bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of effective therapy in Langerhans cell histiocytosis in the adult population.
Authors: Ma Jennifer , Laird James , Chau Karen , Chelius Monica , Bell Andrew C. , Lok Benjamin H. , Yahalom Joachim
Published: September 2018

7065

Background: Langerhans cell histiocytosis (LCH) is a rare disorder of histiocytic proliferation most commonly observed in children. LCH in adults is less characterized and a standard of care has not been established. Here we review clinical outcomes of adult LCH patients (pts) treated with various therapies at a large referral center. Methods: We identified 108 pts over 18 years of age with histologically confirmed LCH presenting to our center between 1990-2015. Clinical and treatment characteristics were examined and classified by single or multi-system involvement (SSI or MSI, respectively) and risk-organ involvement (ROI; liver, spleen, hematopoietic system and CNS). Overall survival (OS) and freedom from first progression (FFFP) were calculated by the Kaplan-Meier method. Univariate analysis was performed with the Cox proportional hazards model. Results: Median age at diagnosis was 44 years (range 18-89) with a median follow-up of 3.9 years (0.1-9.1). Median OS was 16.1 years and FFFP was 5.6 years, with 94 (87%) pts alive at last follow-up. Eighty-three (77%) had SSI and 13 (12%) had ROI. The most common sites of disease were bone (52 pts; 48%), lung (28; 26%), and skin (24; 22%). Only 11 pts (9%) experienced progression of disease (POD) after first treatment. Twenty-four (22%) received radiotherapy, 42 (39%) underwent excision, and 26 (24%) received systemic therapy at any point during treatment. The most common systemic agents were vinblastine, 6-mercaptopurine (6-MP), methotrexate (MTX), and cladribine. Eight received combination vinblastine, 6-MP, and MTX (VMM), 4 of which had MSI. Median progression-free survival (PFS) of VMM pts was 6 months, compared with 2.8 for all other systemic agents (p = 0.1). For OS, lack of ROI was the only significant variable upon univariate analysis (HR .22, 95%CI 0.06-0.75, p = 0.016). No variables were significant for PFS. Conclusions: Effective therapy for adult LCH has not been clearly identified. In our cohort of both low and high risk patients, the low POD rate observed is encouraging. VMM, a regimen previously studied in pediatric pts, is also effective in adults and may be considered the combination of choice for treatment of adult LCH. Further prospective study is warranted.
Trabectedin (T) as second line treatment option for patients with epithelioid malignant pleural mesothelioma (MPM) in progression following pemetrexed/platin-derivates chemotherapy: ATREUS trial.
Authors: Cortinovis Diego Luigi , Hollander Lital Hannah , Carlucci Luciano , Grosso Federica , Ceresoli Giovanni Luca , Pacchetti Ilaria , Zucali Paolo Andrea , D'Incalci Maurizio , Tiseo Marcello , Legramandi Lorenzo , Canova Stefania , Ugo Francesca , Abbate Maria Ida , Taverna Giacomo , Cogliati Viola , Bidoli Paolo
Published: September 2018

8513

Background: Systemic chemotherapy in MPM is inevitably followed by relapse, and response rates to second line treatment are limited. T is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment with demonstrated activity against a range of tumors. We aimed to study the activity and safety of T in advanced MPM. Methods: ATREUS, an Italian multicenter single arm phase II trial, assessed the activity T in MPM evaluating the proportion of patients responding to treatment and achieving progression free survival for 12 weeks (PFS12w). Pre-treated epithelioid and naive or pre-treated biphasic/sarcomatoid pts were treated until progression or unacceptable toxicity. Initial dose was 1.3 mg/m2, over 3 hours every 21 days, later reduced to 1.1 mg/m2to improve tolerability. In the epithelioid cohort, sample size was based on a Simon's Optimal Two-Stage Design. The study was set to reject, at an alpha error of 10% the hypothesis that PFS12w was ≤25% and to demonstrate, with a power of 85% the hypothesis that PFS12w was ≥40%. At least 20 out of 62 pts with assessed disease, no major protocol violations, either receiving ≥12 weeks of treatment or interrupting before for progression or death (per protocol – PP analysis) were to reach PFS12w in order to consider T effective. Results: 71 pts were enrolled and evaluable. Average age was 65.8 ± 8.75 years. 71.8% were male and 82.5% presented stage III or IV disease. 42.4% (25/59) of pts included in the PP analysis obtained PFS12w (95% CI: 29.6% - 55.9%). In a second, more conservative analysis, including pts withdrawn prematurely for toxicity or intercurrent illness as failures, PFS12w rate reached 38.5% (25/65 pts). The most frequent grade ≥3 treatment-related toxicities werehepatic toxicity (60.5%), non-febrile neutropenia (21.1%), and fatigue (6.6%). Five pts (7%) interrupted treatment for toxicities (2 liver, 1 multi-organ failure, 1 thrombocytopenia, 1 T intolerance). Conclusions: In pts with advanced epithelioid MPM, second line treatment with T showed an elevated rate of disease stabilization. Safety data is promising but require further evaluation. Clinical trial information: NCT02194231.
Humanistic burden of disease in earlier stage metastatic (stage IIIb/c-IVM1a) versus late stage metastatic (IVM1b/c) melanoma patients in a real-world setting in the U.S.
Authors: Buchanan Jacqueline , Murugappan Swaminathan , Moon Rebecca , Roughley Adam , Rider Alex
Published: September 2018

9561

Background: To assess melanoma specific health-related quality of life (HRQoL) and health states in patients with earlier stage metastatic (IIIb/c-IVM1a) versus late stage metastatic (IVM1b/c) melanoma. Methods: Data were collected from the Adelphi Real World Advanced Melanoma Disease-Specific Programme, a cross-sectional survey of 112 physicians and their patients (N = 666). Data were collected between March and July 2016 in the US. A subset of 183 patients completed the Functional Assessment of Cancer Therapy Melanoma (FACT-M) and EuroQol-5D (EQ-5D) one time. Patients were classified by stage of melanoma at time of consultation. Descriptive analyses of HRQoL scores between earlier and late stage metastatic melanoma were assessed using Mann-Whitney U tests. Results: The mean age of the earlier stage and late stage metastatic patients was 62 and 64 respectively. More earlier stage metastatic patients had an ECOG status of 0 or 1 versus late stage metastatic patients (85%, 75% respectively). A total of 31% of late stage metastatic patients required caregiver support and had a median time since primary diagnosis of 5.0 months whereas earlier stage metastatic patients reported 14% and 5.2 months respectively. Patients with earlier stage metastatic melanoma had better mean EQ-5D index scores versus late stage metastatic melanoma patients (0.81 (n = 84), 0.76 (n = 93); p = 0.0103). Higher scores indicating better HRQoL were observed between earlier stage metastatic versus late stage metastatic melanoma patients for the FACT-M (120.7 (n = 81), 107.4 (n = 91); p = 0.0017) and subscales (except Social Well Being). Clinically meaningful differences between groups using published minimal important differences (MIDs) were observed in in 6/7 FACT-M subscales and EQ-5D VAS. Conclusions: Differences in HRQoL and health states were observed between earlier stage metastatic and late stage metastatic melanoma populations, highlighting the detrimental effect of developing metastatic disease. These results suggest that treatments that delay progression of the disease are important to conserve patients HRQoL
Determinants of adjuvant chemotherapy use in small luminal-like breast cancer.
Authors: Bonotto Marta , Gerratana Lorenzo , Bettini Alessandro , Cinausero Marika , Basile Debora , Pelizzari Giacomo , Vitale Maria Grazia , Bozza Claudia , Lisanti Camilla , Fanotto Valentina , Bartoletti Michele , Andreetta Claudia , Russo Stefania , Poletto Elena , Iacono Donatella , Mansutti Mauro , Minisini Alessandro Marco , Fasola Gianpiero , Puglisi Fabio
Published: September 2018

e12010

Background: The use of adjuvant chemotherapy (CT) in small luminal-like breast cancer (BC) is still heavily debated. International guidelines identify endocrine therapy as the backbone of adjuvant treatment for these patients (pts), while the addition of CT should be limited to high risk cases. The aim of this study was to evaluate the association between patient- or disease-related factors with the prescription of adjuvant CT. Methods: This retrospective study reviewed data from 559 consecutive pts with pT1 ( < 2 cm) luminal-like BC treated between 2004 and 2015 at the Department of Oncology of Udine (Italy). No restrictions were applied regarding lymph node status. The cut-off point of 1% was used to define ER and/or PgR positivity. Factors influencing the prescription of CT were investigated through uni- and multivariate logistic regression with odds ratio (OR) calculation. Prognosis was explored through Cox regression. Results: About thirty percent (173/559) of pts received adjuvant CT. By multivariate analysis, lymph node involvement was highly associated with CT prescription (OR 16.94, 95% CI 7.86-36.50, P < 0.001 for pN1; OR 3.92, 95% CI 1.45-10.58, P = 0.007 for pNmi). Tumor size drove towards the use of CT among pts with pT1c tumors (OR 12.87, 95% CI 1.49-110.88, P = 0.020) but not in pts with pT1b BC (OR 2.38, 95% CI 0.26-21.38, P = 0.437). In addition, a higher CT use was observed in pts with luminal B-like disease (OR 3.79, 95% CI 2.16-6.65, P < 0.001) or in presence of a Ki67 > 14% (OR 1.05, 95% CI 1.03-1.07, P < 0.001). On the contrary, pts with age > 60 years had a very low chance of receiving adjuvant CT (OR 0.09, 95% CI 0.04-0.20, P < 0.001). Notably, the use of CT was not associated with Disease Free Survival or Overall Survival (HR 1.3, 95% CI 0.77-2.17, P = 0.320; HR 1.05, 95% CI 0.56-2, P = 0.866; respectively). Conclusions: Nodal status, tumor size, disease sub-type, Ki67 expression and age are determinants of adjuvant CT prescription in pts with small luminal-like BC. Prospective studies are needed to identify which pts could safely avoid CT without influencing prognosis.
Effect of trastuzumab emtansine (T-DM1) on autologous platelet kinetics.
Authors: Gadi Vijyakrishna , Corson Jill , Cundy Arianne , Bailey Shawn , Pellham Esther , Christoffel Todd , Gettinger Irena , Barroso Jeffrey , Slichter Sherrill
Published: September 2018

e12521

Background: T-DM1 treatment results in Grade 3-4 thrombocytopenia in 8%-13% (1.4% with clinically significant bleeding). Prior in vitro studies reported T-DM1 inhibition of megakaryocyte maturation as the cause of decreased platelet production. The current study was initiated to evaluate the cause of thrombocytopenia in patients. Methods: Patients with HER2-positive metastatic breast cancer (N = 10) were enrolled in this Phase 1 study. 111In radiolabeled autologous platelet recoveries and survivals as well as serial platelet counts, bleeding time assays, platelet aggregation responses to epinephrine, adenosine diphosphate, collagen, arachidonic acid, ristocetin, and thromboxane were performed at baseline and during two consecutive cycles (C) of the drug (3.6mg/kg IV q3weeks). Results: Platelet nadir occurred on days (D) 7, 8, or 9 post-T-DM1 in C1 and at D5-6 in C2. Average nadir counts (% baseline) in C1 and C2 were 116,000/µl (52 ±22%) and 117,000/µl (48 ±31%), respectively, with return to baseline by D15 in both cycles. Autologous 111In-labeled platelet recoveries averaged 64 ±10%, 65 ±12%, and 65 ±12% at baseline, C1 and C2, respectively. Baseline platelet survival averaged 8.8 (±1.1) days but progressively shortened to 5.4 (±1.6) days during C1 and 4.6 (±1.0) days during C2 (p < 0.001 compared to baseline for both cycles). Bleeding times were appropriate for the corresponding platelet count throughout both cycles. Aggregation responses to all agonists decreased during the study, more in C2 than in C1. Conclusions: Following T-DM1 administration, platelet kinetic measurements demonstrated statistically significant progressive decreases in platelet survivals from normal baseline values (decreased survivals were observed in all patients treated on study). In distinction to published in vitro studies, these unexpected results indicate a direct toxic effect of T-DM1 on patients’ autologous circulating platelets. In addition, autologous aggregation responses were decreased, suggesting drug-induced platelet dysfunction. Clinical trial information: NCT01816035.
Targeted combination therapy with fulvestrant (FUL) for second-line (2L) treatment of hormone receptor-positive (HR+) advanced breast cancer (ABC).
Authors: Mayer Ingrid A. , O'Regan Ruth , Kornblum Noah Saul , Blackwell Kimberly L.
Published: September 2018

e12527

Background: FUL is the recommended 2L treatment for patients whose HR+ ABC progressed after aromatase inhibitor (AI) therapy. In first line ABC adding targeted therapy, eg. cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib or ribociclib, or mammalian target of rapamycin inhibitor (mTORi) everolimus (EVE), to endocrine therapy (ET) has shown superior efficacy vs ET alone. The use of similar strategies to delay disease progression on ET in the 2L setting is an area of active research. Methods: PubMed and ClinicalTrials.gov were searched for trials investigating FUL + targeted therapies in 2L HR+ ABC. Search terms: (advanced OR metastatic) AND (breast cancer) AND (FUL OR faslodex) AND (2L OR relapse OR refractory OR resistant OR progression). Efficacy, adverse events (AEs) and quality of life were assessed. Results: 28 studies of FUL + targeted therapies in 2L ABC were found. Key randomized trials include 8 studies exploring FUL + CDK4/6i: palbociclib, ribociclib or abemaciclib. Palbociclib + FUL significantly improved progression-free survival (PFS) vs FUL in 2L HR+ ABC (p < 0.0001; PALOMA-3), AEs were manageable. Assessment of FUL + ribociclib (MONALEESA-3) or FUL + abemaciclib (MONARCH-2) in 2L HR+ ABC is ongoing. Ten studies are evaluating FUL + phosphatidylinositol 3-kinase (PI3K)/AKT/mTORi in 2L HR+ ABC. FUL + EVE significantly prolonged PFS vs FUL (p = 0.02; PrECOG 0102). Two trials evaluated buparlisib (pan-PI3K inhibitor [PI3Ki]) + FUL in HR+ ABC post-AI (BELLE-2) and post-mTORi (BELLE-3). In both trials, buparlisib + FUL improved PFS vs FUL in patients with PIK3CA-mutated tumors, FUL alone led to a poor response in this subgroup. However, pictilisib (pan-PI3Ki) + FUL did not improve PFS vs FUL even in the PIK3CA-mutated subgroup (FERGI). Ongoing phase 3 trials are exploring FUL + alpelisib (α-specific PI3Ki; SOLAR-1) or FUL + taselisib (β-sparing PI3Ki; SANDPIPER) in PIK3CA-mutant HR+ ABC. Pts who have progressed on AI, CDK4/6i or (neo)adjuvant chemotherapy are eligible for these studies. Data on FUL + other targeted therapies will also be discussed. Conclusions: Addition of targeted therapy to FUL demonstrates promising efficacy beyond first line.
Surgical ovarian ablation for hormone receptor positive primary breast cancer in premenopausal women.
Authors: Oseledchyk Anton , Gemignani Mary , Dickler Maura N. , Goldfarb Shari Beth , Iasonos Alexia , Zhou Qin , Carter Jeanne , Barakat Richard R. , Abu-Rustum Nadeem , Zivanovic Oliver
Published: September 2018

e12536

Background: Ovarian ablation is increasingly used to complement endocrine therapy in select premenopausal women with hormone-receptor positive (HR+) breast cancer (BC). It can be achieved by either medical ovarian suppression (OS) or therapeutic bilateral salpingo-oophorectomy (BSO). We sought to investigate trends of therapeutic BSO in premenopausal patients at our institution. Methods: Premenopausal women with HR+ primary BC diagnosed from 2010-2014 were identified in our prospectively maintained BC database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of patient and disease characteristics between treatment groups were assessed using univariate logistic regression analyses. Surgical details and complications were extracted from our surgical database. Results: We identified 2,854 eligible patients; 2,113 (74%) received endocrine therapy without ovarian ablation, 246 (9%) received endocrine therapy plus medical OS, 180 (6%) underwent additional BSO, and 315 (11%) did not receive endocrine therapy at the time of analysis. Independent predictors for undergoing ovarian ablation were younger age (OR 0.98; 95%CI, 0.96-0.99; p < 0.001), higher grade (grade 3 vs 1: OR 3.17; 95%CI, 1.70-5.90; grade 2 vs 1: OR 3.13; 95%CI, 1.64-5.95; p < 0.001), lymph node involvement (OR 1.46; 95%CI, 1.19-1.80; p < 0.001), and higher AJCC stage as well as de novo metastatic BC (II vs I: OR = 1.35; 95%CI, 1.03-1.76; III vs I: OR 2.57; 95%CI, 1.86-3.55; IV vs I: OR 19.69; 95%CI, 12.76-30.39; p < 0.001). Among patients who underwent ovarian ablation, patients of younger age (1.04; 95%CI, 1.01-1.07; p = 0.009) and with metastatic BC (stage IV vs I: OR 0.36; 95%CI, 0.20-0.68; p = 0.007) were less likely to undergo BSO than OS. In 180 patients undergoing BSO, five adverse events were noted: two grade 1, two grade 2, and one grade 3 complication. Conclusions: Premenopausal women with HR+ BC with high-risk features or metastatic disease were more likely to undergo ovarian ablation at our institution. Surgical ovarian ablation is a safe alternative, with low complication rates. Understanding patient preferences, side effects, and quality of life implications will help guide personalized treatment decisions.
Incidence patterns and survival of gynecological sarcoma in Germany: Analysis of population-based cancer registry data on 2106 women, 2009-2013.
Authors: Pietzner Klaus , Buttmann Nina , Sehouli Jalid , Kraywinkel Klaus
Published: September 2018

e13058

Background: Sarcoma of the female genital tract are rare tumors. They are described to be associated with a poor prognosis, when compared to gynecogical carcinoma. Aim of this study was to report incidence patterns and survival rates for gynecological sarcoma in Germany. Methods: Clinical data and survival rates for patients with gynecological sarcoma diagnosed in Germany between 2009 and 2013 were extracted from the German national centre for population-based cancer registry data. Incidence patterns and 5-year-relative survival rates were calculated. Results: A total of 2,106 gynecological sarcoma (GS) were eligible for analysis. The uterus was the most common site with 87.2% of all cases. The annual age-standardized incidence rate was 7.7 per 1 million women for all gynecological sarcoma. The median age at diagnosis was 59 years. The prognosis ranged according to site and subtype from a poor 5-year-relative survival of 47.6% (uterine leiomyosarcoma) to a very good 5-year-relative survival of 97.2% (endometrial stromal sarcoma). Conclusions: Despite the rareness of gynecological sarcoma, the size of the dataset allows a differentiation of subtypes according to morphology and site of origin. Clinically relevant differences in incidence and prognosis between subgroups were observed.
Triple negative breast cancer in a South African urban breast care centre.
Authors: Prodehl Leanne , Benn Carol
Published: September 2018

e13067

Background: Triple negative breast cancer (TNBC) is associated with advanced stage at presentation, aggressive tumour biology and poor outcomes. There is no published data for South Africa. Methods: A retrospective file review of TNBC cases at the Milpark Breast Care Unit in Johannesburg, South Africa, data were collected on presentation, treatment and outcomes. A prospective file review and telephonic interview were done for further follow up. Results: There were 196 patients with TNBC identified out of 1407 patients (13.9%), 135 patients were analysed. Stage at presentation was IIa and IIb in approximately half (46.7%) of the patients and IIIa, IIIb and IV in a third (31.8%). Patients presented with large tumours -71.8% were T2 to T4; and lymph node positive disease (55.6%). The majority of patients had high-grade, poorly differentiated tumours. The challenges when treating TNBC were reflected in the use of multimodality therapy; 92.2% of patients had chemotherapy, as neoadjuvant (59.3%), adjuvant or both. There were 93 (68.9%) patients treated with adjuvant radiation therapy. If neoadjuvant chemotherapy was given 91.2% had a response. Recurrences occurred in 33 patients, with a 5-year disease free survival of 72.5%, and preponderance to visceral metastases (45.2%). Recurrences occurred early, the median was 23.1 months and all had occurred within eight years. Younger patients (HR 1.58), tumour size and lymph node positivity (HR 4.42) were associated with increased risk of recurrence, but only lymph node positivity was significant (HR 4.42). Complete pathological response to neoadjuvant chemotherapy was associated with fewer recurrences if no tumour was found in either the breast or the lymph nodes (HR 0.33). The 5-year overall survival was 76.4%. There was no significant difference in survival for age, node status, nuclear grade, or complete pathological response, only tumour size at presentation was significantly associated. Conclusions: The prevalence of triple negative breast cancer in a South African breast care unit was similar to some European studies but less than studies in West and East Africa. Patients presented at an advanced stage and had poorer outcomes than luminal breast cancers.
Breast cancer screening in patients with cancers other than breast.
Authors: Maurer Stephen M , Leopold Robin Berton , Thomas Alexander W , Concannon Kyle Francis , Correll Alissa Dorothy , LaPenta Catherine M , Sprague Brian L , Herschorn Sally D. , Verschraegen Claire F.
Published: September 2018

e13095

Background: Screening mammography can detect early breast cancers and reduce subsequent cancer mortality. However, there is a lack of consensus as to what should trigger screening discontinuation. This absence of clear-cut guidelines means that many patients with advanced malignancies continue screening despite unclear benefit. Methods: We performed a retrospective cohort study of female patients diagnosed with a non-breast malignancy to explore the incidence and effects of screening mammography. Female patients, who were diagnosed between 2007 and 2012 with a non-breast malignancy stage II or higher, were cross-referenced with the Vermont mammography screening logs from January 1, 2007 to September 30, 2014. Additional data was collected through chart reviews, in May 2016. Results: Of 1501 women, 398 (26%) who met the above criteria had a screening mammogram within first 5 years of their cancer diagnosis. Of these 398 women, 193 (48.5%) were alive without cancer, 132 (33.2%) had died, and 73 (18.3%) were alive with cancer at the time of chart review. Of those who died, 84 (63.6%) had a stage III or IV cancer. Eighteen (4.5%) had a breast biopsy following a suspicious screening mammogram, resulting in 13 (3.3%) benign diagnoses and 5 (1.3%) breast cancer diagnoses. No patient died of breast cancer. Conclusions: Female patients diagnosed with an advanced non-breast malignancy have a mortality risk that outweighs the known breast cancer mortality benefit from screening mammography. [Table: see text]
Application of liquid biopsy to uncover critical cancer insights using the GeneReader NGS system.
Authors: Andruzzi Luisa
Published: September 2018

e13102

Background: NGS studies of cancer are primarily based on studies of FFPE samples, the use of which is limited by surgical feasibility, tissue availability and patient preference. An emerging field of study is focused on circulating-free DNA (cfDNA), sometimes termed “Liquid Biopsy”. While holding great promise as the future of cancer understanding and management, the liquid biopsy field is still nascent, lacking an integrated NGS workflow solution with proven performance. Methods: QIAGEN is an established expert in the field of sample preparation for liquid biopsy. The combination of the QIAamp Circulating Nucleic Acid Kit, the GeneReader NGS System using a new proprietary sequencing chemistry, and an optimized bioinformatics solution, provides the first fully integrated workflow specifically designed for analyzing cfDNA. A set of liquid biopsy samples from non-small cell lung cancer (NSCLC) patients and cfDNA reference standards (Horizon), with allelic frequency down to 1%, were used for this study. cfDNA was extracted from the liquid biopsy samples, and run through the QIAGEN GeneReader workflow. Variants were analysed using the QIAGEN Clinical Insight (QCI™) Analyze for liquid biopsy. Results: Expected mutations in all genes (EGFR, KRAS, NRAS, PI3KCA) were identified and verified, at 100% concordance with reported in ddPCR studies. Both single nucleotide and insertion-deletion variants were correctly detected down to a 1% allele frequency threshold which was reproducible between repeat runs. No significant difference was observed between cfDNA reference standards and clinical liquid biopsy samples. Conclusions: These data exhibit high sensitivity and performance consistency of liquid biopsy analysis with the GeneReader system. This study systematically demonstrates the accuracy of a cfDNA assay combined with the robustness of a fully integrated NGS system. As such, laboratories interested in conducting liquid biopsy studies can leverage this study and the system to implement an NGS workflow.
EGFR testing scenario across 111 centres in India: A questionnaire-based survey.
Authors: Prabhash Kumar , Parikh Purvish M. , Rajappa Senthill J , Noronha Vanita , Joshi Amit , Aggarwal Shyam , Bondarde Shailesh Arjun , Patil Shekar , Desai Chirag Jyotiker , Naik Rajesh , Anand Sohit , Chacko Raju Titus , Biswas Ghanashyam , Sahoo Tarini Prasad , Dabkara Deepak , Patil Vijay Maruti , MV Chandrakanth , Das Pratap Kishore , Vaid Ashok K. , Doval Dinesh
Published: September 2018

e13111

Background: Lung cancer diagnosis now involves routine use of biomarker testing to identify the driver mutations. We conducted a survey of 111 medical oncologists across India to understand the current pattern of EGFR mutation testing at their respective centres. Methods: Medical oncologists from 111 institutes across India were interviewed face to face using a structured questionnaire. They were divided into two groups - Group 1 with in-house EGFR testing and Group 2 who send samples to central/commercial labs. Answers of the two groups were analysed to see the prevailing patterns of EGFR mutation testing and differences between the groups if any. Results: In India, 95% of medical oncologists recommend testing for EGFR mutations in patients with adenocarcinoma histology. 40% would also recommend testing in squamous histology. 80% of medical oncologists request for biomarker testing at the time of primary biopsy. From the time of biopsy, the average time duration to get EGFR test results is 18 days. In centres with in-house testing (Group 1), results are available in 10 days. 96% of the medical oncologists from Group 1 centres request for factoring additional sample for biomarker testing compared to only 69% from Group 2. 69% of medical oncologists in Group 1 centres would prefer to wait for the test results before initiating treatment compared to 46% in Group 2. EGFR TKIs are used in 60% of patients with diagnosed EGFR mutation in the first line. For patients in whom chemotherapy is initiated while waiting for test results, 50% of medical oncologists prefer completing 4-6 cycles before switching to targeted therapy. At the time of progression, rebiopsy is possible in 25% of the patients. Rapid disease progression and poor PS were the two most common reasons given for the low rebiopsy rates. Conclusions: Application of molecular testing is ‎improving. Yield can be improved by training of multidisciplinary team involved in tumor biopsy. There is scope and need to reduce the turnaround time. This will reduce the current scenario of commencing chemotherapy while waiting for test results. Increasing application of liquid biopsy will help in initial diagnosis as well as at relapse, especially for patients with poor PS or difficult access to tumor site.
Antitumor effect of levetiracetam combined with temozolomide in glioma cell lines.
Authors: Chen Zhong-ping , Wu Qing-wu , Wang Jing
Published: September 2018

e13530

Background: The antitumor effect oftemozolomide (TMZ) is still remitted for portion of glioma patients, and if anti-epilepcy drug levetiracetam (LEV) may help TMZ for anti-glioma is not clear. Methods: The cell proliferation with Cell Counting Kit-8 (CCK-8) assay was performed in two O6-methylguanine DNA methyltransferase (MGMT) positive cell lines (T98G and U138) and two other MGMT negative cell lines (SKMG-4 and U87). The cells were treated with LEV and TMZ alone or in combination. Results: LEV inhibited the proliferation of glioma cell lines but not reach therapeutic effect, especially in U87cell line. The 50% inhibitory concentration (IC50) of TMZ was significantly decreased in cell lines (T98G, U138 and SKMG-4, P< 0.05) which were treated with TMZ and LEV, but no significantly changed in U87 (P> 0.05). Conclusions: LEV may inhibit the proliferation of glioma cell lines (both MGMT- positive and MGMT-negative) and also sensitizes cell lines (T98G, U138 and SKMG-4, but not U87) to TMZ.
Brain tumors: Regulation of angiogenesis.
Authors: Rostorguev Eduard Evgenevich , Frantsiyants Elena Mikhaylovna , Pogorelova Yulia A. , Cheryarina Natalia D. , Kozlova Larisa , Tkalya Lyudmila Dmitriyevna , Tavaryan Irina Stasio , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H. , Porksheyan David H. , Kit Oleg I.
Published: September 2018

e13540

Background: Cancer implicates pathological angiogenesis. The problem of treatment for primary and metastatic brain tumors is still unsolved. In addition to main angiogenic functions, VEGF family performs important mediator functions in the immune system. The role of VEGF family in central nervous system tumors is poorly studied. Our purpose was to study the levels of factors of angio- and lymphangiogenesis in tissues of glioblastomas (G), brain metastases (MTS), meningiomas and corresponding peritumoral area. Methods: Tissues of tumor and peritumoral zone (PZ) obtained during the surgery from 22 patients with G, 14 patients with brain MTS from breast cancer and 12 meningioma patients, mean age 39.2±4.8 years, were studied. Levels of VEGF-A, VEGFR-1, VEGF-C and VEGFR-3 were determined by ELISA. The data were processed using Statistica 10 program. The significance of differences was determined by Student's t-test. Results: VEGF-A levels in tissues of G and MTS were higher than in meningioma tissues by 74.7 and 94.5 times, respectively; levels of VEGF-R1 were 2.7 and 3.9 higher, and the VEGF-A/VEGF-R1 coefficient was 28.1 and 24.1 times higher, respectively. Levels of VEGF-C and VEGF-R3 were escalated only in G tissues compared to meningiomas (by 1.7 times on average). The VEGF-С/VEGF-R3 coefficient was similar in all studied tumors. VEGF-A levels were higher in PZ of G and MTS compared to PZ of meningiomas – by 78.2 and 110.7 times, respectively, while VEGF-R1 level was higher in G PZ only (by 5.5 times). The VEGF-A/VEGF-R1 coefficient was 14.5 and 128.5 times higher, respectively. VEGF-C level in PZ of G was escalated compared to meningiomas by 6.5 times, in MTS – by 1.6 times. VEGFR-3 contents did not differ significantly in all PZ samples, but the VEGF-С/VEGF-R3 coefficient was higher in PZ in G by 9 times and in MTS by 2 times. Conclusions: Compared to benign meningiomas, angio- and lymphangiogenesis are activated in glioblastoma tissue and angiogenesis – in metastatic tissue. Lymphangiogenesis is more active in peritumoral zone of glioblastomas compared to metastatic tissue, and angiogenesis is more active in peritumoral zone of metastases.
Kinin system of blood plasma as pathogenesis factor in brain tumors.
Authors: Kozlova Larisa , Frantsiyants Elena Mikhaylovna , Tkalya Lyudmila Dmitriyevna , Rostorguev Eduard Evgenevich , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H. , Kit Oleg I.
Published: September 2018

e13542

Background: The kallikrein-kinin system (KKS) does not only perform its adaptive-regulatory function; it is confirmed to be involved into pathology, neoplastic processes in particular. Our purpose was to study the kallikrein family (KLKs), pro-KLKs and carboxypeptidase N (CPN) in the blood plasma of patients with benign and malignant brain tumors. Methods: We studied citrated blood plasma of 164 patients with brain neoplasms: 37 meningiomas (M), 74 primary glioblastomas (G) and 53 brain metastases (MTS) from breast cancer. The kinetics of KKS enzymatic reactions was determined in the blood plasma before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA). The results were compared to the values in 39 healthy donors (N). The data were processed using the Statistica 10 program. The significance of differences was determined by Student's t-test. Results: Activity of KLKs in the blood plasma in patients with M exceeded N by 1.3 times (p≤0.05), in G – by 3.9 times, in MTS – by 5.1 times. Levels of pro-KLKs in M were lower than in N by 1.6 times, and in G and MTS they were similar to N. CPN activity in M was decreased compared to N by 3.1 times; in G and MTS it did not differ significantly from N. The pro-KLKs/KLKs coefficient in patients with M was lower than in N by 2 times, in G – by 3.7 times, and in MTS – by 5.1 times. Activity of KLKs in G and MTS was 3 and 4 times higher, respectively, than in M (p < 0.001). It supposed realization of effects of KLKs and produced bradykinin on cells, blood enzymes and microvessel walls in malignant brain tumors to a greater extent than in benign ones. Conclusions: Activation of KKS in the blood plasma in malignant brain tumors is more intense than in benign tumors, it directly and indirectly influences cell migration, increases capillary permeability and causes an imbalance in the related enzyme systems becoming a pathogenesis factor.
Impact of features of brain lesion in prognosis.
Authors: Castaneda Altamirano Carlos , Castillo Garcia Miluska , Belmar Lopez Carolina , Bernabe Luis A. , Sanchez Joselyn , Galvez Renato , Orrego Enrique , Garcia- Corrochano Pamela
Published: September 2018

e13549

Background: Brain metastasis (BM) is an event with poor prognosis. Different scores predict outcome in patients with BM. One of them is Graded Prognostic Assessment (GPA) score and includes clinical features like age and performance status of the patients. The frequency of patients with available tissue from brain lesions is increasing because of improvement of surgical techniques. It allows to include the evaluation of pathological features in order to improve prognosis determination. Our study aims to evaluate if tumoral proliferation and lymphocyte infiltration in brain lesions can improve prognostic accuracy of clinic-pathological features in patients with BM. Methods: We obtained BM samples from 113 cases that came to the Instituto Nacional de Enfermedades Neoplasicas from 2001 to 2015. We evaluated clinicopathological features from patient files and prospectively evaluated pathological features: Ki67 and lymphocytes in 64 BM lesions from slides scanned in a BX63-Olympus. The image analysis software use for calculating KI67 index and CD3 was Tissuemorph, with a median count of 5135 cells and 5391 cells, respectively. We calculated GPA score and evaluated the value to add pathological features of BM. We also evaluated distribution of mononuclear cells. Results: Median age at first diagnosis of BM was 52 years (range 11–75 years), 35.4% were male. BM at debut and extra-brain disease was found in 33.6% and 39.3%. The most frequent primary tumor location was breast (31%) and lung (18.6%). Most frequent procedure for brain lesion was biopsy (9.8%), subtotal resection (8.9%) and total resection (81.3%). Distribution of lymphocytes was perivascular in 57 cases. Median ki67 and CD3 TIL were 30 and 44, respectively. GPA 0-1, 1.5-2.5, 3 and 3.5-4 were found in 18 (16.2%), 61 (55.0%), 27 (24.3%) and 5(4.5%), respectively. Higher GPA (p = 0.196) had a trend to shorter survival. Higher ki67≥ 15% (p = 0.013) index was associated with shorter survival. The CD3 lymphocytes count was not associated with survival (p = 0.754). Adding ki67 index to GPA was associated with better outcome (p = 0.033). Conclusions: Our results find that patients with high ki67 index in brain lesions carry a worse prognosis and adding this information to GPA score can improve prognostic accuracy of the tool.
Survival analysis of a phase IB/II study of everolimus and metformin for patients with advanced cancer.
Authors: Molenaar Remco Jurriaan , van de Venne Tim , Weterman Mariette , Mathot Ron , Klumpen Heinz-Josef , Richel Dirk , Wilmink Johanna
Published: September 2018

e14020

Background: Fundamental research suggests that a combination of everolimus and metformin has synergistic anti-tumour effects with lower chances of drug resistance. Methods: 9 patients with advanced refractory cancer received everolimus and metformin in a 3+3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results: We enrolled 9 patients who stayed on the study for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. 4 out of 9 patients experienced a DLT and we terminated patient enrollment. Metformin was eliminated slower and metformin trough concentrations were higher when co-administered with everolimus than as single-agent (half-life: 9.3 h vs 4.3 h; P= .03 and Ctrough: 0.47 mg/l vs 0.2 mg/l; P =.01). After 9 weeks of treatment, 3 patients were still on study and all had stable disease as evaluated using CT scans and RECIST criteria. The 3 patients that received everolimus and metformin for at least 9 weeks had a significantly longer survival than the 5 patients who had to stop study treatment prematurely due to toxicity (median overall survival: 184 days vs 82 days; P= .048). Conclusions: The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. This may be due to pharmacokinetic interactions between everolimus and metformin and has implications for diabetic cancer patients that are treated with these drugs. Patients that tolerated the combination survived longer than patients who did not, suggesting that the combination of an mTOR inhibitor and metformin is clinically effective against cancer. This advocates for future clinical trials with combinations of other mTOR inhibitors and biguanides. [Table: see text]
Comparison of adverse events beyond cycle 1 between cytotoxic combination and molecularly targeted phase I trials.
Authors: Jordan Emma J. , Spicer James F. , Sarker Debashis
Published: September 2018

e14028

Background: Traditionally, only grade 3 and 4 adverse events (AEs) occurring during cycle 1 are used for dose escalation decisions in phase I oncology trials. With the shift in cancer drug development away from cytotoxic chemotherapy towards molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered to be of increasing relevance. This study evaluated differences in AE incidence between trial types (combination cytotoxic vs. single MTA) and cycle number (1 vs. 2-6). In line with previous work suggesting ethnic and age related differences in toxicities, we evaluated AE incidence across a range of patient demographics. Methods: Retrospective analysis of toxicity data in patients enrolled onto phase I clinical trials at a single UK centre between 2006 and 2016. All AEs in the first six cycles of treatment deemed at least ‘possibly related’ were recorded. Results: A total of 912 AEs (664, grade 1; 194, grade 2; 54, grade 3 and 4) were identified in 127 patients across 15 different trials (420 treatment cycles). Mean AE totals for patients on cytotoxic combinations and MTAs respectively were 4.51 and 2.94 in cycle 1, 3.47 and 3.04 in cycles 2-6. Patients on cytotoxic combinations experienced a significantly higher mean number of AEs in six cycles compared to those on MTAs (7.98 vs. 5.98, p = 0.0135). Of the patients experiencing grade 3-4 AEs, 57% (cytotoxic combinations) and 75% (MTAs) occurred for the first time after cycle 1. No significant difference in incidence of AEs was found between any subgroups of patient demographic variables. Conclusions: Incidence of AEs is less in MTAs than for cytotoxic combinations across cycles 1-6. The significant incidence of first grade 3-4 AEs occurring from cycle 2 onwards supports incorporation of AE assessment beyond cycle 1 into recommendations for phase II doses in MTAs.
Efficacy of a repeat dose injection of CLR 131 (I-131-CLR1404) in U87-MG tumor-bearing athymic nude mice.
Authors: Oliver Katherine , Longcor Jarrod , Kandela Irawati
Published: September 2018

e14089

Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a repeat dose intravenous injection in U87-MG tumor bearing mice. Malignant gliomas are associated with a low survival rate, and treatment with chemotherapy, external beam radiation, or surgery have shown limited effectiveness. In this study, therapeutic effect was evaluated by measurement of tumor volume increase and by survival of CLR 131 treated animals compared to animals dosed with a I-127-CLR1404 control. Methods: The U87-MG cell line (human glioma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in MEM media supplemented with 10% fetal bovine serum. Twenty female athymic nude mice (Harlan, Indianapolis, IN) weighing between 16-20 g were anaesthetized with isofluorene and inoculated subcutaneously in the right flank with 1 x 106 U87-MG tumor cells suspended in 50 μL PBS. The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation, with the addition of 0.4% (w/v) sweetener (Sweet and Low) to aid palatability, three days prior to injection and continuing through two weeks post injection. Doses of 95.7µCi and 109.0 µCi of CLR 131were given at Day 0 and Day 7 (N = 8 per group). Control doses of I-127-CLR1404 were given at the indicated dose and was injected via tail vein on Day 0 and Day 7. Results: The control group’s tumors increased 25-fold over a period of four weeks and the treatment group’s tumors increased 12-fold over the same period. There was a significant difference between the control and treatment tumor volumes. Mean survival time was 24.5 days and 31.9 days post injection, respectively. Conclusions: CLR 131 represents a unique, first in class targeted radiotherapeutic currently in clinical development. This study shows that CLR 131 dosed twice provides significant inhibition of tumor growth in a U87-MG tumor model which is known for very aggressive growth. Additionally, CLR 131 provided an overall survival benefit over the control group.
Evaluation of advanced lung cancer inflammation as potential prognostic markers in patients with colorectal cancer.
Authors: Rowe Julie Haewon , Kamil Fathima , Yu Andre , Wray Curtis Jackson , Cen Putao , Jafri Syed Hasan Raza
Published: September 2018

e15142

Background: The Advanced Lung cancer Inflammation (ALI) prognostic index evaluates the degree of systemic inflammation in cancer patients and has been validated in small cell lung and esophageal cancer. The “sidedness” of the colon primary has prognostic implications with left sided tumors having longer survival rates than right sided. Our hypothesis is that right sided colorectal cancers (CRC) will have a lower ALI. Methods: We conducted a retrospective review of newly diagnosed CRC patients who were seen and evaluated at a tertiary Cancer Center from 1/1/2005 to 12/31/2015. ALI is calculated as ALI = BMI x (serum albumin/NLR). NLR is the neutrophil to lymphocyte ratio. Logistic regression models were used to determine the association between primary colon cancer location and ALI. Results: A total of 279 patients were included in this study. 53% of patients were male and mean age was 63.4 years (SD 13.7). 52% of cancers were located on the right side. Using an ordered logistic regression, ALI was predictive of higher stage disease (p = 0.04). In those patients with stage III (n = 64) or IV (n = 136) disease, the likelihood of a low ALI was significantly higher for right-sided colon cancers (OR 2.12, 95%CI:1.18-7.76). Conclusions: The Advanced Lung Cancer Inflammation index appears to be related to both CRC stage and primary cancer location. Ongoing studies are needed to determine the relationship between ALI and CRC survival.
Association between promoter methylation and protein expression of tumor suppressor genes with clinical characteristics in gastric carcinoma and its effect on the biological function of gastric cancer.
Authors: Ying Jieer , Jingjing Li
Published: September 2018

e15509

Background: Studies showed that the gene promoter methylation may be the third important mechanisms of gene expression regulation. Abnormal methylation of tumor suppressor gene can be detected in the early stage of tumor, by screening the methylation profile of gastric cancer (GC), it can provide theoretical and experimental evidence for early diagnosis, treatment and prognosis. Methods: Detecte p16, hMLH1 and CDH1 promoter methylation, the p16, hMLH1 and E-cadher expression in GC tissues and its correlation with clinicopathological features and prognosis. Detect methylation of hMLH1 promoter and mRNA expression in GC cell line and normal gastric mucosa cell line. Clone formation assay and Transwell test. Results: The methylation of hMLH1 and CDH1 in GC and adjacent tissues were statistically significant . The methylation of hMLH1 was related to alcohol , CA199 level and Borrman. The methylation of CDH1 was related to the CEA level. The methylation of hMLH1 promoter is related to OS in GC patients. The methylation of p16 and CDH1 was not related to the OS ofGC patients. The GC patients with 0 or 1 gene methylation had a better prognosis than those with 3 or 2 gene methylation. The p16, hMLH1 and E-cadherin protein expression in GC and adjacent tissues were statistically significant. The p16 protein expression was related to tumor size. The hMLH1 protein expression was related to the CA199 level and tumor size. The E-cadherin expression in GC patients with drinking history was lower than ones without drinking history. The p16, hMLH1 and E-cadherin protein expression was not related to the OS of GC patients. There was a negative correlation between hMLH1 gene methylation and its protein expression in GC. The number of clones in the control group and the experimental group were 180 ± 3 and 169 ± 6. The number of cells in the control group and the experimental group were 135 ± 4.08 and 125 ± 4.18. Conclusions: The methylation of multiple genes is associated with the prognosis, which can provide theoretical basis for accurate treatment and prognosis for GC patients.