bluuebunny/crossref_metadata_2025 huggingface dataset:
Relating tissue selenium to anthropometric and receptor status in Nigerian patients with breast cancer.
Authors: Alatise Olusegun Isaac , Omoniyi-Esan Ganiyat Oluwatoyin , Lawal Olukayode O , Adesunkanmi Abdulrusheed Kayode , Agbakwuru Augustine
Published: March 2020

e12022

Background: The aim of this study was to identify the relationship of tissue selenium to anthropometric data and receptors status among Nigerian women with breast cancer. Methods: Consecutive consenting patients who had histologically confirmed breast cancer and fibroadenoma at Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, were recruited for the study. One gram of disease breast tissue was taken for selenium analysis from the subjects. The specimens were analyzed using graphite furnace atomic absorption spectrometer. Subjects’ demographics, anthropometric and breast cancer receptor status were recorded on a standard proforma. Results: There were 127 female subjects in the 2 groups. There were 95 (74.8%) cases of fibroadenoma and 32 (25.2%) of breast cancer. While the median tissue level of selenium in patients with fibroadenoma was 0.0272mg/g with a range of 0.0124 to 0.0576mg/g. The median tissue level of selenium in patients with breast cancer was 0.0178mg/g with a range 0.0072 to 0.0436mg/g. This was statistically significant (r=-0.613; p=0.0001). The anthropometric data of the patients such as weight, height, body mass index (BMI), body surface area, mid upper arm circumference and waist over hip ratio were correlated with tissue level of selenium and only waist over hip ratio and mid upper arm circumference were statistically significant (p<0.0001, 0.049 respectively). When association of the breast cancer receptor status was tested against the tissue level of selenium, while the ER and PR receptors were significantly related to tissue level of selenium (F= 41.765, p= <0.0001; F= 3.904, p=0.021), the HER receptor status was not (F= 1.100, p= 0.467).There was negative correlation between the tissue selenium and waist over hip ratio as well as tissue estrogen receptors status. Conclusions: Tissue selenium in patients with breast cancer was significantly low than that of fibroadenoma group. Similarly, tissue selenium is inversely related to waist over hip ratio and estrogen receptor status in subjects with breast cancer. It therefore implies that low tissue selenium may be an underlying factor in the occurrence of breast cancer in Nigeria.
Risk of skeletal-related events (SREs) in patients with breast cancer (BC) and newly diagnosed metastases to bone.
Authors: Taneja Charu , Lamerato Lois , Glass Andrew , Richert-Boe Kathryn E. , Edelsberg John , Wolff Greg G. , Czapski Natalie , Chung Karen , Richhariya Akshara , Oster Gerry
Published: March 2020

e12024

Background: Bone is a common site of metastatic involvement in patients (pts) with BC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large US Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary BC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 378 pts with primary BC and newly diagnosed bone mets; 87 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 291 pts, mean (SD) age was 58.2 yrs (14.3 yrs), and 99% were women; 46% were Caucasian and 48% were African-American. Median duration of follow-up after diagnosis of bone mets was 16.1 months (mos). At 12 mos, cumulative incidence of SREs was 44.5% (SCC, 5.2%; PF, 21.0%; SCC and/or PF, 23.3%; SB, 7.6%; RT, 34.3%) (Table). Corresponding figures at 24 mos were 53.8% (SCC, 7.5%; PF, 29.3%; SCC and/or PF, 32.5%; SB, 9.4%; RT, 41.7%). Approximately one-half (45.0%) of study subjects received intravenous bisphosphonates prior to SRE. Conclusions: Pts with BC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
Epidemiologic, clinical, and pathologic features of lymphomas at the Peruvian hospital: Hospital Nacional Cayetano Heredia.
Authors: Padilla Juan , Venegas Diego , Rodriguez Miro , Caceres Jaime , Cok Jaime , Tokumura Carolina , Ruiz Wilson , Ulloa Victor , Grados Sanchez Oswaldo Abelardo
Published: March 2020

e12041

Background: During the decade 70’ to 90’ incidence of lymphomas in Lima, Peru increased from 3.4 to 7.5 per 100 000 females and from 6 to 8.3 per 100 000 males. We describe epidemiological, clinical and pathologic features of patients with lymphoma diagnosed at the Hospital Nacional Cayetano Heredia (HNCH), center of reference of Lima north. Methods: Retrospective study of 433 patients with lymphoma diagnosed from 1998 to 2008 at the HNCH. Results: The mean age was 44.8 years (range 1 to 93 years), the ratio was 1.5:1 for male and female respectively, 85.9% were Non Hodgkin Lymphoma (LNH). In Hodgkin diseases’ patients the mean age was 34 years and ratio male: female was 2:1; whereas, in NHL, the average age was 45.9 years and ratio male: female was 1.4:1. The more frequently symptoms were weight loss (40.5%) and lymphadenopathy (36.7%). The 55.08% were clinical stage I-II. The most frequent location was nodal (55.1%). More frequently extra nodal locations were: gastrointestinal (15.2%) and skin (10.8%). In NHL, the immunophenotype B were: B (57.8%), T (19.6%) and not determined ( 22.6%). The most common histological type was large diffuse cells lymphoma (35.8%). T-cell lymphoma adults occurs in 6.9% of cases, follicular in 4.7% and anaplastic in 4.7%.According to RECIST 1,1: 78.12% had remission completed and parcial. In Hodgkin’s disease’s treatment with ABVD was 90.97% of responses complete and parcial. During this period 23.45% of patients reported died Conclusions: Our patients with lymphoma retain the same general characteristics of the worldwide. ATLL had prevalence high relative to others series
Clinical profile and outcomes in glioblastoma multiforme: Institutional experience.
Authors: Adavikolanu Kesava Ramgopal , Syed Fayaz ahmed , Malik Monica , K Jagannathrao Naidu , Pamidighantam Suresh , Sunkavalli Venkataratnam
Published: March 2020

e12501

Background: The standard of care for glioblastoma is surgical resection followed by adjuvant RT (radiotherapy) with concurrent and adjuvant temozolomide. Methods: Between January 2006 to December 2010, patients of glioblastoma who underwent surgery and RT to a dose of 60 Gy were analysed retrospectively. Age, KPS, extent of surgery, RPA class were noted and patients were divided into two groups, RT alone (Group I) or RT with concurrent temozolomide 75mg/m2/day followed by adjuvant temozolomide 150 mg/m2/dayX5days q28days for 6 cycles(Group II). Results: A total of 62 patients were analysed, 23 patients in group I and 39 in group II. Median age in group I was 48 years (range 16-60, 19 male, 4 female), 8(34.8%) patients underwent gross total resection, 12 (52.2%) had partial resection and 3(13%) had stereotactic biopsy. The median overall survival (OS) was six months. Median age in group II was 50 years (range 13-76, 26 male, 13 female), 17(43.6%) patients underwent gross total resection, 19(48.7%) had partial resection and 3 (7.7%) had stereotactic biopsy. The median OS was nine months (p=0.018). Patients were analysed according to the RPA class (III-VI). Median OS and 1 yr survival for group I for RPA class III,IV,V/ VI were 12, 6 and 4 months and 50%,15.3%,0% respectively. Median OS and 1 yr survival rates for group II for RPA class III, IV,V / VI were 20, 8 and 5.5 months and 66.6%, 35%, 30% respectively. On multivariate analysis age(p=0.005), KPS(p=0.05), extent of surgery(p=0.043) were found to affect survival. Conclusions: Concurrent radiotherapy and temozolomide followed by adjuvant temozolomide results in improved survival in glioblastoma.
Bevacizumab (BEV)-based therapy in the treatment of recurrent glioblastoma (GBM) in patients (PTS) treated at a Brazilian cancer center.
Authors: Munhoz Rodrigo Ramella , Braghiroli Maria Ignez Freitas Melro , Rego Juliana Florinda De Mendonga , Hoff Paulo Marcelo , Feher Olavo , Katz Artur
Published: March 2020

e12513

Background: Temozolomide (TMZ) both concurrently and after radiation therapy constitutes the standard of care for newly diagnosed GBM PTS. BEV is FDA approved option for recurrent high-grade gliomas PTS based on the results phase II trials. Reports of the use of BEV in these setting have been limited to USA and European academic centers thus far. Methods: We conducted a cross sectional retrospective study of 39 consecutive PTS with histologically confirmed GBM that received BEV in the second or third line setting. The main objective of this analysis was to assess the efficacy and safety of BEV given “off protocol” in an unselected cohort of PTS treated at a Brazilian teaching hospital cancer center and to compare our results to those reported by North American and European academic centers. PTS received first-line treatment with TMZ plus radiotherapy and most received maintenance TMZ and received Bev-based therapy at the time of disease progression. Main endpoints were the evaluation of progression-free survival (PFS), overall survival (OS) and safety. Results: Between 2007 and 2011, 39 PTS with recurrent GBM that received BEV in second (92%) or third-line (8%) were identified. Seven PTS progressed during concomitant RT and TMZ, and 40 during or after TMZ maintenance. 72% were male; median age: 56 years (range 22-79). Most patients (89,7%) received BEV in combination with irinotecan, and the median number of cycles, regardless of combination, was 14. Reasons for BEV discontinuation were disease progression in 79,5% and toxicity in 4 patients. There was one treatment related death due to thrombocytopenia and bleeding. Twenty-four PTS (61,5%) achieved an objective response with BEV. Median PFS of the patients that received BEV in either second or third line was 7.5 months and median OS was 22.6 months. No bowel perforations or any unexpected toxicities occurred. Conclusions: This constitutes the first report of recurrent GBM PTS treated with Bev in the Southern Hemisphere. In this unselected “real life” cohort of PTS with recurrent GBM we have been able to reproduce and confirm the efficacy and safety of this agent used in the treatment of GBM in the second and third line setting.
Are generic multisource (generic) chemotherapy (CT) drugs as effective as proprietary single-source (proprietary) drugs: Evidence from in vitro CT-induced apoptosis (APOP) in non-small cell lung cancer (NSCLC), colorectal cancer (Colon CA) compared to recurrent/metastatic breast carcinoma (Breast CA).
Authors: Karimi Misagh , Rajurkar Swapnil Padmakar , Bosserman Linda D. , Rogers Karl , Davidson Dirk C. , Willis Carl Rogaston , Rutledge James , Hallquist Allan , Presant Cary A.
Published: March 2020

e13003

Background: We have demonstrated that cancer cells from patients (Pts) with recurrent or metastatic Breast CA frequently show as much or better APOP with Generics compared to Proprietaries (separately submitted to ASCO, 2012). We have compared these observations to in vitro APOP in Pts with NSCLC and Colon CA. Methods: Purified tumor cells from Pt biopsies were placed into short term culture using the microculture kinetic (MiCK) assay. APOP was analyzed every five minutes over 48 hours. APOP was defined in kinetic units (KU) of apoptosis. Significant APOP was > 1.0 KU, significant differences between individual assays were defined as > 0.57 KU based on replicate analyses. Results from Breast CA, Colon CA and NSCLC were compared. Results: 41 Pts with NSCLC, 8 Pts with Colon CA and 67 Pts with Breast CA had successful cultures. Generics produced APOP greater than Proprietaries in 25/32 Pts with NSCLC (78%), 4/7 Pts with Colon CA (57%) and 36/43 Pts (84%) with Breast CA. Generics produced APOP = Proprietaries in 5 Pts with NSCLC (16%), 1 Pt with Colon CA (14%) and 6 Pts (14%) with Breast CA. Proprietaries produced APOP greater than Generics in 2 Pts with NSCLC (6%), 2 Pts with Colon CA (29%) and 1 Pt (2%) with Breast CA. There were 0 Pts with NSCLC, Colon CA or Breast CA in whom no drug produced significant APOP (KU less than 1.0). Proprietaries produced more APOP in Colon CA than in Breast CA (p<0.05). Detailed comparisons of drugs by disease will be presented. Conclusions: Generic drugs can produce APOP in vitro equal to or better than Proprietary drugs in most Pts with NSCLC, Colon CA, and Breast CA. The frequency of Generic drugs being at least as active as Proprietary drugs varies by disease, and was higher in Breast CA compared to Colon CA. However, the MiCK APOP assay can identify which individual Pts might require use of Proprietary drugs. These conclusions justify prospective clinical trials to confirm these in vitro results. Increased use of Generic drugs based on the APOP assay may help to control healthcare costs.
Targeting of tumor cells and tumor stem cells by antibodies specific for the cell-bound alpha/beta junction of MUC1.
Authors: Pichinuk Edward , Benhar Itai , Jacobi Oded , Ziv Ravit , Smorodinsky Nechama , Rubinstein Daniel B. , Wreschner Daniel H.
Published: March 2020

e13018

Background: MUC1 is a glycoprotein over-expressed on the cell surface of a variety of malignancies and has long been a subject of interest in targeted therapy.Cleavage of MUC1 yields two unequal chains, a large extracellular a subunit non-covalently bound to a smaller b subunit in an on-and-off mechanism. Because it is released into the peripheral circulation, the MUC1 a subunit readily sequesters antibodies directed against it. In order to avoid such peripheral sequestration, Abs directed against MUC1 must be engineered as to target cell bound moieties of MUC1. Methods: Seven anti-MUC1 monoclonal antibodies were generated, five Ig-gamma1 and two IgA, all directed against the MUC1 a/b junction, a structure which remains cell bound at all times. Results: In addition to their binding differentiated breast cancer cells at pico Molar concentrations, the anti-MUC1 mAbs strongly bind breast cancer stem cells. With a view for clinical application, the DMB5F3 anti-MUC1 mAb was partially humanized with resultant production of chimeric IgG1. In order to demonstrate that chimeric anti-MUC1 antibodies can be used in tumor cell killing, mAb DMB5F3 was linked to the pseudomonas bacterial exotoxin ZZ-PE38. The resultant anti-MUC1 immunotoxin not only efficiently internalized the toxin, it resulted in strong cytotoxicity of MUC1+ breast cancer. In fact, DMB5F3:PE38 immunotoxin bound MUC1+ cancer cells with an affinity (Ab concentrations as low as 20pM) exceeding that seen with cetuximab (anti-EGFR1)-PE38 and tratuzumab (anti-erbB2)-PE38 immunotoxins. Conclusions: Taken together, these findings indicate [1] the therapeutic use of targeting cell-bound MUC1 [2] high affinity activity against both tumor and tumor stem cells suggests that the anti-MUC1 mAbs target not only 'mature' differentiated malignancy but self-reproducing cells giving rise to new malignant growth as well [3]tumor can be targeted directly by anti-MUC1 antibodies or by linking anti-MUC1 to toxin, resulting in efficient immunotoxin cytotoxicity [4] as it was shown to be a targetable entity, the SEA domain represents a promising immunogen for MUC1 tumor vaccines.
Dextromethorphan phenotyping as a test for prediction of tamoxifen (TAM) activation in breast cancer patients receiving adjuvant hormone therapy.
Authors: Gusella Milena , Bertolaso Laura , Pasini Felice , Modena Yasmina , Bononi Antonio , Fraccon Anna Paola , Da Corte Donatella , Cretella Elisabetta , Modonesi Caterina , Vastola Francesca , Nicolardi Linda , Pegoraro Cristina , Rosti Giovanni , Brunello Antonella , Segati Romana , Durante Emilia , Falci Cristina , Raiti Concetta , Rampello Elvira , Padrini Robeto ,   Northern Italy TAM Group
Published: March 2020

e13019

Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.
Administration of contrast media just before the cisplatin-based chemotherapy increases the cisplatin-induced nephrotoxicity.
Authors: Sendur Mehmet Ali Nahit , Aksoy Sercan , Yaman Sebnem , Kos Fahriye Tugba , Arik Zafer , Civelek Burak , Özdemir Nuriye , Uncu Dogan , Zengin Nurullah
Published: March 2020

e13031

Background: The most important dose-limiting manifestation of cisplatin is renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the glomerular filtration rate (GFR). There is a clinical need to predict the probability of cisplatin-induced nephrotoxicity (CIN), in order to support decisions about patient management and preventive measures. The aim of the present study was to develop risk prediction of CIN. Methods: Consecutive 197 patients with documented serum creatinine before at least 48 hours every cycle cisplatin-based chemotherapy were included the study. Demographic and medical data including age, performance status, tumor characteristics and comorbid diseases were collected from the medical charts. Renal function was evaluated for each cycle before treatment (day 0) and before next cycle (day 21) based on the Modification of Diet in Renal Disease (MDRD) formula. Cisplatin-induced nephrotoxicity (CIN) was defined as decrease of ≥ 25% in GFR compared to baseline GFR values. Results: The mean age of the study population was 54.5±9.6 years. Baseline MDRD levels had decreased of ≥ 25% in 58 (29.4%) patients accepted as CIN group, the rest of 139 patients of the study population accepted as a non-CIN group. There was no difference of age, gender, body mass index and smoking history between groups. In both group, the hypertension (p=0.81), diabetes mellitus (p=0.72), and cardiovascular disease (p=0.58) were seen equally. Types of concomitant therapy with cisplatin-based chemotherapy were similar between CIN and non-CIN groups. The applied radiologic examinations with contrast media was observed higher in CIN group than non-CIN group (P=0.01). In patients exposure the contrast media within one week before cisplatin administration, the risk of CIN was observed 2.56 (95%CI: 1.28-5.11) times higher than in patients not exposure to the contrast (p=0.009). Conclusions: In patients exposure the contrast media within one week before cisplatin administration, the risk of CIN was observed higher than in patients not exposure to the contrast. No additional risk factor of CIN was found in this retrospective observational study.
New clinical trial of DNA-based vaccines for patients with non-small cell lung cancer.
Authors: Cohen Edward P. , Cohen Jonathan M.
Published: March 2020

e13034

Background: We report a new immunotherapeutic trial for patients with non-small cell lung cancer (NSCLC). The trial to be conducted at the University of Pittsburgh Cancer Institute is a two-stage uncontrolled non-randomized Phase IB study designed to evaluate the safety, immunogenicity and feasibility of a new vaccine, consisting of human allogeneic fibroblasts transfected with DNA derived from the patient’s own tumor. The vaccine is prepared by transfer of genomic DNA-fragments (25 kb) from the patient’s tumor into MRC-5 cells, a human embryonic fibroblast cell line. The rationale is that numerous mutant and dysregulated genes in the tumor specifying an array of patient-specific tumor antigens are expressed in a highly immunogenic form by the DNA-transfected cells. A large body of preclinical studies in tumor-bearing mice supports this approach. An IND has been issued. Cohort 1 is underway without DLT. Methods: We plan to use a two-stage trial design. Initially, 15 early-stage patients with NSCLC will be enrolled. If there is no evidence of toxicity, and >3 of the initial patients show an immunologic response, the second stage of the study will be opened for the accrual of 22 additional patients. A portion of the primary tumor removed at surgery will be obtained to serve as a source of tumor-DNA. Each vaccine will contain 1 X 10E7 DNA-transfected fibroblasts. The vaccine will be lethally irradiated before it is administered. It will be injected intradermally in the Outpatient Clinic. Immunologic responses to the vaccine and to the autologous tumor will be evaluated by IFN-g secretion in ELISPOT assays prior to and after vaccination for the frequency of T-cells responsive to the autologous tumor. Additional assays will include lymphocyte proliferation determinations in response anti CD3 and anti CD28 monoclonal antibodies and the effect of the immunizations on the proportion of myeloid-derived suppressor T cells in the patient’s peripheral blood. The patients will also be evaluated before and after immunization for the capacity of their T cells to respond to activating signals delivered via the T cell receptor (TcR). Results: Vaccines have been prepared. First patient has been enrolled. Conclusions: No data to report in this early trial.
Serum lipocalin-2 as a potential biomarker of liver irradiation.
Authors: Sultan Sadaf , Ramadori Giuliano , Ahmad Shakil , Rave-Fraenk Margret , Christiansen Hans , Cameron Silke
Published: March 2020

e13039

Background: Lipocalin-2 is a pleiotropic protein synthesized under acute phase conditions. The source of increased serum levels and the major organ responsible for its production are still unknown. The aim of our study was to prospectively evaluate the Lipocalin-2 (LCN-2) expression in rat liver exposed to single dose x-irradiation. Methods: A single dose of 25 Gy was administered percutaneously to the liver of randomly paired rats after a planning CT scan. Male Wistar rats were sacrificed 1, 3, 6, 12, 24 and 48 hours after irradiation along with sham irradiated control. Blood was taken for ELISA of LCN-2, and organs were removed and deep-frozen for RT-PCR and Western Blot or prepared for immunostaining. Furthermore, hepatocytes, myofibroblasts and Kupffer cells were isolated from the liver of healthy rats and irradiated with 2 Gy ex-vivo. Results: LCN-2 serum levels increased significantly (2.5 mg/ml) within 24 hours after direct liver irradiation. In the liver, LCN-2 specific transcripts increased significantly up to 552 ±109-fold at 24 hours which was further confirmed by Western blot analysis. Immunohistology of liver sections detected positivity in recruited granulocytes within 1 hour after irradiation around the central and portal areas. Ex-vivo irradiated hepatocytes showed a significantly higher LCN-2 expression as compared to myofibroblasts and Kupffer cells. Treatment of isolated, irradiated hepatocytes with acute phase cytokines (IL-6, IL-1b, TNFa, IL-6+TNFa) showed that the main inducer of LCN-2 was IL-1β. Conclusions: Single dose liver irradiation, induces a fast and significant increase of LCN-2 serum level. Hepatocytes are the major producers of LCN-2 in oxidative stress conditions. LCN-2 may represent a new serum-biomarker when the liver is hit by irradiation.
Phase II study of personalized peptide vaccine for refractory breast cancer patients.
Authors: Toh Uhi , Iwakuma Nobutaka , Takahashi Ryuji , Otsuka Hiroko , Matsueda Satoko , Shichijo Shigeki , Sasada Tetsuro , Itoh Kyogo , Shirouzu Kazuo
Published: March 2020

e13050

Background: To develop therapeutic cancer vaccine, we conducted a phase II study of personalized peptide vaccine (PPV) for refractory breast cancer patients. Methods: Thirty-four refractory breast cancer patients, including 8 triple negative (TN) cases, were enrolled to this study. A maximum of four HLA-class IA (A2, A3s, A24, A26)-matched peptides showing higher antigen-specific IgG responses were administered. Inflammatory markers, cytokines, and peptide-specific CTL and IgG responses were examined before and after vaccination to identify prognostic factors for overall survival (OS). Results: No vaccine-related severe adverse events were observed. Median numbers of preceding chemo- and/or hormone therapy regimens and median treatment duration from the recurrence to the vaccination were 2 regimens and 37 months, respectively. Three patients did not complete the 6th vaccination because of rapid disease progression. CTL or IgG boosting by PPV was observed in 16 or 18 of 31 patients at the time of 6th vaccination. IgG boosting was observed in all 24 patients tested at 12th vaccination. Median survival time of 31 patients receiving > 6th vaccination after the vaccination was 474 days with 2 complete responses and 1 partial response. There were no significant differences between 8 TN cases and the other cases from points of immunological and clinical responses. Lymphocyte frequency (Hazard ratio of 0.906, p=0.019) well associated with OS by multivariate Cox proportional hazard regression analysis for pre-vaccination samples. Conclusions: Next steps of PPV for the refractory breast cancer patients were warranted because of the lower toxicity and favorite immune responses along with possible clinical benefits.
Comparing the outcomes of noninferiority (NI) and superiority phase III trials.
Authors: Saad Everardo D. , Buyse Marc E.
Published: March 2020

e13055

Background: We compared the outcomes of NI and superiority trials on advanced breast cancer (BC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: We searched PubMed for phase III trials on systemic antineoplastic treatments for advanced BC, NSCLC and CRC published between 1/1998 and 12/2009 in 11 leading journals. We categorized primary endpoints (PEP) as time-to-event (overall survival or any variant of progression-free survival), response rate, or other (quality of life or toxicity). We used the PEP (defined as the one stated explicitly, used for N calculation, or cited first) to ascertain trial positivity. Results: We retrieved a total of 262 trials (93 on BC, 102 on NSCLC, and 67 on CRC), 36 of which (13.7%) used a NI design (12 in each tumor type). There was no significant trend in the proportion of NI trials in the two 6-year periods compared (1998-2003 vs 2004-9). The median number of patients/arm for NI and superiority trials were 284 and 164, respectively (p<0.001). There was no significant difference in the distribution of the PEP categories between NI and superiority trials. We could ascertain trial positivity in all but six trials: 24 (66.7%, 95% confidence interval [CI], 49.1% to 81.2%) NI trials were positive, compared with 89 (39.4%, 95% CI, 33.0% to 46.1%) superiority trials (p<0.001). NI trial positivity could be determined by finding a CI for the estimated treatment effect that excluded the NI margin in 15 of 27 trials (otherwise, positivity was based on authors’ conclusions, or the experimental therapy was superior to control for the PEP). The overall rates of trial positivity varied across tumor types: 48.4% for BC, 31.4% for NSCLC, and 53.7% for CRC (p=0.002). When adjusted for trial size, NI design (vs. superiority; odds ratio [OR]=4.2; 95% CI, 1.7 to 10.3) and tumor type (BC [OR=2.2; 95% CI, 1.2 to 4.0] and CRC [OR=2.8; 95% CI, 1.4 to 5.5] vs. NSCLC as reference) remained significantly associated with trial positivity. Conclusions: NI trials are more likely than superiority trials to yield positive results. The influence of NI margin width on trial results should be investigated.
Results of a comprehensive pharmacogenetic analysis of dihydropyrimidine dehydrogenase in patients treated with fluoropyrimidines and patterns of polymorphisms partially related to treatment tolerability.
Authors: Del Re Marzia , Schirripa Marta , Michelucci Angela , Cubelli Marta , Magagna Silvia , Minichillo Santino , Loupakis Fotios , Simi Paolo , Zamagni Claudio , Falcone Alfredo , Danesi Romano
Published: March 2020

e13057

Background: Metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, except the G>A mutation in the splicing consensus sequence of intron 14 (IVS14+1G>A), which is responsible of severe enzyme impairment, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens. Methods: Patients affected by colorectal, breast and head/neck cancers requiring standard treatment with 5-FU or capecitabine in combination with other cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled: 224 suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 61 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (IVS14+1G>A, 496A>G, 1601G>A, 1627A>G, 1896T>C, 2194G>A and 2846T>C) by automatic sequencing. The study was approved by local Ethics Committee. Results: A complex pattern of DPYD variants was identified in both cohorts; the following genotypes were detected in patients with severe toxicities vs controls: 496AG+GG: 24.1 vs 21.3%; 1601GA: 12.5 vs 1.6%; 1627AG+GG: 37.1 vs 32.8%; 1896TC+TT: 6.25 vs 8.2%; IVS14+1GA: 4.9 vs 0%; 2194GA: 25.9 vs 9.8; 2846AT: 1.3 vs 0%. Conclusions: Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated, with the exception of IVS14+1GA and 2846AT which were found only in patients with poor tolerability. This study was supported in part by a grant from AIRC to R. Danesi.
A phase I study of NK012 in combination with 5-fluorouracil with or without leucovorin in patients (pts) with advanced solid tumors.
Authors: Jones Suzanne Fields , Burris Howard A. , Infante Jeffrey R. , Greco Frank A. , Spigel David R. , Kawamura Shigeyuki , Ishioka Tatsunari , Yamazaki Hiroko , Bendell Johanna C.
Published: March 2020

e13076

Background: NK012 is a micelle-forming macromolecular prodrug of EHC (7-ethyl-10-hydroxycamptothecin), also known as SN-38, the active metabolite of irinotecan. Irinotecan-based regimens (including FOLFIRI) are commonly used in the treatment of gastrointestinal malignancies. The development of an improved irinotecan-based regimen either by improved efficacy, schedule, or toxicity profile, has the potential for a major role in the treatment of GI malignancies. Methods: Dose escalation study to determine the maximum tolerated dose and recommended phase II dose (RD) of NK012 (day 1) in combination with bolus 5FU/LV (400 /400 mg/m2) followed by continuous infusion 5FU (2400mg/m2 over 46 hrs) on days 1 and 15 every 28 days. Results: Twenty-three pts have been enrolled. NK012 was dosed at 16, 20, and 24 mg/m2 in combination with 5FU/LV bolus + CI 5FU. Two of 3 pts at 24 mg/m2 required a delay in the day 15 treatment due to myelosuppression. As a result, 20 mg/m2 was determined to be the recommended NK012 dose in combination with 5FU/LV bolus + CI 5FU. The protocol was amended to eliminate the bolus 5FU/LV due to the potential for added myelosuppression, and NK012 was re-escalated with CI 5FU only. NK012 was dosed at 24 and 28 mg/m2. One DLT (nausea/vomiting requiring hospitalization) was reported among 6 pts treated at 28 mg/m2. The RD of NK012 in combination with CI 5FU is 28 mg/m2. Treatment-related toxicities included nausea (61%, 13% gr 3), fatigue (48%), neutropenia (44% gr 3-4), vomiting (35%, 4% gr 3), diarrhea (30%), anorexia (30%), stomatitis (26%), and alopecia (26%). Six pts (including 3 pancreatic) remained on study for > 4 cycles, and two continued treatment for ≥ 1 year (colon, pancreatic). Conclusions: The combination of NK012 and CI 5FU is well tolerated, with NK012 administered at the recommended single-agent dose of 28 mg/m2. Further exploration of the regimen is warranted, particularly in patients with GI malignancies.
Clinical experience of a targeted TCR-IL2 fusion protein in combination with cisplatin (CDDP) in patients (pts) with metastatic melanoma.
Authors: Milhem Mohammed M. , Weber Jeffrey S. , Amin Asim , Agarwala Sanjiv S , Lawson David H. , Thompson John A. , O'Day Steven , Pennock Gregory K. , Richards Jon M. , Kuzel Timothy , Hernandez Liza , Huang Bee-Yau , Rhode Peter , Wong Hing C.
Published: March 2020

e13088

Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In melanoma xenograft mouse models, this fusion protein alone demonstrated potent, targeted antitumor activity and synergistic efficacy was observed in combination with CDDP. A prior phase I study in pts with metastatic malignancies, including metastatic melanoma, showed that ALT-801 monotherapy could be safely administered and was associated with immunologic changes of potential antitumor relevance (Fishman 2011 CCR 17:7765). Here we report the results of a phase Ib study of ALT-801+ CDDP in pts with metastatic melanoma. Methods: The primary objectives of this multicenter study are to: 1) define an MTD and evaluate the safety of ALT-801+CDDP and 2) assess the objective response rate according to RECIST criteria in treated patients. Eligible pts (histologically confirmed advanced/metastatic melanoma, p53 peptide/HLA-A2+ tumor, chemotherapy naive, PS (ECOG) 0-1, adequate renal and cardiac functions) received 2 consecutive 4-wk courses of CDDP (70 mg/m2 iv, Day 1) and ALT-801 (iv, Days 3, 5, 15, 17 & 19). Pts with SD or better after 2 courses received 2 additional courses of treatment. Up to 5 cohorts (3+3 dose escalation) of ALT-801 (0.04 - 0.12 mg/kg) were planned with a 2-stage design of expanded pt enrollment at the MTD. Results: 22 patients (11M, 11F, 30-74 yrs) were evaluable at ALT-801 dose levels from 0.04 to 0.10 mg/kg. The MTD has not been reached at 0.10 mg/kg ALT-801. Toxicity was manageable and transient. RECIST-confirmed tumor response and disease stabilization was reported for some patients. Overall survival rates (6 mon, 87%; 12 mon, 58%) observed to date suggest durable clinical benefit. Conclusions: ALT-801+CDDP can be safely administered in an out-patient setting to pts with metastatic melanoma. Preliminary evaluation suggests durable clinical activity of the ALT-801+CDDP regimen in melanoma patients. A trial using ALT-801 at the 0.1 mg/kg dose level in combination with a BRAF kinase inhibitor is being planned for patients with metastatic melanoma (CA097550).
Preclinical study of adoptive immunotherapy with natural killer cells in metastatic colorectal cancer.
Authors: Brugnatelli Silvia , Turin Ilaria , Manzoni Mariangela , Maestri Marcello , Montini Enrica , Caliogna Laura , Paulli Marco , Dionigi Paolo , Pietrabissa Andrea , Delfanti Sara , Rovati Bianca , Mariucci Sara , Maccario Rita , Pedrazzoli Paolo , Montagna Daniela
Published: March 2020

e13103

Background: Several immune-based approaches for treatment of metastatic colorectal cancer (mCRC) are currently under investigation. Aims of our study were to grow and characterize tumor cells (TC) obtained from mCRC patients, and to investigate their susceptibility to autologous natural killer (NK) cell recognition and killing in vitro. Methods: Tumor samples and peripheral blood mononuclear cells from 10 mCRC patients undergoing surgery were collected. Establishment of TC lines that are representative of the original tumor and could be expanded in vitro for a significant number of passage was performed according with our previously described method (Turin I et al, Cytotherapy 2007). CD56+CD3- NK cells were incubated overnight with medium alone or activated with IL-2 (100U/ml) or IL-15 (20ng/ml) and tested against 51Cr-labeled primary TC in NK assay or in ADCC assay after pre-coating of TC with anti-EGFR monoclonal antibody cetuximab. Results: Eight stable mCRC lines have been obtained and characterized to confirm their neoplastic origin. Patient NK cells display low capacity to lyse autologous TC (median 12%, range 5%-17%). IL-2 and IL-15 incubation significantly potentiate NK cytotoxic capacity (median18%, range 6%-62% and median 35%, range 28%-65%, respectively). These results refer to an effector:target ratio of 25:1. ADCC assay has shown that cetuximab pre-coating of TC results on an increasing of their susceptibility to NK-mediated lysis. Phenotypical and molecular analysis of activating NK receptors and their ligands present on surface of TC are currently under evaluation. Conclusions: NK cells derived from mCRC patients display measurable cytotoxic activity against autologous primary TC. Susceptibility of NK-mediated lysis is strongly enhanced by pre-incubation of NK cell with cytokines and by pre-coating of TC with cetuximab. These findings, presented upon approval by the study’s data monitoring committee and undergoing confirmation in a larger series, may support a pilot study of NK cells pre-activated ex vivo for treatment of mCRC patients.
Effect of heparin and its derivatives on the progression of tumor growth in mouse Lewis lung carcinoma model.
Authors: Gray Angel , Hoppensteadt Debra , Hejna Matthew , Fareed Jawed
Published: March 2020

e13115

Background: Preclinical evidence suggests that heparins have an effect on tumor progression independent of their anticoagulant activity. Heparins have also been shown to exhibit interactions with growth factors and other cellular receptors. This study was designed to investigate whether heparin and its derivatives are able to inhibit tumor growth. Methods: Female C57BL/6 mice were obtained at 6-8 weeks of age and were implanted with 5X105 LN7 tumor cells by dorsal subcutaneous injection of in the upper back. When tumors were first palpable, after 7-10 days of growth, mice were treated with subcutaneous injections of heparin, a low molecular weight heparin (LMWH), namely enoxaparin, an ultra LMWH, semuloparin or saline, daily for two weeks in a dose range of 1.0 – 0.25 mg/kg. After the treatment period, animals were sacrificed and the spleens and tumors were removed and their weight, volume, spleen weight and size were measured. Results: At the 1.0 and 0.5 mg/kg dosages, both enoxaparin (p<0.01) and semuloparin (p<0.01) showed a decrease in tumor volume compared to the saline control animals. At the 1.0 mg/kg dosage, the mortality was high in the heparin group due to bleeding. At 0.5 mg/kg heparin was not different from the saline control. In addition, at a dosage of 0.25 mg/kg, only semuloparin showed a difference compared to the saline control (p<0.01). Similar results were observed for the tumor weight. There were no significant differences noted in spleen weight or spleen size among these agents. The mortality rates between the mice treated with enoxaparin and semuloparin were comparable. Conclusions: These studies suggest that heparin and its derivatives are capable of inhibiting tumor growth in a dose dependent manner. Enoxaparin and semuloparin are more effective at reducing tumor growth compared to heparin. Clinical studies have shown that semuloparin is safe and effective for the prevention of venous thromboembolism in cancer patients and compares favorably to enoxaparin in terms of antithrombotic effect and safety profile. Therefore, semuloparin may be a better alternate for the prevention of cancer associated thrombosis.
A method for assessing tumor response to therapy and more precisely guiding treatment decisions so as to improve survival.
Authors: Wilkerson Julia , Amiri-Kordestani Laleh , Madan Ravi A. , Adesunloye Bamidele , Zhuang Sen Hong , Wells Samuel A. , Fojo Antonio Tito , Bates Susan Elaine , Stein Wilfred Donald
Published: March 2020

e13122

Background: The response of tumors to chemotherapy is monitored using imaging data or tumor markers and this quantitative data provides a rich source for an objective response assessment and treatment decisions. Responses are usually assessed as categorical variables based on percentage increase or decrease in tumor size. Methods: We have developed mathematical equations that describe efficacy as a continuous variable, enabling the extraction of the appropriate rate constants for tumor growth and regression (decay), designated g and d, respectively. Both are used to describe the rates of tumor growth and regression for the fraction of tumor that is growing despite treatment and the fraction dying as a result of therapy, respectively. Results: Using data from randomized phase III trials in kidney and breast cancer, multiple myeloma, and medullary thyroid carcinoma; as well as phase II trials in prostate cancer we have shown that: (1) values of g but not those of d are strongly correlated (negatively) with patient survival; (2) g can be discerned early in treatment, before growth is demonstrated clinically, providing an early efficacy measure; (3) g typically does not change over time, even over years, suggesting resistance is intrinsic and predictable and does not worsen over time; (4) effective therapies both increase d, and reduce g; and (5) in every cancer studied, the evidence suggests tumor growth reverts to its pre-treatment rate when chemotherapy is discontinued. Conclusions: The observation that g remains stable allows one to predict the most likely outcome of continued therapy. The evidence indicates that the increase in g occurring after treatment discontinuation is due to a resumption of a pre-treatment growth rate and not a change in biology. Our hypothesis is that if a favorable growth rate that slows tumor growth can be identified, survival might be improved if therapies that achieve this favorable growth rate are continued despite crossing conventional disease progression boundaries. We plan a prospective test of this model to provide a more informed decision and better survival outcome by maximizing the benefit obtained from approved therapies.
Improved 5-year overall survival (OS) in breast cancer (CA) patients from 1994 to 2008.
Authors: Aljadir David Naji , Cummings Francis J.
Published: March 2020

e13126

Background: A Canadian Study (Chia, ASCO 2003, Abstract 22) comparing OS across 4 time cohorts in patients with metastatic Breast CA demonstrated OS benefit at 1 and 2 years that appears related to the release of aromatase inhibitors (AI)/docetaxel and trastuzumab/capecitabine but not paclitaxel or vinorelbine. Methods: 5 yr overall survival (OS5) in breast CA patients (all stages) was separated into 3 time cohorts corresponding to dates of release of chemotherapy or hormonal treatments (cohort 1:1994-1997 (paclitaxel/vinorelbine), cohort 2:1998-2002 (AI /trastuzumab) and cohort 3:2003 (bevacizumab)) to determine if there was an impact on OS5 in all stages and if there was a relation to survival based on stage of disease. Data was extracted from the National Cancer Database (NCDB) for the US and Northeastern US (MA, ME, CT, RI, VT, NH). Results: The OS5 in the US was 80.0% [CI 80.6-80.9], 84.7% [CI 84.4-84.6] and 85% [CI 84.8-85.2] for cohorts 1, 2 and 3, respectively. The OS5 in the Northeast US was 82.3% [CI 81.8-82.8], 85.7% [CI 85.4-86.1] and 87.3% [CI 86.6-88.0] for cohorts 1, 2 and 3, respectively. Stage II 5 yr survival in the US was 78.9% [CI 78.7-79.1], 82.8% [CI 82.6-83.0] and 84.8% [CI 84.4-85.2] and in the Northeast US was 79.1% [CI 78.2-80], 82.4% [CI 81.7-83.1] and 83.7% [CI 82.2-85.3] for cohorts 1,2, and 3, respectively. 5 yr survival for stage III in the US was 53.8% [CI 53.2-54.3], 57.8% [CI 57.3-58.3] and 64.5% [CI 63.7-65.4] and in the Northeast US was 53.2% [CI 50.9-55.6], 58.8% [CI 56.7-60.8], and 70.7% [CI 67.3-74.1] for cohorts 1,2 and 3, respectively. Stage IV patients showed no change in 5 yr survival over the 3 cohorts, but showed improvement in 2 yr survival at the National Level (44.6%, 46.1%, and 46.7%) and in the Northeast US (46.7%,47.5% and 49.4%) for cohorts 1,2 and 3,respectively. Conclusions: 5 yr survival in stage II and stage III breast CA between cohorts 1 and 3 has improved, whereas stage IV survival at 5 yrs showed no improvement in any cohort, even though there was an improvement in stage IV 2 yr survival in the US and within the Northeast US. The improvement in OS5 is more pronounced between cohorts 1 and 2 than between cohorts 2 and 3, which appears to correspond to the addition of AI and trastuzumab.