥120 d; 3) ≥6 Privigen infusions; 4) stable dosing, defined as identical doses from the 2nd up to the last administration (a differing loading or test dose at baseline was accepted); 5) a series of at least 4 consecutive dosing intervals each with a duration of at least 21 d and not more than 35 d (any time during the observation period); 6) no other IVIG indication than SID. The cut-off date was Dec. 19, 2016. Results: 835 patients (454 m, 381 f; average 68 years, 76 kg) in 112 centers fulfilled the above criteria. The most frequent underlying diseases were CLL (n = 422), myeloma (175) and NHL (182). The mean observation period was 20.5 mo; the median dosing interval was 28 d. Most patients had a stable Privigen dosing of either 10 g (n = 575; 69%) or 20 g (n = 192; 23%); 68 patients (8%) received other dosages. In order to reduce potential confounding effects of varying dosing intervals, only intervals ( = cycles) complying with the following "steady-state rules" were included in the analysis: 1) duration 21-35 d; 2) each of the 3 preceding intervals also 21-35 d long. 7,858 out of 15,687 treatment cycles (50%, all dosages) complied with these rules and were evaluated for severe and serious infections (acc. to FDA criteria). With the 10 g regimen, 34 severe or serious infections occurred in 5,306 evaluable treatment cycles, while with the 20 g regimen, it was only 2 in 1,851 (p = 0.003). This corresponds to rates of 8.3 vs. 1.4 severe/serious infections per 100 patient years (about half of them pneumonias). There was no increase of reported adverse reactions with the higher dose. Conclusions: With a monthly dose of only 10 g IVIG compared with 20 g, adult SID patients have a considerably higher risk of severe and serious infections.
The effect of clinical outcome on patient's perception of physician compassion: A randomized clinical trial (RCT).
Authors: Tanco Kimberson , Azhar Ahsan , Rhondali Wadih , Rodriguez-Nunez Alfredo , Liu Diane D , Wu Jimin , Baile Walter F. , Bruera Eduardo
Published: September 2018

e21694

Background: We previously found in a RCT video study that patients perceived a physician delivering a more optimistic message as more compassionate and professional. The primary objective of this study was to determine if the clinical outcome modifies the patient’s perception of physician compassion. Methods: 128 patients were randomized to observe a standardized video depicting a physician discussing treatment information (more optimistic [MO] vs. less optimistic message [LO]) with a patient with advanced cancer followed by a vignette depicting the clinical outcome of the patient who continued to decline and now under hospice care. Both physicians displayed identical number of empathetic statements (5) and posture. Surveys were completed after the video and repeated after the vignette including the Physician Compassion Questionnaire (0 = best, 50 = worst). Actors and patients were blinded to the purpose of the study. Investigators were blinded to the video observed by the patient. Results: No significant difference was found in change in compassion scores between [p = 0.40] and within each group (MO vs. LO) after the vignette and video [mean difference(SD): MO 1.7(8.74) p = 0.47 vs LO 0.89(10.24) p = 0.12]. There was a significant decrease of impression of the physician within each group [mean difference(SD): MO -0.79(1.62) p < 0.0001 vs LO -1.17(1.91) p < 0.0001]. There was a significant decrease in total professionalism score within each group [mean difference(SD): MO -0.88(2.25) p = 0.0022 vs LO -0.76(2.22) p = 0.0094]. Overall patient preference decreased for the MO group for the physician being their own physician [mean difference(SD) -0.29(0.77) p = 0.0049] and to recommend the physician to their family [mean difference(SD) -0.29(0.71) p = 0.0009]. Conclusions: The perception of physician compassion was not affected by the actual outcome of the patient. However, the physician was considered less professional. Furthermore, there was also worse preference for the more optimistic physician as physician for self and family after the poor outcome (vignette). More research is necessary to understand the association of clinical outcome and patient perception of physician attributes. Clinical trial information: NCT02498899.
Evaluation of the nutritional status in children with acute lymphoblastic leukemia and its effect on the outcome of induction in a developing country.
Authors: Khalid Arifa ,   Syed Nasir Bukhari, Alia Ahmed, Mahwish Faizan, Safia Khan
Published: September 2018

e22004

Background: Acute Lymphoblastic Leukemia (ALL) is the most frequently occurring cancer among the children and adolescents. Cure rate is improved up to 90% with early diagnosis and better supportive care. Under nutrition among pediatric acute leukemia patients is more in developing countries 60% as compared to 10% in developed countries. The poor nutritional status is found to be associated with poor outcome. Therefore, optimum nutritional support can play a vital role in the outcome of induction. Methods: The population of research was newly diagnosed patients of ALL, reported from June 2016 to January 2017, in the Pediatric Hematology & Oncology Department of Children’s Hospital, Lahore. A sample of 151 patients of Acute Lymphoblastic Leukemia was analyzed prospectively. The study subjects were stratified into undernourished & well nourished based on the Z-score for weight for age.The data was collected irrespective of any discrimination based on demographic factors. and the following characters were recorded in both the groups: Mid treatment & end of treatment bone marrow response, culture proved infection, duration of hospital stay & outcome. Results: Among the 151 patients of ALL 80.1 % (n = 121) were Pre-B and 19.8% (n = 30) were Pre-T .Male to female ratio was 1.5:1. Malnutrition was established in 98 (64.9%) patients on the bases of Z-score. The undernourished group had significantly increased rate of culture proven sepsis (11% vs. 2%) respectively and required longer duration of hospital stay (p < 0.001).Rapid early response was observed in 21.8% malnourished and 32.8% well-nourished patients. End of treatment complete response was recorded in 63% vs. 69.1% respectively with significant p value. Expiry was observed in 9.1% malnourished patients. Conclusions: On the basis of this study it is concluded that the nutritional status at the initial presentation had a significant impact on the induction outcome. The undernourished patients of ALL are more prone to infections, requiring longer duration of hospital stay. Therefore, optimum nutritional support to such patients can help to decrease the chances of infections & ultimately improve the outcome.
Pediatric cancer registry Turkey: 2009-2016 (TPOG & TPHD).
Authors: Kutluk M. Tezer , Yesilipek Akif
Published: September 2018

e22015

Background: Each year 300.000 new cancer cases are expected in children & adolescents aged 0-19 years at global level. Although the long term survival rates have been improved to 85% in high income countries it is lower than this LMICs. Pediatric registries are essential for planning, evaluation, comparison for pediatric cancer care. This study focuses to pediatric cancer registry in Turkey. Methods: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association established a WEB based cancer registry in Turkey in 2002. The registry information for 2002-2008 was presented earlier. This study, now, is including the distribution of pediatric cancer registry for the years of 2009-2016. International Childhood Classification System was used in classification. Basic demographic findings, ICD-O-3 morphology & topography codes were recorded for each cases. Results: During the 8 years from 2009 to 2016, 13123 pediatric cancer cases were recorded. For all cases, median age was 6.5 year (0–17; M/F 7356/5759, 3 hermaphrodite). Age distribution was 0–4 yrs, 41.3%; 5–9 yrs, 24.3%; 10–14 yrs , 23.2%; 15–19 yrs, 11.0%. 7 cases older than were registered (%0.1). The distribution of tumor types were [number of cases, percentage of total, median age years, M/F]: Leukemia (3751, 28.6%, 5.5, 2148/1603); Lymphoma and other RES tumors (2381, 18.1%, 9.5, 1613/763); CNS [brain & spinal] (1672, 12.7% , 7.13, 908/764); Symphatetic system (1053, 8.0% , 2.42, 550/503); Retinoblastoma (339, 2.6%, 1.33, 188/151); Renal (675, 5.1%, 3.33, 314/361); Liver (217, 1.7% , 1.75, 116/101); Malignant bone (892, 6.8 %, 12.55, 486/406); Soft tissue sarcomas (868, 6.6% , 7.21, 518/350); Germ cell (818, 6.2%, 7.58, 292/523); Carcinoma and other malignant epithelial (391, 3.0% , 13.60, 191/200); Other/non-specific malignant (66, 0.5%, 6.54, 32/34) tumors. Five year survival rate was found as 69.5 %. Conclusions: This registry since 2002 became a critical source for health care professionals in Turkey. Survival rates for children increased from 65% to 70% based on the latest information from this study. This is compatible with Turkey’s development level as an upper middle income country. This data also allows us to use the registry information at national and international studies.
Relationship between inhibin B, puberty, and secondary sex characteristics in childhood cancer survivors.
Authors: Unal Emel Cabi , Simsek Gulsum KADIOGLU , Tacyildiz Nurdan , Dincaslan Handan , Yavuz Gulsan , Siklar Zeynep , Berberoglu Merih
Published: September 2018

e22018

Background: Prognosis in childhood cancer improved with intensive tx regimens, improved survival,concerns&issues related to QOL become crucial point of interest. Methods: Gonadal functions were studied in 33M,22F survivors of childhood cancers treated w gonadotoxic chemotherapy,with HL,NHL, ALL,Osteosarcoma,Rhabdomyosarcoma. All event-free survivors for > 1year, postpubertal, > 15 years of age at the time of study, 8 pts received abdominal RT,9 pts had prophylactic cranial RT. Patients answered a questionnaire concerning sexual functions,underwent a comprehensive physical examination, clinical evaluation of pubertal development, secondary sex characteristics,menstrual history, measurement of FSH, LH,sex steroids, inhibinB, compared w age-matched controls. Results: All patients had normal pubertal development for age,Females showed no significant differences in secondary sex characteristics, than controls &the progression of puberty, adult-type hair growth in males were significantly late (P:0.002) than controls, low levels of testosterone were found in all.Pubertal development normal in female patients, w elevated FSH than control.(P:0.025)FSH levels in males didn't differ,inhibinB levels were significantly lower than control.(P:0.022).We couldn't demonstrate significant association with age at dx,time elapsed after tx,dx type,gonadotoxic agent.. Conclusions: Our study showed tx of childhood cancer could lead to gonadal toxicity.Our study investigating relationship between puberty,secondary sex characteristics,inhibinB in early postpubertal stage. Findings suggest that, even in the presence of gonadal toxicity, in females, secondary sex characteristics&puberty weren't affected.Inhibin B as a marker for gonadal toxicity is not superior to FSH. In fact that, we found a decrease in InhibinB as the only marker of gonadal dysfunction in males.With normal pubertal development &FSH levels in postpubertal males,low detection of inhibinB can be used as an early,sensitive marker for gonadal toxicity.Late adult-type hair growth with low testosterone demonstrating chemotherapy-induced testicular damage. Clinical trial information: BAP-2734.
Cross sectional survey of male adolescent and young adult (AYA) childhood cancer survivors regarding fertility.
Authors: Harrison Douglas James , Welch Jennifer JG , Matook Katherine , Schwartz Cindy L.
Published: September 2018

e22019

Background: 30% of male cancer patients receive gonadotoxic therapy that results in infertility. Research exploring male cancer survivors’ attitudes regarding risk of infertility has focused on adults. To understand how AYA survivors perceive their risk of fertility, a cross sectional survey was conducted of male AYA survivors of pediatric cancer. Methods: After IRB approval, the home institution’s database was queried to identify subjects. Eligibility criteria included male survivors between the ages of 15-25 years who had completed treatment in the last 5 years. A self-report survey was designed to assess perspectives of male survivors of pediatric cancer on survivorship with a focus on fertility. Descriptive analysis was performed for all demographic variables collected. To identify whether there was an association between specific demographic variables on survivors’ perspectives regarding their fertility, Fisher’s Exact Test was used (cut-off p-value: 0.05). Results: 33 patients enrolled. Two were deemed ineligible (n = 31). Median age was 20 yrs. Disease and treatment demographics encompassed a wide range of diagnoses and therapy. Subjects were evenly divided as to whether they expected difficulty siring a successful pregnancy. No demographic variable was significantly associated with survivors’ belief that they would have difficulty. A majority recalled being informed during treatment that they may have difficulty siring a pregnancy and having been offered sperm cryopreservation. Of the 22 patients who did not participate in cryopreservation, 12 reported they would have done so to protect their fertility; one would not. Subjects were split as to whether they would have waited to start treatment to allow for cryopreservation. Conclusions: Male survivors of pediatric malignancy are concerned with their future fertility and are informed regarding their risk. Male patients should be counseled regarding their fertility risk and options for fertility preservation. [Table: see text]
Areas for quality improvement in pediatric supportive oncology services.
Authors: Reichek Jennifer , Weldon Christine B. , Ganesan Rani , Suh Eugene , Dighe Dipti , Trosman Julia Rachel , Choi Daniel K. , Berardi Rosa , Sanford Stacy D. , Downing Kim , Owen Erika D , Kim Molly , Boss Kathleen , Kniola Allison , Newmark Monica , Pillay Smiley Natasha , Brown Melanie
Published: September 2018

e22022

Background: In 2013, the Institute of Medicine report recommended that supportive oncology services be initiated at time of diagnosis. Providers of pediatric cancer care in the Chicagoland community, supported by The Coleman Foundation, sought to define areas for quality improvement of supportive oncology delivery to children. Methods: Focus groups and surveys with clinicians providing pediatric cancer care and supportive services at 14 sites were used to prioritize areas needing improvement. Results: 100% (14/14) of sites participated. Of the eligible sites, 6 were pediatric cancer treatment sites and 8 cancer care community organizations. Sites demonstrated consistent agreement for 8 of the 12 areas of focus for improvement. Over 50% of sites reported areas of focus (table) as important or very important. Conclusions: Sites identified the need for quality improvement in delivery of psychosocial, survivorship and palliative care for pediatric cancer patients. Survey results demonstrate a need for collaboration and efforts to guide care delivery improvement across sites. [Table: see text]
Next generation sequencing (NGS) in wild type GISTs.
Authors: Qiu Haibo , Zhuang Wei , Wu Ting , Huang Min , Zhou Zhiwei , Wang Xueding
Published: September 2018

e22507

Background: The majority driven mutation of GIST are located in KIT and PDGFRA. A proportion of the remaining 10% of GIST without KIT or PDGFRA mutations called wild type GIST (wt-GIST). It is poor response to imatinib, sunitinib or regorafenib in these wt-GIST patients. It is lack of precise drug target of wt-GIST. We analyzed next generation exome sequencing (NGS) results in wt-GISTs. Methods: Whole exome sequencing was performed on freezing tumor tissue and peripheral blood DNA with 100X sequencing depth. The low frequency somatic mutation was confirmed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and Sanger sequencing. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: A total of 11 wt-GIST samples were analyzed. ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) was mutated in one CD117 negative patients with 5.3% mutation frequency of c. 364G > A (p. A122T). Sanger sequencing couldn’t found the ROS1 mutated in tumor tissue. But this low frequency somatic mutation was verified by MALDI-TOF. Conclusions: This is the first report showed a new ROS1 somatic mutation in wt-GIST. Our results indicated that ROS1 could be a new possible driven mutation in wt-GIST. ROS1 rearrangement have been described in a subset of non-small-cell lung cancers (NSCLC). Crizotinib shows a potent curative effect in ROS1 rearrangement NSCLC. Therefore, crizotinib might be an appropriate drug to GIST patients with mutated ROS1.
Clinical evidence from two phase 3 trials supporting statistical adjustment methods to assess confounding impact of treatment crossover on overall survival (OS).
Authors: Kappeler Christian , Wagner Andrea , Kalmus Joachim , Brose Marcia S. , Schlumberger Martin , Demetri George D.
Published: September 2018

e22509

Background: In controlled trials that allow patients to crossover from placebo (PBO) to active treatment (ACT) after progression, OS in PBO patients is confounded by ACT. Statistical methods to adjust OS for crossover rely on an assumption of common treatment effect (i.e. PBO to ACT crossover after progression has the same impact as ACT started at randomization). This exploratory analysis of two phase 3 trials (PBO-controlled and allowing crossover) with regorafenib in GIST and sorafenib in thyroid cancer provides evidence to support this assumption. Methods: Target lesions were assessed at baseline and at regular intervals post baseline. Progression-free survival (PFS) was assessed during double-blind (DB) treatment and secondary PFS (SPFS) in PBO patients during open-label (OL) treatment. Changes in target lesion diameter over time were estimated by a parametric model. Early tumor growth rate (TGR), defined as percent change from baseline/month in the sum of target lesion diameters, was calculated as the model curve slope at earliest time on the TGR curve. Results: SPFS during OL in PBO patients is closer to DB PFS in ACT patients than to DB PFS in PBO patients (Table). Early TGR during OL in PBO patients is closer to DB early TGR in ACT patients than to DB early TGR in PBO patients. Conclusions: Currently available statistical methods to adjust for the impact of treatment crossover are supported by clinical results from two independent randomized, controlled phase 3 studies. These results provide validity to crossover correction analyses. Clinical trial information: NCT01271712; NCT00984282. [Table: see text]
Clinicopathological features and prognosis of primary GISTs with tumor rupture in the real world.
Authors: Nishida Toshirou , Cho Haruhiko , Masuzawa Toru , Chiguchi Gaku , Tsujinaka Toshimasa , Hirota Seiichi
Published: September 2018

e22510

Background: Ruptured GIST has poor prognosis and patients (pts) with ruptured GISTs are recommended for imatinib adjuvant therapy, however, their clinicopathological features and the prognosis in the era of imatinib are unknown. Using data obtained from two different registry studies in Japan, we examined ruptured GIST patients in clinical practice. Methods: The study cohort registered 665 pts (339 male and 326 female; median age 66 yrs) with histologically-proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007. The validation cohort included 172 pts (100 and 72; median age 62.5) between 2000 and 2014. Pathological Dx was done with H&E, KIT- and DOG1-IHC. Results: Disease located in the stomach (n = 506), small intestine (n = 119), large intestine (n = 26), or others (n = 14) in the study cohort and it was 120, 37, 14 or 2 in the validation, respectively. Median tumor size was 4.0 and 5.0 cm, median mitosis 2.6 and 5.0 /50HPF, and tumor rupture was seen in 21 pts (3.2%) and 5 pts (2.9%) in the study and validation cohorts, respectively. Rupture occurred preoperatively in 12 pts and intraoperatively in 9 of the study cohort. Ruptured GISTs showed high mitotic activities (median mitosis 13.0 vs 2.5 /50HPF; P < 0.0001), larger tumor (median size 9.6 vs 4.0 cm; P = 0.0008), and were more symptomatic than non-ruptured in the study cohort. Ruptured GIST pts had more frequent relapses (P < 0.0001) and showed shorter RFS (estimated RFS = 2.4 yrs; P < 0.0001) than non-ruptured (8.4 yrs). There were no difference in age, gender, location, surgical approach, cell type, preoperative and postoperative imatinib use between two groups.These results were confirmed in the validation cohort. Ruptured GISTs showed more frequnent relapses in the peritoneum. Multivariate analysis indicated that location (HR = 1.6), size (1.07), mitosis (1.01), and rupture (4.5) were independent prognostic factors of RFS. Rupture was not always prognostic for OS, and age (1.03), gender (2.3), and mitosis (1.01) were independent prognostic factors of OS. Conclusions: Ruptured GISTs were symptomatic larger tumors with high mitotic activity and showed frequent relapses, however, it was not independently prognostic for OS in the era of imatinib.
Primary pulmonary sarcomas: The results of surgical treatment.
Authors: Golota Janusz , Rucinska Monika , Osowiecka Karolina , Orlowski Tadeusz
Published: September 2018

e22540

Background: Primary pulmonary sarcomas (PPS) are the very rare cancer type (0.01% - 0.4% of all malignant tumours of the lung). PPS can derive from stromal elements of the bronchial wall, blood vessels and connective tissue steep of lung parenchyma. The aim of the study was evaluation of PPS patients’ outcome. Methods: The analysis included 23 patients (11 males, 12 females) age 28-70 years (median 49.6 years) with PPS treated surgically in the Department of Surgery, Institute of Lung Diseases and Tuberculosis in Warsaw from 1994 to 2009. Results: There were 3 leiomyosarcomas (13%), 3 hemangiopericitomas (13%), 3 MFH (13%), 3 malignant peripheral nerve sheath tumours (13%), 3 PNET (13%), 2 fibrosarcomas (8.8%), 2 liposarcomas (8.8%), 2 sarcomas synoviale (8.8%), 1 angiosarcomas (4.3%), 1 chondrosarcomas (4.3%) (according to the 3rd edition of the WHO Classification of Tumours of Soft Tissue and Bones). There were performed 5 pneumonectomies (21.7%), 5 lobectomys (21.7%), 5 wedge resection (21.7%), 6 exploratory thoracotomys (26.1%), 2 stent inserts (8.8%). In the case of 15 patients (65%) were performed operation R0. Adjuvant therapy was used in 7 patients (30%), 3 patients (13%) received chemotherapy, 2 patients (13%) radiotherapy and 1 patient (4%) chemo-radiotherapy. Palliative chemotherapy and or radiotherapy were given to 6 patients (26%). Median overall survival (OS) was 22 months (5- and 10-years OS was 26% and 17%, respectively) and depended on sex (p = 0.006), tumor size (p = 0.02), operation R0 (p = 0.07). Conclusions: Surgery, especially operation R0, is the most effective treatment method of PPS. Subsequent studies on larger groups are necessary.
Effects of a combination of antiangiogenic and antilymphangiogenic therapies on a death receptor-5 mediated antitumor immunotherapy in mice.
Authors: Tsukita Yoko , Okazaki Tatsuma , Komatsu Riyo , Nihei Mayumi , Kobayashi Makoto , Sato Yasufumi , Yagita Hideo , Ichinose Masakazu
Published: September 2018

e23001

Background: In angiogenesis, VEGF-A and its receptor VEGFR-2, and in lymphangiogenesis, VEGF-C and VEGFR-3, play central roles. An anti-tumor immunotherapy using an agonistic antibody (Ab) to death receptor (DR)-5, the apoptosis inducing receptor, exhibits antitumor effects. VEGF-A or -C inhibition augmented the effects of immunotherapy. However, little is known about the effects of combining anti-angiogenesis, anti-lymphangiogenesis, and immunotherapy. Here, we combined sunitinib, which mainly inhibits VEGFR1-3 and PDGFRs, as anti-angiogenic and anti-lymphangiogenic therapies, with anti-DR-5 Ab as an immunotherapy in mice. Methods: Mice were injected with breast carcinoma 4T1 cells into the footpad, and treated with sunitinib and/or anti-DR-5 Ab. On day 14, mice were anesthetized, and the popliteal lymph nodes and tumors were isolated for immunohistochemistry, flow cytometry, hypoxia, and lymphatic flow analysis. To evaluate the tumor growth rate, mice were injected with 4T1 cells into the hindflank, treated with the combination or monotherapy and sacrificed on day 21. CD4+ and/or CD8+T cells were depleted by anti-CD4 and/or anti-CD8 Ab, respectively. Results: Sunitinib decreased endothelial cells, pericytes, and hypoxic area densities in the tumors suggesting blood vessel normalization. Sunitinib also decreased the amount of evans blue injected into tumors and hyaluronic acid in tumors, suggesting improved lymphatic flow. In draining lymph nodes, sunitinib and anti-DR-5 Ab combination increased the numbers of activated dendritic cells and CD8+ T cells than controls. In tumors, the combination increased the numbers of infiltrating effector CD4+FOXP3- and CD8+ T cells compared to controls. Sunitinib and anti-DR-5 Ab combination augmented the decrease in the tumor growth rate compared to each mono-therapy. CD4+ and/or CD8+ T cell depletion showed anti-tumor effects of the combination were partially CD8+T cell-dependent. Conclusions: Blood vessel normalization and improved lymphatic flow in tumors may improve circulation between the tumors and draining lymph nodes, which has a potential to augment the effects of immunotherapy.
Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy.
Authors: Kikuchi Hiroshi , Maishi Nako , Akiyama Kosuke , Morimoto Masahiro , Yanagiya Misa , Miyajima Naoto , Tsuchiya Kunihiko , Maruyama Satoshi , Abe Takashige , Hida Yasuhiro , Harabayashi Toru , Ameda Kaname , Matsumoto Ryuji , Kashiwagi Akira , Matsuno Yoshihiro , Shinohara Nobuo , Hida Kyoko ,   Hokkaido University Oncology Group
Published: September 2018

e23004

Background: ABCB1, a multidrug transporter, is encoded by multidrug resistance (MDR) 1 gene and plays a major role in drug resistance. Recently, we have reported that not only tumor cells, tumor vascular endothelial cells (TECs) also confer cancer drug resistance. We isolated TECs and found that they have various abnormalities such as aneuploidy or stemness characteristics. TECs showed resistance to Paclitaxel (PTX) with ABCB1 up-regulation. Furthermore, their resistance to PTX was abrogated by ABCB1 inhibition of TECs in vivo. In clinical urology, gemcitabine / cisplatin (GC) is standard 1st line chemotherapy for metastatic urothelial carcinoma (mUC). PTX is often selected in 2nd line chemotherapy for GC resistant cases, however the therapeutic outcomes are limited. We hypothesized that ABCB1 inhibitor/PTX combination would be more effective strategy for mUC, if TEC ABCB1 expression is upregulated. In this study, we investigated ABCB1 expression in tumor blood vessels of UC during 1st line chemotherapy. Methods: Paraffin-embedded samples were corrected from 50 patients who were performed tumor resection before and after 1st line chemotherapy. ABCB1 expressions were analyzed by immunohistochemical staining and the ratio of ABCB1 positive (+) vessels in total vessels were quantified. In vitro assays were performed to address how endothelial cells (ECs) are affected by change of tumor microenvironment during chemotherapy. Results: The ABCB1 (+) vessels were 0.00 – 16.80% (Median 0.00%) and 0.00-58.94% (Median 4.49%), before and after chemotherapy, respectively. In 32 of 50 cases (64%), the ratio of ABCB1 (+) vessels increased after 1st line chemotherapy. Additionally, gemcitabine induced MDR1 mRNA expression in ECs via NF-kB activation. Furthermore, gemcitabine and cisplatin induced IL-8 secretion from tumor cells, and MDR1 mRNA expression level was elevated in ECs. Conclusions: It was suggested that conventional chemotherapy may cause inflammatory change in tumor tissues, which causes in ABC transporter induction in tumor blood vessels. It was suggested that inhibition of ABC transporter in TECs is one of important new strategy to overcome cancer drug resistance.
Can 18F-alfatide micro-PET predict the radiotherapy response in Lewis lung carcinoma tumor-bearing C57BL/6 mice?
Authors: Wei Yuchun , Liu Ning , Huang Yong , Hu Xudong , Yuan Shuanghu
Published: September 2018

e23011

Background: Integrin αvβ3 plays a major role in angiogenesis, tumor growth and progression. A new tracer, 18F-AL-NOTA-PRGD2, denoted as 18F-Alfatide, has been developed for positron emission tomography (PET) imaging of integrin αvβ3. This study aimed to explore the predictive role of integrin αvβ3 imaging with 18F-Alfatide PET in non-small cell lung cancer (NSCLC) for radiation and also to assess changes in tumor uptake during the course of radiotherapy. Methods: A total of 40 mice with lewis lung carcinoma (LLC) xenografts were divided into 4 groups (Ⅰ, Ⅱ, Ⅲ and Ⅳ) randomly. The Ⅰ underwent 18F-Alfatide Micro-PET scanning before and after radiotherapy, and so did the Ⅱ except for radiotherapy. The xenografts of Ⅲ were removed at the time before radiotherapy, while the Ⅳ’s were removed after radiotherapy. Tumor and muscle uptakes before and after radiotherapy of Ⅰ(SUVrad-1, SUVrad-2, SUVM-1, SUVM-2) and Ⅱ(SUVblank-1, SUVblank-2, SUVm-1, SUVm-2) depict 18F-Alfatide Micro-PET uptake. The expression of integrin αvβ3 in Ⅲ and Ⅳ xenografts was analyzed by western blotting. Results: The changes of ΔSUV1 ( SUVrad-2/SUVM-2―SUVrad-1/SUVM-1) was significantly lower than ΔSUV2 (SUVblank-2/ SUVm-2―SUVblank-1/ SUVm-1 ) (2.65±1.72 versus 5.16±2.50, P = 0.019. Overall survival (OS) of Ⅰ(56.70±25.34 day) is significantly longer than Ⅱ(35.00±5.27 day), P = 0.002. Significant negative correlation was found between ΔSUV and OS (R = 0.640, P = 0.002). Significant higher αvβ3 was observed in Ⅲ(0.52±0.09) than Ⅳ(0.41±0.07), P = 0.007. Conclusions: Decrease of ΔSUV and integrin αvβ3 during the course of radiotherapy may predict improved response in LLC xenografts and affirm the predictive role of 18F-Alfatide for radiation in NSCLC.
The novel long non-coding RNA PANCR: A p53 activator and potential breast cancer biomarkers.
Authors: Cao Yu , Cao Deliang , Ling Hongyan
Published: September 2018

e23016

Background: Long non-coding RNAs (LncRNAs) may serve as a biomarker and potential therapeutic target of cancers. Chromosome 16q22.1 is frequently deleted in breast cancer and may contribute to breast carcinogenesis by inactivation of tumor suppressor genes. This study characterized a new LncRNA tumor suppressor in this region, named p53 activating non-coding RNA (PANCR). This LncRNA consists of 1.5kb in length. Methods: Quantitative real-time PCR was used for examine the PANCR expression in breast cancer tissues. RNA-pull down and RNA-Immunopreicitation were used to analyze PANCR targeted protein. Results: Our data showed that PANCR was downregulated in breast cancer cell lines and tissues. In the breast cancer cell lines, PANCR expression appeared reversely correlated with cell malignancy, and in breast cancer tissues, PANCR was downregulated over 2 times in 31(62.0%) of 50 cases compared to adjacent normal breast tissues. In breast cancer cells MCF7 and immortalized human mammary epithelial cells MCF10A, ectopic expression of PANCR induced marked apoptosis, suppressing cell proliferation in culture and tumor growth in xenografts, but in contrast, shRNA–mediated silencing of PANCR promoted cell growth and proliferation. Mechanistic approaches revealed that in both MCF7 and MCF10A cell, PANCR activated p53 and upregulated pro-apoptotic proteins bid and bim and cell cycle inhibitors p21waf/cip1 and p27Kip1. We further found that the PANCR binds to and activates p53 by dissociating the p53-MDM2 complex. We further characterized the functional domain of PANCR that interacts with p53. Conclusions: The LncRNA PANCR located in the deleted Chromosome 16q22.1 region is a novel intracellular p53 activator and tumor suppressor, which may be used as a target for cancer therapy through mimicking its binding domain and activation of p53.
Immunomonitoring in patients with stage II and III colon cancer.
Authors: Vocka Michal , Spacek Jan , Netikova Irena , Zavadova Eva , Němejcová Kristýna , Konopasek Bohuslav , Dundr Pavel , Geppert Carol-Immanuel , Fucikova Terezie , Hartmann Arndt , Petruzelka Lubos B.
Published: September 2018

e23038

Background: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Immunoscore has been shown to be a very powerful prognositc indicator in patients with clinically localized colorectal cancer, with no detectable tumour spread to lymph nodes or distant organs. These patients are usually treated with only surgical removal of the tumour; however, approximately 25% of these patients will have recurrence of their disease, indicating that occult metastases were already present at the time of curative surgery. VEGF is the factor responsible for neoangiogenesis and it is being considered as a possible prognostic marker of disease progression. Transforming growth factor-beta (TGF-beta) is also neoangiogenic and a highly immunosuppressive factor. The purpose of this study was to monitor the immune response in patients with stage II and III CRC, with a focus on cellular as well as humoral immunity. TGF-beta and VEGF levels were followed. Methods: 25 patients with stage II and III colon cancer included in the research project received routine cancer teratment. Basic parameters - histological type and grade - were established at baseline. Patients were evaluated by a clinical immunooncolgist to exclude any immune disorders of allergic or autoimmune origin. TGF-beta and VEGF were measured using ELISA, and anti-tumour cellular immunity (CD4, CD8, T-reg, B cells ) were measured via flow cytometry. Results: In patients with stage II and III colorectal cancer, predominantly a depression in cellular immunity was seen. Plasma levels of immunglobulins were also reduced, particularly the IgG4 subtype. Most patients showed some clinical symptoms of immunodeficiency, such as frequent respiratory tract infections and/or herpetic infections. TGF-beta and VEGF plasma levels were increased. Conclusions: The correlation of these neoangiogenic and immunosuppressive factors, as well as the state of anticancer immunity with the clinical outcome of the patients, could help in the future as a prognostic marker and contribute to the selection of targeted immune therapy in patients with colorectal cancer. Dedication: Ggrant of Czech Ministery of Health, 15-28188A, League against cancer and PRVOUK-P-27/LF1/1
Dynamic process of circulating tumour DNA (ctDNA) profiling as a predictor of efficacy of pemetrexed combined platinum chemotherapy in advanced lung adenocarcinoma.
Authors: Han Ying , Han Xiaohong , Wang Zhe , Luo Wen , Zheng Wenyuan , Dai Wumin , Yu Huang , Yao Jiarui , Zhang Zhishang , Wu Di , Shi Yuankai
Published: September 2018

e23048

Background: Pemetrexed combined platinum is recommended as first line chemotherapy regimen for non-squamous non-small cell lung cancer. However, the efficacy is variable for individuals. Methods: We conducted a prospective study with 52 consecutive patients enrolled who were histologically confirmed advanced or metastatic lung adenocarcinoma, of whom, 32 had their plasma samples collected both baseline and follow-up when efficacy evaluation. We used a next-generation sequencing to assess the dynamic change of ctDNA across 87 plasma samples. Results: 34 blood samples from 61.5% of patients demonstrated smoking status is an infavorable factor to drug efficacy ( p= 0.02, fisher’s exact test, two-sided). Simultaneously, we found positive correlation between decreased mutation burden and chemotherapy sensitivity (the mean mutation rates of pre chemotherapy, PD, PR, SD and SDA were 4.5, 6.3, 2.1, 1.6 and 2.4, respectively, p= 0.004, one way ANOVA test, two-sided).The mean mutation rates with T > G substitution mutation of pre and post chemotherapy were 1.5 and 0.6 ( p= 0.014, Mann-Whitney U test, two-sided). 34.4% (11/32) individuals harbor those mutation pre chemotherapy, 6 out of them were characterized by DNA repair signatures, of which 83.3% (5/6) cases were positively related to platinum sensitivity. In addition, T > G substitution was still detected from 5 patients at cycle 2, 60% (3/5) individuals were characterized by DNA repair signatures and 2 out of them had better platinum-based chemotherapy response.Neoplastic cells carrying a specific set of somatic mutations were sensitive to platinum treatment, including USP9X (pre vs post chemotherapy: 10.3% vs 0%), ZRSR2 (pre vs post chemotherapy: 6.9% vs 0%) and PIK3C2G (pre vs post chemotherapy: 10.3% vs 0%). Nonetheless, persistence of gene ROBO2 (pre vs post chemotherapy: 10.3% vs 4.6%) may be correlated with tumorigenesis. Conclusions: Dynamic monitoring of ctDNA mutation status may be contributed to advanced or metastatic lung adenocarcinoma patients stratification and prediction for pemetrexed combined platinum as first line chemotherapy regimen.
Enumeration of circulating tumor cells using a non–EpCAM-dependent device.
Authors: Amato Robert J. , Brobey Reynolds , Wang Yue , Murphy Kent , Smith Jeff
Published: September 2018

e23064

Background: One component of the metastatic process is the circulation of tumor cells. Identification of these circulating tumor cells (CTCs) provides important insights into cancer biology. There is enormous heterogeneity among CTCs, necessitating capture of both epithelial and non-epithelial subtypes. Detection and monitoring of CTCs will provide a non-invasive biomarker for the detection of early progression and assessing therapeutic response. Methods: The AxonDx nCyte™ System is designed to detect rare circulating cells from peripheral blood without enrichment or selection. An epi-fluorescence microscope scans pathology glass slides on which a sample has been applied, and high-resolution images of potential CTCs are captured at four emission wavelengths. The proprietary Cancer Cell Detection Cocktail is designed to detect CTCs from numerous solid tumors, including various stages (e.g., mesenchymal-epithelial transformation) and stem cells. The software distinguishes cancer-derived material (nucleus+/cytokeratin+/WBC marker-/ > 4 µm); from leukocytes (nucleus+/cytokeratin-/WBC marker+). Vimentin is used to distinguish epithelial from mesenchymal CTCs. We obtained informed consent from 32 genitourinary cancer patients to participate in this IRB-approved study. Red blood cells from 6 mL of whole blood were lysed and removed from 32 patient samples. Nucleated cells from the blood sample were fixed, permeabilized, and stained with AxonDx’s Cancer Cell Detection Cocktail. The prepared cells were dispensed onto two microscope slides, cover-slipped, and analyzed. Results: We detected CTCs in 32 of 32 samples (100%), in a range of 0.6–64.3 CTCs/mL. Number of CTCs correlated with metastatic tumor burden. Conclusions: The AxonDx nCYTE™ system can reliably detect CTCs from genitourinary patient samples. The AxonDx nCyte™ System has also successfully detected CTCs in other tumor types, e.g., breast, lung, CRC, and HCC. Because the system is not EpCAM-dependent, it captures the heterogeneous population of CTCs. Prospective longitudinal studies are ongoing to determine trends in CTC counts.