bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of maintenance of normal circadian function while undergoing chemotherapy on advanced cancer patient outcomes.
Authors: Block Keith I. , Carome Edward , Blask David E , Huff Dinah Faith , Kaslausky Thomas , Gyllenhaal Charlotte , Block Penny B. , Reynolds Justin , Grutsch James F. , Hrushesky William J.
Published: September 2018

e21650

Background: Cancer patients develop symptoms that are pathognomonic of a failing circadian organization [CO]. Our concurrent study of 84 advanced cancer patients on randomly timed chemotherapy revealed that each suffered more disrupted circadian rhythms, sleep disorders, anxiety/depression, and quality of life scores compared to healthy age-adjusted controls, as well as poor survival. Herein, we report relationships between CO of advanced cancer patients and their functioning, symptoms, mood, and quality of life during chemotherapy in a clinic that uses comprehensive integrative therapies to maintain patient CO. Methods: 30 patients with advanced cancer participated in a randomized single-blind crossover trial of whether nightly use of blue-light blocking eyeglasses improved circadian organization during chemotherapy. Chemotherapy was applied at or near times of day known to be least toxic and most effective. CO was measured serially using actigraphy and patients provided data on their sleep quality [PSQI], mood [HADS], fatigue [Piper], and quality of life [EORTC QLQ-C30 and Ferrans/Powers QLI]. Kruskal-Wallis tests were used to detect the differences between groups [p < 0.05]. Results: These cancer patients’ actigraphy data were indistinguishable from a convenience control of healthy individuals. Sleep quality, Piper Fatigue, and HADS scores were in the non-symptomatic range; and all functional and symptomatic parameters of the EORTC QLQ-C30 and three of four QLI subscales were within population-based norms. Only the EORTC health-related quality of life and the QLI health/function parameters were lower than non-cancer controls. Median overall survival was 38.4 months. Conclusions: Actigraphy-measured COs of advanced cancer patients are damped, disorganized and accompanied by a heavy symptom burden. These cancer patients reported good quality sleep, normal function, good mood, low intensity of cancer-related symptoms and extended survival while undergoing circadian timed cancer chemotherapy and integrative support. This CO maintenance among such cancer patients is unprecedented and requires attention especially as it is achievable entirely without risk. Clinical trial information: ISRCTN16219928.
Feasibility of incorporating patient reported outcomes (PROs) into routine care for oropharyngeal carcinoma (OPC).
Authors: Baxi Shrujal S. , Cracchiolo Jennifer R , Patel Snehal G. , McBride Sean Matthew , Migliacci Jocelyn , Lee Nancy Y. , Kurtzman Rachel , Pfister David G. , Wong Richard J.
Published: September 2018

e21652

Background: We assessed the feasibility of using PROs as part of routine care to better understand the trajectory in quality of life (QOL) following treatment of OPC. Methods: The Memorial Sloan Kettering Cancer Center (MSK) head and neck disease management team (DMT) assembled a parsimonious paper survey composed of validated PRO measures (EORTC QLQ 30 and HN-35, Neck Dissection Impairment Index, Skindex-16, and COST-FACT) to assess QOL at baseline, immediately and 3 months post treatment. From Jan-May 2016, a DMT PRO coordinator identified patients with non-metastatic OPC and notified clinical teams to print the surveys to be completed in the waiting room. We assessed the feasibility of incorporating PROs into routine care across the DMT using this process by examining response rates (RR) and identifying potential barriers (i.e., regional site of treatment, number of treatment modalities, hospitalizations, demographic variables) to completing PROs. Results: Of 54 patients with non-metastatic OPC, 3 non-English speakers and 5 protocol patients were excluded. Median age was 61.3 years (43.8-78.4). Patients were mostly male (89%), married (74%) and presented with locally-advanced OPC (89%) due to HPV (89%). 89% received multimodality therapy (89%), of which 36 (88%) received chemoradiation, and nearly half (48%) were treated at MSK regional sites. The RR decreased substantially over time (Table 1). 2 patients died* and 17 patients were hospitalized within these 3 months. In bivariate analyses, no prespecified demographic or clinical barriers to completion of PROs were identified. On deeper investigation, decline in RR overtime resulted from not capturing change in scheduling, which occurs more frequently after treatment completion. Conclusions: Implementation of longitudinal PROs into routine care is feasible and generally acceptable by the patients, but requires a coordinated effort to sustain an acceptable RR. For future efforts, the project coordinator will use a portal messaging system to communicate directly with patients and use an electronic PRO format. [Table: see text]
Weight changes at diagnosis in solid tumours.
Authors: O'Donoghue Niamh , Shrotriya Shiva , Aktas Aynur , Hullihen Barbara , Ayvaz Serkan , Walsh Declan
Published: September 2018

e21655

Background: Unintentional weight loss is common in cancer and associated with increased morbidity and mortality. Most research to date has examined weight loss in advanced disease. The clinical significance of any weight change (WC) (loss/gain) before/at cancer diagnosis remains unclear. This study aimed to determine the prevalence and clinical significance of WC at diagnosis in out-patients with solid tumours presenting to a tertiary academic medical centre. Methods: A retrospective study of the electronic medical record (EMR) was conducted (n=6477). Those with a pre-diagnosis weight, T0, (recorded within 6 months of cancer diagnosis) and 2 subsequent weights (diagnosis, T1; final visit, T2) were identified (n=4258). Logistic regression and survival analysis identified WC predictors and overall survival respectively. The significance threshold was p < 0.05. Results: Mean age was 61 ±12.5 years. 54% (n=2315) were male. Common tumour sites were breast (17%; n=725), prostate (16%; n=664), lung (14%; n=599) and upper GI (11%; n=470). Known metastatic disease present at T1=15% (n=652). 68% (n=2908) were overweight or obese (WHO BMI Classification) at T1. 98% (n=4159) had WC from T0-T1(loss: 58%; n=2454; gain: 40%; n=1705). Primary tumour sites significantly associated with weight loss (WL) included colon, head & neck, kidney, lung and upper GI. 8% (n=320) were cachectic (>5% WL in previous 6 months) and 50% (n=2134) were pre-cachectic (≤ 5% WL) at T1; 3% had “Abnormal Weight Loss” (ICD 9 Code). Survival was worst with WL >5% and weight gain (WG) ≥ 10% from T0-T1 (p<0.05). However, those with 2.5-5% WL from T0-T1 were also at risk (p<0.05); 0.1-2.4% WG was protective. Primary tumour site (lung, upper GI) and normal/underweight BMI at T1 predicted poor prognosis. Conclusions: Weight changes were highly prevalent, but WL typically was undiagnosed. Most were overweight or obese at diagnosis. Nevertheless 58% (n=2454) of those reviewed at T1 met current criteria for cachexia or pre-cachexia. Those with WL > 5% or WG ≥ 10% had worst survival. The majority had evidence of significant, yet frequently undiagnosed, WC abnormalities at diagnosis.
Does chemotherapy work in reversal of malignant obstruction due to gastric cancer?
Authors: Santos Vanessa Montes , Azevedo Renata Gondim Meira Velame , Lopez Rossana Veronica Mendoza , Hoff Paulo Marcelo , Sabbaga Jorge , Glasberg Joao
Published: September 2018

e21676

Background: Malignant obstruction (MO) is a common complication in patients with gastric cancer. Although palliative chemotherapy has already shown beneficial for overall survival in advanced cases, its value for MO reversal is still unknown. Methods: Inthis retrospective study we analyzed all consecutive patients with metastatic gastric cancer admitted with MO at the Instituto do Câncer do Estado de São Paulo (ICESP) from 2008 to 2016. The primary and secondary endpoints were overall survival and obstruction reversal rate respectively. Clinical measures other than chemotherapy and alimentary pause included the use of octreotide 0.1 mg, 3 times a day, steroids, antiemetics and anticholinergic drugs. Survival curves were calculated by Kaplan-Meier and log-rank test was used to compare them. The Cox regression model was used to evaluate risk factors for overall survival and the hazard ratio (HR) was calculated with its respective 95% confidence intervals. The analysis was performed in SPSS v.18 for Windows statistical software, and the significance level was 5%. Results: One hundred and eighteen(118)patients were included. Median overall survival was 11.2 months and survival time after the MO was 3.6 months for the whole group. Median time of use of octreotide was 3 days. Reversal of obstruction was seen in 16 of 36 patients (38.4%) in which chemotherapy was used and only in 22 of the 92 patients (24%) treated with exclusive clinical measures. In spite of these figures a significant better overall survival (p 0.002) was achieved in the group of patients that reached obstruction reversal without chemotherapy (13.6 months vs. 11.6 months for the clinical treatment group). Conclusions: This study suggests that chemotherapy even when reversing MO, has no impact in patients overall survival. These finding is particularly relevant for cost contingency in settings with limited resources. .
Efficacy of olanzapine for prevention of chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis.
Authors: Kumar Rohit , Singh Naina , Thekkekara Romy Jose , Singh Sunny R K , Harrington Sarah Elizabeth , Shah Mousami
Published: September 2018

e21692

Background: Olanzapine is an atypical antipsychotic medication which has shown efficacy in prevention of chemotherapy-induced nausea and vomiting (CINV) in multiple trials. This study aims to investigate the efficacy of Olanzapine to prevent CINV with an up-to-date systematic review and meta-analysis. Methods: A literature search of Ovid MEDLINE, Embase and Cochrane library was performed to identify randomized controlled trials of olanzapine compared to other antiemetic therapy (5HT3 and/or NK1 antagonist with or without steroids) for prevention of CINV in patients age >=18 years up until December 2016. The primary endpoint was no emesis or nausea episodes in acute (0-24hrs), delayed (24-120hrs) and overall (0-120hrs) period in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). Statistical analysis was performed using Review Manager (RevMan 5.3). The Mantel–Haenszel method was applied and random effect analysis model was used to calculate risk ratios. Results: From the literature, 12 RCTs met the inclusion criteria. The age range of patients was 18-89 years. Seven trials included only patients who received HEC while 5 trials included patients receiving either HEC or MEC in various proportions. Olanzapine was statistically superior for 5 primary endpoints except for no nausea in acute period (Table 1). In the non-steroids cohort, olanzapine was superior for no emesis in all 3 periods but statistically significant only for delayed period. Conclusions: Olanzapine is superior to other antiemetic therapy for prevention of CINV. It is less expensive and can improve patient’s quality of life and chemotherapy adherence. [Table: see text]
Randomized study comparing high-dose (HD) influenza vaccine to standard-dose (SD) influenza vaccine in patients with breast cancer age < 65 receiving chemotherapy.
Authors: Jamshed Saad , Falsey Ann R , Thushara Paul , Walker Jennifer , Walsh Edward E
Published: September 2018

e21695

Background: Patients on chemotherapy often fail to develop a robust response to influenza vaccine. We had previously demonstrated that HD vaccine improved immunogenicity in cancer patients receiving chemotherapy. The present subgroup analysis evaluates immunogenicity & tolerability of HD to SD vaccine specifically in breast cancer pts <65 yrs receiving chemotherapy. Methods: 35 breast cancer pts were randomized to receive either SD or HD (17 vs 18) vaccine on day1 of chemotherapy during 2 influenza seasons. HAI titers were measured prior to & 4-wks after vaccination. HAI were summarized as geometric mean titer (GMT) and seroconversion (>4-fold titer rise) & seroprotection (GMT ≥40) rates calculated. t-test was used to compare log2-transformed GMT titers between groups and χ2 for comparison of seroconversion and seroprotection rates. Results: 2 pts were included only once (yr 1) as they received study vaccine both yrs. Mean age (50.4 vs 51.3 yrs) and baseline HAI titers were equivalent; 81 vs 88% were receiving therapy with curative intent in SD vs HD arms, respectively. Both vaccines were well tolerated with no SAEs. Post vaccination GMT were greater after HD vaccine, but was statistically significant only for H3N2 virus. Seroconversion rates for B strain was significantly improved with HD vaccine while seroprotection was excellent for all antigens in both arms. Conclusions: Trivalent HD influenza vaccine can be safely administered with increased seroconversion over SD vaccine. Most patients with breast cancer should be offered vaccination even if they are receiving chemotherapy, as they demonstrate robust response to either influenza vaccine. A larger study is needed to show clinical benefits with HD vaccine. Clinical trial information: NCT01666782. [Table: see text]
Clinical observation of yizhongshengxue capsule on the treatment of advanced gastric cancer-related anemia.
Authors: Hou Li , Wang Jia , Wang Jing , Li Ya , Chen Xinyi
Published: September 2018

e21696

Background: Cancer-related anemia is an important factor that affects the clinical efficacy and quality of life for patients with advanced gastric cancer. This study is to observe the clinical efficacy of Yizhongshengxue Capsule, which is an herbal formula, on advanced gastric cancer-related anemia. Methods: A total of 96 eligible patients were randomized into three arms: 46 patients in the experimental arm, 26 patients in the positive control arm, and 24 patients in the negative control arm. All three arms received basic treatment of conventional medicine. Meanwhile, the experimental arm received Yizhongshengxue Capsule at the dosage of 3 capsules, 3 times daily. The positive control arm received Fufangejiao Syrup at the dosage of 20 ml, 3 times daily. The negative control arm received only basic treatment of western medicine. The course of treatment was 5 weeks. Results: After the 5-week-treatment, there was a statistically significant rise ( p<0.05) of hemoglobin(HGB) in both experimental arm and positive control arm. The negative control arm had no statistically difference of HGB ( p>0.05) before and after the treatment. Symptoms of dizziness, fatigue, loss of appetite, palpitation and insomnia in experimental arm were improved after the treatment ( p<0.05). Symptoms of fatigue and loss of appetite in positive control arm were alleviated after the treatment ( p<0.05). The negative control arm had no statistically difference in the above symptoms ( p>0.05) before and after the treatment. Furthermore, there was a significant improvement of dizziness, loss of appetite, palpitation and insomnia in the experimental arm compared to the negative control arm ( p<0.05). Finally, an improvement of the Karnofsky Performance Score(KPS) was seen only in the experimental arm after the treatment compared to that before the treatment ( p<0.05). Conclusions: Our study shows that Yizhongshengxue Capsule can not only improve the clinical symptoms and quality of life in patients with advanced gastric cancer-related anemia, but also reduce or even reverse the trend of HGB decrease. Therefore, it is very promising in treating cancer-related anemia. Clinical trial information: ChiCTR-TRC-13003604.
Association of Met-BDNF allele with pre-existing peripheral neuropathy in breast cancer patients.
Authors: Azoulay David , Leibovici Anca , Sharoni Rivka , Goldberg Hadassah
Published: September 2018

e21702

Background: We previously published preliminary results suggesting an association between the met-BDNF allele and vulnerability to paclitaxel-induced peripheral neuropathy (PIPN) in breast cancer patients. Here we present updated data obtained from our extended study. Methods: 35 patients; 34 women (33 with breast cancer and 1 with ovarian cancer) and one man (breast cancer) completed their follow-up. Peripheral neuropathy (PN) was assessed at diagnosis and along the treatment protocol, using the reduced version of Total Neuropathy Score (TNSr). Patients with TNSr≥2 at diagnosis were determined with pre-existing PN (Pre-PN). Allelic discrimination of BDNF polymorphism (rs6265) was determined by Sanger sequencing. Results: BDNF genotype Val/Val was found in 20 patients (57.14%), Val/Met in 15 patients (42.86%). No patient had the Met/Met genotype. 10 patients (28.57%) were diagnosed with Pre-PN, 3 of them with diabetic-related neuropathy. A higher incidences of the Met-BDNF allele was found in patients with Pre-PN as compared to patients with no Pre-PN (7/10 (70%) vs. 8/25 (32%) Val/Met in Pre-PN and no Pre-PN respectively, prob > ChiSq < 0.05). The three patients with diabetic related Pre-PN were genotyped Met-BDNF. The maximal TNSr scores developed by each patient during follow-up were higher in Met-BDNF patients compare to Val/Val patients. (Maximal TNSr mean ± SEM in Val/Val 4.80±0.62 vs. 7.73±1.34 in Val/Met BDNF, prob < t 0.04). No difference in the maximal TNSr scores between Met-BDNF and Val/Val patients were shown after excluding the patients with Pre-PN (Maximal TNSr mean ± SEM in Val/Val 5.05±0.78 vs. 5.25±0.62 in Val/Met BDNF, prob < t 0.44). Conclusions: Our data demonstrate an association between met-BDNF and Pre-PN. Higher maximal TNSr scores in our met-BDNF patients is generally the consequence of their higher Pre-PN.
Race-specific genetic aberrations in B-acute lymphoblastic leukemia in children.
Authors: Reddy Amit , Espinoza Ingrid , Johnson Dana , Schallheim Jason , Bhanat Eldrin , Zhou Yunyun , Zabaleta Jovanny , Megason Gail , Gomez Christian
Published: September 2018

e22000

Background: B-Acute Lymphoblastic Leukemia (B-ALL) is the most common childhood cancer and the leading cause of death in children. Studies have shown that African-American (AA) children have significantly lower survival rates compared to European-American (EA) children. This disparity is not related to socioeconomic variables, suggesting a molecular basis for the lower survival. Here we present a study showing genetic aberrations (GA) involved in race-specific leukemogenesis and contribute to health disparities in B-ALL in AA and EA children. Methods: A total of 20 newly diagnosed pediatric patients were studied (5 AA and 15 EA) at University of Mississippi Medical Center. Ages range between 1 and 18 years with a median age of 4 years. None of the patients in our study had a relapse. Frozen bone marrow (BM) aspirates were used to extract DNA and whole-exome DNA sequencing was performed, focusing on race and B-ALL specific germ-line mutations. Results: Most GA were shared between AA and EA, for example those present in the Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) gene. Some genes with GA were specific to AA and others to EA. Genetic non-synonymous germ-line aberrations were identified such as, Lipoma Preferred Partner Gene, in AA and Leukemia Inhibitory Factor Receptor, in EA. Ingenuity pathway analysis revealed these genes clustered in race-specific canonical pathways. In AA, the pathways were related to telomerase signaling and cancer signaling. While in EA, it was related to stem cell pluripotency and hereditary cancer. Conclusions: The prevalence of GA in B-ALL may contribute to differences in outcomes between AA and EA children. Aberrant biological networks revealed by our study, will provide information on distinguishing signaling networks involved in race-specific leukemogenesis. Our study provides a strong basis to develop a race-specific prognostic assay for B-ALL in BM aspirates. In the future, this can help guide risk stratification and treatments based on race and advance the prognostication of B-ALL in AA children. Funding: Hyundai Hope on Wheels Scholar Grant, UMMC Division of Pediatric Hematology Oncology.
Patterns of care in treating childhood neuroblastoma: Evidence from a population level study (SEER) in the United States.
Authors: Coughlan Diarmuid , Lynch Charles , Gianferante Matthew , Stevens Jennifer , Harlan Linda C
Published: September 2018

e22011

Background: Childhood neuroblastoma describes a heterogeneous group of extracranial solid tumors. This heterogeneity is reflected in the sequence and variety of treatment modalities administered. We describe the treatment pattern and survival of childhood neuroblastoma patients using population-based data in the United States. Methods: Using the National Cancer Institute’s (NCI) Patterns of Care data, we examined treatment provided to childhood neuroblastoma patients newly diagnosed in 2010 and 2011 and registered to one of 14 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Data were re-abstracted from hospital records and treating physicians were contacted to verify the treatment given. Stratifying by the Children’s Oncology Group (COG)’s 3-level (low, intermediate and high) neuroblastoma risk classification system for therapeutic decision-making, gave a snapshot of community-based treatment patterns. Kaplan-Meier survival analyses were also performed. Results: The majority of 250 patients (76%) were enrolled on an open/active clinical trial. All low-risk patients received surgery with/without chemotherapy. The majority of intermediate-risk patients (77%) received chemotherapy regimen that included carboplatin, etoposide, cyclophosphamide and doxorubicin. High-risk patients received extensive, multimodal treatment consisting of chemotherapy, surgery, high dose chemotherapy with stem cell rescue (transplant), radiation, immunotherapy (dinutuximab), and isotretinoin therapy. Cyclophosphamide was the most utilized chemotherapy agent (94%) in high-risk patients. Survival with a maximum follow-up of 48 months, was lowest (68%) for patients diagnosed with high-risk disease. Conclusions: The majority of childhood neuroblastoma patients are registered on a risk-based open/active clinical trial. Variation in modality, systemic agents and sequence of treatment reflects the heterogeneity of therapy for childhood neuroblastoma patients.
Lack of micro-RNA 128A expression as a novel prognostic marker in neuroblastoma patients and combination with TERT hyperexpression to define patient outcomes.
Authors: Druy Alexander , Tsaur Grigory , Shorikov Egor , Zaychikov Artem , Olshanskaya Yulia , Saveliev Leonid , Fechina Larisa
Published: September 2018

e22014

Background: Rearrangements of TERT gene with its correspondent hyperexpression were identified as adverse prognostic markers in neuroblastoma (NB) patients, while significance of microRNAs expression is undiscovered. Methods: RNA from 103 fresh-frozen NB tissues was subjected to reverse transcription qPCR for miR128A and TERT expression evaluation. Copy number variations were determined by MLPA and FISH. Correspondence of miR128A and TERT expression levels to event-free survival (EFS) was proved by ROC-analysis and established threshold levels (TL) were utilized for group separation in subsequent survival analysis. Median of follow-up time achieved 5.8 years. Results: Abundant TERT expression and lack of miR128A expression resulted in superior frequency of adverse events (p = 0.027, TL = 4,7E-3 and p = 0.004, TL = 4.6E-2 respectively). EFS in group of patients with TERT expression above 4,7E-3 (group TERT) was 0.66SE0.07, in patients with miR128A expression below 4.6E-2 (group miR128A) was 0.64SE0.15, patients harboring both TERT overexpression and lack of miR128A expression (group miR128/TERT) had dismal outcome: EFS 0.29SE0.11, comparing to patients without these abnormalities (group "neither"): EFS 0.92SE0.06, p < 0.001. Analogously, cumulative incidence of progression differed significantly between all these groups, p < 0.001. MYCN amplified (MNA) samples were accumulated in the groups TERT and miR128/TERT (p = 0.061), while chromosome 17 gain, 9p and 14q deletions prevailed in the group "neither" (p = 0.014, 0.043 and 0.017 accordingly). MNA and 14q deletion had prognostic significance in the correspondent groups (p < 0.001, p = 0.022). The classifier was proposed for distinguishing patients with unequal outcome: MNA EFS = 0.25SE0.11, MYCN single copy patients divided into groups miR128A/TERT (0.40SE0.15), miR128A (0.60SE0.15) and TERT (0.74SE0.08). Group "neither" was separated basing on presence (0.71SE0.17) and absence (EFS = 1.00) of 14q deletion, p < 0.001. Conclusions: Levels of miR128A and TERT expression together with cytogenetic data allow discriminating patients into groups with significantly different outcome.
Human chorionic gonadotropin (HCG) as a biomarker in sarcoma: A systematic review.
Authors: Schoen Martin W. , Al-Taee Ahmad , Jallad Bassel
Published: September 2018

e22503

Background: Human chorionic gonadotropin (HCG) has been reported in soft tissue sarcoma and osteosarcoma. In some patients, the ectopic production of HCG can lead to delays in diagnosis due to concern for pregnancy or germ cell tumors. Methods: We performed a systematic review of the scientific literature in English using PubMed to categorize cases of sarcoma search terms were HCG, sarcoma, human chorionic gonadotropin and osteosarcoma. Cases of sarcoma associated with HCG production were identified and further categorized by type and grade of tumor. Initial HCG, Peak HCG, response to therapy and case outcome were collected when available. We also included a case seen at our institution of osteosarcoma with ectopic HCG production. Results: We identified 21 manuscripts and 23 cases of patients with both sarcoma and elevated serum HCG. 10/23 patients were male (43%).The most frequent type of sarcoma was osteosarcoma with 9/23 (39%) of cases, leiomyosarcoma was identified in 7/23 (30%) and liposarcoma in 3/23 (13%) of cases. When described, all tumors were high grade or poorly differentiated. 20/23 tumors (87%) had HCG expression of the tumor by immunohistochemistry. Mean initial HCG was 3607 with a peak value of 6188. In 19 cases, HCG was used to monitor disease after treatment and 14/19 (74%) responded with a decrease in HCG after treatment. Of responders, 3 patients were considered cured and 2 were put into remission, while none of the patients without response survived. Overall, outcomes were poor with 16/23 (70%) deaths within one year. Conclusions: Sarcomas that secrete HCG tend to be high grade, poorly differentiated and appear to portend a poor prognosis. When expressed, HCG can be used as a marker of disease and response to therapy. Oncologists should consider checking HCG as a potentially low-cost marker of prognosis and response to treatment in patients with sarcoma. [Table: see text]
Safety and efficacy of trabectedin when administered in the inpatient vs. outpatient setting in a subset analysis of a phase III randomized clinical trial.
Authors: Jones Robin Lewis , Maki Robert G , Patel Shreyaskumar , Wang George C. , Shin Chu Ri , Knoblauch Roland Elmar , Parekh Trilok V. , von Mehren Margaret , Demetri George D.
Published: September 2018

e22516

Background: Trabectedin (T) has been shown to improve progression free survival (PFS) (4.2 vs 1.5 months, HR 0.55, p < 0.0001) in comparison to dacarbazine (D) in patients (pts) with advanced leiomyosarcoma or liposarcoma following failure of prior chemotherapy. Pts randomized to T in this phase III trial (ET743-SAR 3007) received T as a 24 hr IV infusion in either an inpatient (InP) or outpatient (OP) setting, based upon site preference. Here we report the safety, efficacy, and patient reported outcomes (PROs) of pts based on first infusion site of care. Methods: Pts were randomized 2:1 to receive T (1.5 mg/m2) or D (1 g/m2 over 20-120 min). Site of T infusion was based on institutional preference/standard of care. The site of T administration (InP vs OP) was collected for the first infusion with the assumption that site of care was unchanged for subsequent doses. Results: Of 378 pts treated with T, 100 (27%) and 277 (73%) pts received T as InP or OP, respectively. No differences were observed in PFS or overall survival (OS) by site of care (InP vs OP): Median PFS of 4.1 vs 4.2 months; HR 0.90, p = 0.49 and median OS of 14.3 vs 13.7 months; HR 0.89, p = 0.40. No difference in other efficacy endpoints between InP vs OP were observed: disease control rate (CR+PR+(SD≥18wks)) (38% vs 33%; Odds Ratio [OR] 1.22; p = 0.44) and Overall Response Rate (14% vs 8%; OR 1.76; p = 0.15)). Grade 3-4 adverse events (AEs) occurred in 87% InP vs 79% OP pts and grade 3-4 SAEs occurred in 43% InP vs 33% OP. The most common grade 3-4 AEs in both groups were increased ALT/AST, hematologic toxicity, nausea and fatigue. The incidence of grade 3-4 febrile neutropenia was similar in both groups at 5.0% InP vs 4.7% OP, as was increased blood creatine phosphokinase at 5.0% InP vs 6.1% OP, and catheter related complications of any grade at 16% InP vs 15% OP. No clinically meaningful differences were observed in PROs measured by MD Anderson Symptom Inventory scores. Conclusions: The majority of patients randomized to the trabectedin arm of the ET743-SAR-3007 Phase III study received trabectedin in the OP setting. Treatment outcomes with trabectedin suggest equivalent efficacy and safety when administered in the InP or OP setting. Clinical trial information: NCT01343277.
BMI as a risk factor for toxicities in patients with advanced soft tissue sarcoma treated with trabectedin.
Authors: Silletta Marianna , Armento Grazia , Badalamenti Giuseppe , spalato Ceruso Mariella , Catania Giovanna , Incorvaia Lorena , Santini Daniele , Tonini Giuseppe , Vincenzi Bruno
Published: September 2018

e22517

Background: Since the first steps of its clinical development, trabectedin was noticed to be extremely active against myxoid liposarcoma (MLS), whose pathogenesis seems to be associated to the presence of the t(12;16)(q13;p11) translocation, resulting in the expression of FUS-DDIT3 fusion genes. Therefore, the drug seems to induce a maturation of MLS lipoblasts, with transition of the residual spindle non-lipogenic cells into mature vacuolated lipoblasts. This effect could be prevented by the increase of leptin circulating levels in obese patients. For these reasons we designed this retrospective analysis in order to evaluate the BMI status (measure of total adipose content) as a predictors or efficacy of trabectedin in MLS patients. Methods: Patients were treated in cancer centers with trabectedin at the approved dose of 1.5 mg/m2, given as a 24-hour infusion every 3 weeks. This retrospective analysis was preformed on the basis of clinical charts or databases. For the purpose of this analysis only patient with a BMI > 18.5 were included and an the population divided into two categories: normal weight if BMI < 25, overweight > 25. An analysis of the correlation between BMI and objective response (OR) rate, tumor control (TC) rate (OR+stable disease lasting ≥3 months), progression-free survival (PFS) and overall survival (OS) was performed. Results: 62 adult patients with recurrent MLS were enrolled (M/F: 33/29; median age: 53 ys). All patients were doxorubicin-pretreated. The median BMI in the whole population was 22.5 (range: 1.85 – 29.8). No statistically significant differences were identified in terms of OR or TC. On the contrary, PFS (6.8 vs. 3.7 months; p< 0.026, log rank test) and OS (14.9 vs. 8.3 months; p< 0.0001, log rank test) were significantly prolonged in normal weighted patients vs over weighted patients. Six and 12-months Kaplan-Meier PFS estimates and survival rates at 12, 24 and 36 months were also better in those patients. Conclusions: these results seem confirm a role o adipose content as a predictor of resistance to trabectedin in MLS patients. Further studies are warranted to confirm this preliminary observation and understand the biological mechanisms of this relationship.
Efficacy of bevacizumab and temozolomide in locally advanced and metastatic hemangiopericytoma (HPC) and malignant solitary fibrous tumor (SFT).
Authors: De Lemos Mario , Kang Isabell , Markarian Adeline , Badry Nadine
Published: September 2018

e22535

Background: Patients with locally advanced, recurrent or metastatic HPC/SFT are often treated with a combination of BEV/TEM based on the clinical efficacy reported in a cases series of 14 patients (Park MS, et al. Cancer 2011). BEV is costly and this regimen should ideally be supported with further data. Given the rarity of HPC/SFT, large trials are not feasible. We report the efficacy of this regimen based on population-based analysis. Methods: This was a population-based retrospective, multi-centre analysis using patient data from the BC Cancer Agency, a government funded, integrated care organization which delivers cancer drug therapy through a network of cancer centres in the province of British Columbia, Canada. Cases from June 2006 through October 2016 were identified from the provincial registry and systemic therapy drug database for patients receiving at least one treatment of BEV/TEM for histologically diagnosed locally advanced, recurrent or metastatic HPC/SFT. The primary outcome was overall response rate (ORR) based on changes of lesion size in computerized tomography scan and clinical assessment through chart review. Secondary outcomes included time to response, progression free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meir method. Results: Fourteen patients were identified: median age 59 (range 44-70), male 78.6%. Diagnoses were HPC 4 (28.6%) and SFT 10 (71.4%), with metastatic disease in 10 (72.7%) patients. Primary sites were: meninges 4 (28.6%), lung/pleura 2 (14.3%), pelvis 3 (21.4%), abdominal wall 2 (14.3%), gluteal regional 1 (7.1%), others 2 (14.3%). Eleven (78.6%) patients had no prior drug therapy. The median follow-up was 15.5 months, with median treatment of 4 months. ORR was 21.4% with median time to response of 4 months (3 [21.4%] partial response, 10 [71.4%] stable disease, 1 [7.1%] progressive disease). Median PFS, 6-month PFS and OS were 17 months, 65.0%, and 45 months, respectively. Conclusions: Efficacy of BEV/TEM in HPC/SFT appeared to be similar to that previously reported. PFS and OS were longer in our patients, probably reflected by having most patients with SFT and less heavily pretreated.
Surgical treatment for intra-abdominal/retroperitoneal soft tissue sarcoma: A single center experience in Japan.
Authors: Yashima Jun , Shirai HIroyuki , Tojimbara Tamotsu , Ono Yasuo , Teraoka Satoshi
Published: September 2018

e22539

Background: Surgical resection is considered the standard treatment for intra-abdominal and retroperitoneal soft tissue sarcoma(IARS) .We here report the outcome of surgical resection for IARS at IUHW Atami hospital, Japan. Methods: A total of 93 patients underwent 165 surgical resections for IARS between 2010 and 2016. Deta on primary and recurrent tumor were collected including staging, histopathological diagnosis, operative procedures, postoperative complications, and perioperative mortality, as well as 5-years survival. Results: The cohort consisted of 14(15.1%) primary and 79(84.9%) recurrent cases. 61(65.6%) were female and 32(34.4%) were male.The age ranged from 17 to 76 years (median 55 years).　Histopathologically, 13 different types of IARS were found in the cohort. Leiomyosarcoma(n = 46, 49.5%) and liposarcoma(n = 23, 24.7%) were the most common. 77patients(82.8%) had far-advanced stage disease(StageIIIA,IIIB,IV, by AJCC cancer stageing manual) The 5-years overall survival rate for all the patients was 56.7%. The 3-years survival rate from the surgery in our center for the recurrent cases was 40.7%. Patients with stageIII or IV disease, the-3years survival rate was 27.3% from the surgery in our center. Conclusions: Surgical resection may contributed to better survival even in the recurrent or far-advanced stage patients. It seems necessary for the better outcome to incorporate with other treatment modalities, such as chemotherapy or radiotherapy or ablation for liver metastasis.
Modulation of the anti-tumor activity of VEGF blockade by metformin.
Authors: Selmy Mohamed , Zulato Elisabetta , Pasto Anna , Indraccolo Stefano
Published: September 2018

e23009

Background: The payoff from first-generation angiogenesis inhibitors was commonly temporary, due to the development of intrinsic as well as acquired resistance. Apart from the vascular resistance due to circumventing VEGF blockade by proangiogenic factors, resistance has also been associated with assortment of resistant clones. Accordingly, a combination strategy was proposed to overcome such resistance. Metformin, as a potential candidate, has received considerable concern as an anticancer agent. Methods: IN-VITRO WORK;Cells were divided into normoxic and hypoxic groups. For both, four subgroups were developed; control, metformin, glucose deprivation and a subgroup in which cells were subjected to both glucose deprivation and metformin treatment. Cells were then subjected to analysis for Apoptosis, Cell cycle progression and western blot. IN-VIVO WORK; Tumor growth was assessed IGROV-1 subcutaneous xenografts. Animal were divided into four groups; control, Metformin, Bevacizumab and a fourth group receiving both drugs. Tumor growth was assessed along treatments and at time of sacrifice.After sacrificing animals, tumors were further analyzed for; necrosis, apoptosis, proliferative capacity, activation of AMPK and its downstream effectors. Results: Our in-vitro results suggested an anti-proliferative effect of metformin in terms of apoptosis, cell cycle arrest, AMPK activation and mTOR inhibition at various time points. In-vivo experiments revealed a significant decrease of tumor weight and proliferative capacity in tumors treated with both drugs and a trend toward a decrease in tumor growth along the treatment. Yet, there was no difference between the bevacizumab and the combination groups regarding AMPK activation suggesting another mechanism to exert the combination effect. The effect of Metformin on CSC percentage and viability was tested. Glucose deprivation plus hypoxia lead to increase in CSC population, while adding metformin to bevacizumab reverse this augmentation in CSC numbers. Conclusions: Study represents a proof of concept study demonstrating a positive modulatory effect of metformin addition to bevacizumab. Additional experimental work on a wider scale is running to ascertain the current results.
Effect of very low doses of chemotherapeutic drugs on proangiogenic factors in tumor cells.
Authors: Ocal Muge , Sonugur Fatma Gizem , Babahan Cansu , Abdi Abgarmi Samira , Icli Fikri , Akbulut Hakan
Published: September 2018

e23013

Background: The efficacy of the metronomic use of conventional chemotherapeutic drugs in the clinic has been linked to their anti-angiogenic activity. However, the dose level for the metronomic use of the drugs with regard to anti-angiogenic activity is not known. In the current study, we aimed to study the effects of very low doses of 5-florouracil (5-FU), irinotecan and oxaliplatin on the synthesis of pro-angiogenic factors in tumor cells. Methods: We first determined the IC50 doses of 5-FU, irinotecan, and oxaliplatin in human tumor cell lines (HT-29: colon cancer cells, MCF-7: breast cancer cells and LNCaP: prostatic carcinoma cells). Then we applied the drugs to the assigned cells at the dose levels of IC50, -1log, -2log and -3log of IC50. The effects of the drugs on both gene expression and protein secretion levels of pro-angiogenic genes including vascular endothelial growth factor A (VEGF-A), basic-fibroblast growth factor (bFGF), matrix metalloproteinase-9 (MMP-9), platelet-derived growth factor-beta (PDGF-B), interleukin-8 (IL-8) and factor secretion by real-time PCR and sandwich ELISA. Results: The IC50 levels of 5-FU, irinotecan, and oxaliplatin in tumor cells were found as shown in the Table. We found that -1logIC50 dose level of 5-FU efficiently suppressed the pro-angiogenic genes both at the gene expression and protein secretion levels. However, the -2logIC50 and -3logIC50 dose levels of both irinotecan and oxaliplatin significantly inhibited gene expression and protein secretion. Conclusions: In conclusion, our results suggest that irinotecan and oxaliplatin could be used as anti-angiogenic agents at the very low doses. The -1logIC50 dose for 5-FU and the -2log and -3logIC50 doses of irinotecan and oxaliplatin could be further tested in animal models and clinical trials. Table. The IC50 dose levels of the drugs in tumor cell lines. [Table: see text]
Association of circulating tumor cells (CTCs) with hyperglycemia in the follow-up of Chinese non-metastatic breast cancer patients.
Authors: Shi Yu-Mei , Zhang Guochun , Ren Chong-Yang , Wen Ling-Zhu , Zhu Wen-zhen , Chen Xiao-qing , Liao Ning
Published: September 2018

e23020

Background: CTCs has been confirmed to associate with a poor outcome of breast cancer at primary diagnosis. To date, CTC has not been studied with sufficient details in the follow-up of non-MBC pts, especially in Chinese population. We investigated the associations of CTC with clinicopathological features and metabolic factors to gain insight into potential interactions between physiology and disease burden. Methods: We recruited 264 cases of postoperative pts with non-MBC in Guangdong General Hospital from Jan 2009 to Dec 2015. For each enrolled pts 7.5mL blood samples were drawn for CTC enumeration using the CellSearch system. CTC results were correlated with clinicopathological features, obesity related indicators and HBsAg. A multivariate logistic regression analysis was performed to further determine the independent predictors of CTC. The study defined CTC positive as CTC ≥1. Results: In 10.6 % of all pts (n = 28) a median of 1 (range, 1–108) CTC was detected. A pT1 tumor was present in 47% of pts, 11.4 % had G1 grading and 64.4 % were node-negative. The positive rate of CTCs in pts with IDC and ILC was lower than that in pts with other pathological types (9% and 11.1% vs 28.6% P=0.02). A similar trend that approached significance was noted for age (p=0.062), histological grade( p=0.087), invasion of the nipple areola (p=0.06). CTCs was positively correlated with blood glucose (p=0.015), and negatively correlated with high density lipoprotein (p=0.049). In addition, glycated hemoglobin was positively associated with CTC in correlations that neared significance (p=0.059). The result of multivariate logistic regression analysis is shown in the Table. No associations were observed in triglycerides, free fatty acid, total cholesterol, low-density lipoprotein and HBsAg. Conclusions: This study suggested pathological type and blood glucose were independent predictors of CTC, supporting the notion that high fasting glucose level in BC pts may have severe disease burden, leading to a higher frequency of CTC. [Table: see text]
LC-hrms metabolomics profiling in breast cancer: Searching for biomarkers in human plasma samples.
Authors: Sánchez Rovira Pedro , Ortega Granados Ana Laura , Fernández Navarro Mónica , Ruiz Sanjuan María , de la Torre Cabrera Capilla , García Verdejo Francisco José , Luque Caro Natalia , Fernández Garay David , Ramirez Tortosa Cesar , Collado Martín Ricardo , Pamplona Gras Reinald , Jové Font Mariona , Olid JA , Rivas V , Genilloud Olga , Díaz Navarro Caridad , Vicente Pérez Francisca , Lomas Garrido Maria , Jaén Morago Ana , Pérez del Palacio Jose
Published: September 2018

e23053

Background: Breast cancer (BC) is most common cancer in women and development of new technologies for understanding molecular changes involved in BC progression is essential. Metabolic changes precede phenotypic changes, due to cellular regulation affects use of small-molecule substrates for cell division, growth or environmental changes, such as hypoxia. Metabolomics (profiling of metabolites in biofluid, cell and tissue) is routinely applied as a tool for biomarker discovery. Liquid chromatography−mass spectrometry(LC−MS)is the dominating platform. Methods: With the aim to find metabolomic profiles for diagnostic and prognostic of newly diagnosticated breast cancer (BC) we have investigated plasma samples in neoadjuvant setting (134 BC patients with median age of 51 years, stages T1-4,N1-2,M0 and 135 healthy controls) using high resolution mass spectrometry couple to liquid chromatography in reverse phase and HILIC modes which provided resolved chromatography of highly polar as well as hydrophobic analytes, enabling the analysis of a wide range of chemicals, necessary for untargeted metabolomics. Chromatograms were processed with software (Markerview) to generate a table listing retention times with associated ion masses and intensities. To identify potential biomarkers, we used in combination 2 independent variable selection techniques: principal component analysis and Student t-test. Results: We observed a significant difference in metabolic profile between the 2 groups. 15 molecular features [oleamide, KDNalpha2-3Galbeta1-4Glcbeta-Cer(d18:1/22:0)] were found significantly down/up regulated in BC patients compared with healthy subjects, and they were selected as diagnostic biomarkers. Additionally, ROC curve analysis was used to assess their clinical usefulness, obtaining an AUC of 0.963 (95% CI 0.919-0.989) when using a multivariate model of 3 features. As an outcome, we showed that selected biomarkers are useful as diagnostic biomarkers. Conclusions: The present study demonstrates potential of metabolomics in identifying novel biomarkers for BC. Further studies may reveal the potential of metabolites as diagnostics biomarkers for BC and their role in pathogenesis.
Comprehensive detection of ctDNA variants at 0.1% allelic frequency using a broad targeted NGS panel for liquid biopsy research.
Authors: Chien Richard , Brinza Dumitru , Gu Jian , Dhingra Dalia , Banjara Kunal , Li Yanchun , Bagai Varun , Schageman Jeoffrey , Ballesteros-Villagrana Efren , Chaudhary Ruchi , Hanif Khalid , Au-Young Janice , Hyland Fiona , Bramlett Kelli
Published: September 2018

e23065

Background: Advances in non-invasive tumor biomarker research have shown that tumor cells release fragments of DNA called circulating tumor DNA (ctDNA) into peripheral blood. Somatic mutations representing the tumors could be successfully detected from isolated ctDNA, providing new potential for tumor sample assessment in addition to traditional tissue biopsy methods. However, the low amount of ctDNA in the blood, which can be less than 1% allelic frequency, presents significant challenges for reliable variant detection with NGS assays. Improvement of sequencing accuracy at low allelic frequency is a critical factor in the implementation of NGS in ctDNA liquid biopsy research. Methods: We demonstrate the technical feasibility for a sample-to-variant NGS workflow that utilizes a broad multi-gene panel to survey a comprehensive list of variants relevant to multiple tumor types for liquid biopsy research. The method includes novel library preparation and analysis reporting for Ion Torrent™ sequencing platforms. 20ng of input cell-free DNA was subjected to the library generation protocol. Prepared libraries were templated on Ion Chef™ and sequenced on Ion S5™. Results: We successfully optimized an NGS workflow that enables the simultaneous examination of more than 360 driver and resistance hotspot mutations in a single-pool assay panel, achieving high sensitivity and specificity with limit of detection at 0.1% allelic frequency. The targeted regions span genes and variants relevant to multiple tumor types for comprehensive variant detection across high-value content reviewed by industry experts and researchers. Sequencing on the Ion S5™ delivered > 95% on-target reads and uniform amplification across targeted regions with deep sequencing depth ( > 40,000x). The workflow is compatible with single or multiple pooled samples on Ion Torrent™ sequencing chips. Conclusions: We demonstrate the ability to accurately detect high-value variants implicated in multiple tumors at 0.1% allelic frequency on Ion Torrent™ NGS. (For Research Use Only. Not for use in diagnostic procedures.)