bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene profiling validation for cancer classification using known primary carcinoma samples
Authors: Lenzi R. , Rashid A. , Ordonez N. , Raber N. M. , Varadhachary G. R. , Floore A. , Stork-Sloots L. , Warmoes M. , Erlander M. , Abbruzzese J. L.
Published: March 2020

21130

Background: Cancer of Unknown Primary Site (CUP) accounts for 3–5% of all malignant neoplasms. With current diagnostic procedures, approximately 20% of CUP patients have a primary identified. Since formulation of prognosis and treatment selection depends largely on the primary type, diagnostic uncertainty unfavorably affects CUP management. Gene expression profiling has permitted the development of diagnostic classifiers. A clinically usable methodology needs to differentiate a sufficiently large number of primary types. This study focuses on the estimate of the accuracy of gene expression for classification of metastatic tumors in formalin fixed (FF) FNA and core/surgical biopsies. Methods: CupPrint® is a 1900 gene microarray optimized for FF samples which uses a database of 643 cancer profiles to provide a robust method for the discrimination of 51 tumor (sub) types. Metastasis samples of six known primary carcinoma types were studied (lung, pancreas, colorectal, breast, liver, ovary/primary peritoneal carcinoma). To examine the impact of the metastatic site on diagnostic accuracy different biopsy sites were studied, including lung, brain, lymph nodes, liver, peritoneum. Samples were deemed evaluable that contained an estimated >33% tumor cells. mRNA samples from the metastatic lesions were provided in a blinded fashion to the microarray laboratory. Results: For 39 evaluable samples studied so far, the CupPrint® prediction was compared with the pathologic diagnosis. Of the 39, in 34 the primary site of origin was correctly predicted (87% accuracy). In two of the incorrectly predicted samples the site of biopsy (brain and liver respectively) was reported as the primary site. Correlations of molecular profiles to clinical parameters are being explored. Conclusions: CupPrint® appears to be sufficiently accurate to be of potential clinical utility in the diagnosis of CUP.

No significant financial relationships to disclose.
Effect of clofarabine on lymphocyte populations in patients treated for solid tumors
Authors: Cunningham C. , Nemunaitis J. , Senzer N. , Richards D. , Vukelja S. , Abichandani R. , Vasconcelles M.
Published: March 2020

21134

Background: Clofarabine (CLOLAR®) is a next-generation nucleoside analog designed as a hybrid molecule to improve the efficacy and minimize the extramedullary toxicity of other nucleoside analogs. Such analogs are known to have a variety of effects on both humoral and T-cell immune function. Fludarabine, the drug most closely related to clofarabine, causes major alterations in the CD4:CD8 lymphocyte ratios, associated with marked increases in the rate of opportunistic infections. In contrast, gemcitabine has a selective detrimental effect on the B-lymphocyte subset. Therefore, while conducting a phase I dose-finding trial of clofarabine in patients with solid tumors, we investigated its effects on lymphocyte sub-populations. Methods: A phase I dose-finding study is ongoing in patients with solid tumors who receive clofarabine once a week for 3 weeks every 28 days. Blood samples were collected from patients in the highest dose levels before, during, and after clofarabine administration for lymphocyte quantitation and phenotyping using flow cytometry. Results: Of the 11 patients who had samples collected, 5 currently have both baseline and postbaseline values available (1 at the 129 mg/m2 dose level and 4 at the 103 mg/m2 dose level). Overall, the percentage of T cells and CD8 suppressor cells did not decrease significantly with clofarabine administration. In 1 patient where data from 2 cycles were available, CD4 cells decreased slightly after the first cycle, suggesting a possible cumulative effect. However, in all 5 patients CD19 cells decreased significantly after the first infusion of clofarabine and remained suppressed for the duration of the study period. Conclusions: Although clofarabine is a purine analog (as is fludarabine), its effects on lymphocyte subsets more closely resemble gemcitabine, a pyrimidine analog. If substantiated, these findings should have bearing on future decisions about appropriate drug combinations involving clofarabine.

No significant financial relationships to disclose.
Zoledronate acid modifies the lipid transporters profile in human prostate cancer cell lines
Authors: Toledo Lobo M. , Arenas Jiménez M. , Huertas Martínez L. , Sacristán lópez S. , Moyano Jato A. , Fernández Fernández E. , Martín Hidalgo M. , Martín del Río R. , Gómez Pinillos A.
Published: March 2020

21135

Background: The mechanism through wich zoledronic acid exerts its activity is poorly understood. Low density lipoprotein receptor (LDLR) and scavenger receptor class B type 1 (SRBI) overproduction is an important mechanism in cancer cells for obtaining more essential fatty acids and cell growth. The effects of in vitro zoledronate treatment on the lipid metabolism of prostate cancer cell lines were studied. Methods: Three prostatic cancer cell lines, androgen insensitive PC3, androgen dependent low-passage (LP) LNCaP and androgen independent high-passage (HP) LNCaP cells were studied. Cells were plated either in RPMI with 5% foetal calf serum and lipoprotein depleted serum (LPDS) and were treated with zoledronate at different concentrations. The lipid transporters profile was analyzed by western blotting for LDLR and SRB1. Results: The same LDLR bands profile was observed in all cell lines, 160 and 105 kDa. The basal levels of LDLR were higher in the PC3 cells. Zoledronate therapy induced LDLR expression in all cell lines but PC3 were less sensitive to this effect. Cells cultured with LPDS showed an enhanced expression of LDLR and PC3 cells were less sensitive to this effect. HP LNCaP cells were the most affected by lipoprotein deprivation however this effect diminished 72 hours after treatment. The bands profile for SRBI consisted of a 65 kDa predominant band and a 40 kDa band in both LP/HP LNCaP cells. In PC3 cells main band was located in 65 kDa and accessory band in 30kDa. The basal levels of the 65kDa band were higher in HP than in LP LNCaP or PC3 cells and zoledronate therapy caused a dose- dependent induction in HP LNCaP and dose-dependent reduction in PC3 cells, LP LNCaP cells were resistant to the treatment. LPDS induced SRBI levels in all cell lines inverting the effect caused by zoledronate in HP LNCaP cells in complete culture medium and at high doses (100μM) a complete inhibition of SRBI protein was found. Low molecular weight bands changed in the same way as the 65 kDa band. Conclusions: LDL-R and SRBI have been isolated in prostate cancer cell lines. Based on previous cell growth studies, the lipid transporters profile might be significantly involved in the resistance to zoledronate therapy. Lipoprotein regulation pathways should be considered in the therapy of metastatic prostate cancer.

No significant financial relationships to disclose.
Association of interleukin-1 gene polymorphisms with gastric cancer: A meta-analysis
Authors: Vincenzi B. , Santini D. , Patti G. , Pantano F. , Venditti O. , Rocci L. , Frezza A. , Coppola R. , Graziano F. , Tonini G.
Published: March 2020

21142

Introduction: Previous studies on the association between interleukin-1 (IL-1) genetic polymorphisms and the risk of gastric cancer have produced conflicting results. The purpose of this study was to examine the association between IL-1 genotype and gastric cancer by systematically reviewing the original studies. Materials and Methods: We searched the MEDLINE, CENTRAL, and PubMed databases (last research performed on July 2005) and reviewed cited references to identify relevant studies. Search key words were: gastric cancer (OR stomach cancer OR gastric adenocarcinoma OR stomach adenocarcinoma) and IL-1 (OR IL1). The literature review identified 23 titles that met the search criteria. Data from 15 articles that investigated the association between any of IL-1B-511 and IL-1B-31 polymorphisms and gastric cancer met the inclusion criteria, and they were included in the meta-analysis. Eight studies evaluated the role of IL-1B-511, four the role of IL- 1B-31 and three investigated both IL-1B-511 and IL-1B-31. Results: By pooling all the studies identified, our study shows that individuals IL-1B-31T carrier have got an increased risk developing gastric cancer (OR of 1.25; 95% CI 1.06–1.47) in particular in Caucasian sub-group (OR of 1.41; 95% CI 0.97–2.05). IL-1B-31CC genotype confers a decreased risk (OR of 0.80; 95% CI 0.68–0.95) especially in Caucasian population (OR of 0.71; 95% CI 0.49–1.03) compared to Asians (OR of 0.83; 95% CI 0.69–0.99). This association might be explained with the well-known near complete linkage disequilibrium between IL1B-511T and IL1B-31C polymorphism. Furthermore our results suggest a strong association between IL1B-511T polymorphism and gastric cancer risk only in Caucasians and not in Asians. Conclusions: In conclusion, although affected by the common bias of each epidemiologic studies, this pooled analysis suggests that IL1B-511T polymorphism is associated with an increased risk of developing gastric cancer in Caucasian population.

No significant financial relationships to disclose.
Trastuzumab-HER/2 binding induced inhibition of cell growth and HER/2 tyrosine kinase activity
Authors: Welt S. , Shay T. , Lanning C. , Horton K. , Kostyal D.
Published: March 2020

21146

Background: Cell lines containing the HER/2 amplicon are sensitive to Trastuzumab (T) mediated inhibition of cell growth. T blockade of cell growth signaling pathways have been hypothesized to occur by two mechanisms, inhibition of homo and hetro-dimerization of HER/2 with members of the EGFr family and inhibition of HER/2 phosphorylation. Methods: BT 474 and SK-BR3 breast cancer cell lines containing the HER/2 amplicon were cultured under condition demonstrating inhibitory effects of T by MTT and 3H-Thymidine incorporation (0.25–50 micrograms/ml for up to 9 days). RNA extracts from treated and un-treated cells were analyzed and compared using two immunoassays for phosphorylated HER/2. Various growth conditions were assessed for T inhibition of phosphorylation including, serum free media, fetal calf serum, human pre and post menopausal serum, breast cancer patient's serum and normal male serum. Results: Breast cancer cell lines BT 474 and SK-BR3 both demonstrated cell growth inhibition when cultured with T over a wide range of concentrations down to 0.25 microgram/ml. The inhibitory effects on SK-BR3 were low but statistically significant in both MTT and 3H-Thymidine incorporation assays. Examining this same concentration range of T on these cell lines demonstrated no appreciable reduction of phosphorylation by western blot analysis at various time points after exposure to T. Two different immune assays for HER/2 phosphorylation were analyzed. Further examination of replacement of fetal calf serum by human female pre and post menopausal serum samples or similar samples from breast cancer patients did not result in reduction of the phosphorylation signal. Conclusions: In this in vitro model T does not mediate effects through HER/2 tyrosine kinase inhibition under conditions that simulate clinical conditions. Whether inhibition of phosphorylation will be apparent at later time points is unknown. These finding may explain the activity of lapatinib, a HER/2 tyrosine kinase inhibitor, on T resistant breast cancer.

No significant financial relationships to disclose.
Preoperative concurrent chemo- and endocrine therapies for women with large operable breast cancer expressing steroid hormone receptors
Authors: Dellapasqua S. , Balduzzi A. , Torrisi R. , Ghisini R. , Peruzzotti G. , Rocca A. , Cardillo A. , Goldhirsch A. , Colleoni M.
Published: March 2020

21153

Background: Preoperative chemotherapy and endocrine therapy yielded low pathological complete remission (pCR) rates in patients with endocrine responsive breast cancer. Methods: Patients with large operable endocrine responsive (ER ≥ 10% of the cells) breast cancer (cT2-T3, N0–2, M0) were treated in 2 consecutive studies with preoperative chemotherapy (Study I: 6 courses of either fluorouracil, leucovorin, vinorelbine (FLN), or vinorelbine, cisplatin, and continuous infusion of fluorouracil (ViFuP), chosen at the discretion of the treating physician; Study II: an oral regimen with capecitabine and vinorelbine (CAVINO). In both studies concurrent endocrine therapies (letrozole, either alone or if premenopause, with triptorelin) were given. Results: Sixty-five (58 evaluable) and fifty-five (all evaluable) patients were enrolled to Studies I and II, (ER >50%, 51 and 50; Ki 67 = 20%, 42 and 39; cT2/3: 36 / 22 and 35 / 20; premenopausal 40 and 38) respectively. In Study I there were 43 objective responders (74%, 95% CI 63–85%), 4 of whom had pCR. In Study II 34 patients (62%, 95% CI 49–75%) had an objective response. Breast conserving surgery became possible for 64% and 62% of the patients in Study I and II, respectively. Conclusions: Intravenous, non anthracycline containing regimens together with tailored menopause status-adapted endocrine therapy, warrants further investigations in the preoperative setting.

No significant financial relationships to disclose.
Immunity to MUC1 in pancreatic and breast cancer
Authors: Geller B. A. , Lepisto A. J. , Ahrendt G. M. , Finn O. J. , Ramanathan R. K. , Brufsky A. M.
Published: March 2020

21166

Background: A cancer vaccine composed of MUC1 loaded DCs was effective at inducing tumor rejection in MUC1 transgenic mice. We present data from a phase IB clinical trial of the same vaccine in patients with pancreatic cancer. Preliminary analysis of this trial was reported at ASCO 2004,# 2578. Our current studies based on the results of this trial explore the importance of anti-MUC1 immunity in patients with early breast cancer, aiming to create a strong rationale for boosting these responses with vaccination in adjuvant settings. Data from both studies will be presented. Methods: The objectives of the vaccine trial were to evaluate toxicity of the vaccine, its ability to boost immunity and clinical outcome. Patients received autologous DC loaded with MUC1 100mer peptide every 3 weeks for a total of 3 doses and a booster dose 6 months later. Blood samples were obtained prior to each dose and at various times post vaccination. For the current study, 100 preoperative/pretreatment peripheral blood samples have been collected prospectively from patients with early breast cancer. Multiple immune parameters are being assessed in each group. Results: Data from extensive immune response analyses of the pancreatic cancer vaccine will be presented in detail at AACR 2007, and summarized here to provide the basis and comparison for our ongoing studies in early breast cancer. 4/12 patients in the vaccine study are alive without recurrence at three years. Even though effector and regulatory T cell responses were detected in several patients, none could be correlated with long-term survival. Several patients had anti-MUC1 antibody responses that remained stable following vaccination, which also did not correlate with survival. Ongoing studies in early breast cancer are assessing the potential differences in the quality of anti-MUC1 responses between early and late stage disease. Conclusions: In the setting of advanced disease, such as pancreatic cancer, the vaccine appears to have an effect on keeping regulatory T cells low and cellular and humoral immunity stable, without causing any significant toxicity. Ongoing studies in early breast cancer are aiming to define the immune parameters that might predict increased survival.

No significant financial relationships to disclose.
Molecular subsets of male breast carcinoma in southern Brazil
Authors: Graudenz M. S. , Silva L. M. , Toscani N. V. , Freitas A. M. , Caleffi M.
Published: March 2020

21167

Background: Molecular profiling can identify subsets of breast cancers with different tumor behavior. There is few data regarding breast cancer in males, since it's an uncommon disease, accounting for less then 1% of all malignancies in man. Treatment and prognosis are often extrapolated from female breast cancer, but differences and/or similarities between these two diseases are not well established. The aim of this study is to report the molecular profile defined by immunohistochemistry (IHC) of male breast carcinoma (MBC) in southern Brazil. Methods: We reviewed 25 cases of MBC diagnosed between January 1993 and December 2006. Retrieved data included disease stage, tumor grade, size, and lymphnode status. IHC was performed with the following primary antibodies: ER (Novocastra), Cytokeratin 5/6, Cytokeratin 8/18 (DAKO, Carpinteria, CA), HER1 (DAKO) and HER2 (CB11 clone, DAKO). Results were scored by IHC according to established criteria in the literature. The study was approved by the institutional Ethics Committee. Results: Patient's median age at diagnosis was 66 years-old (44–84 yrs). All cases were invasive ductal carcinoma of no special type except for one lobular carcinoma. Median tumor size was 2.5cm (0.6–5.2cm). IHC was performed in 17 cases. The overall frequency of ER positivity was 82% (14/17); CK5/6 11.8% (2/17); CK8/18 94.1% (16/17); HER1 23.56% (4/17) and HER2 17.6% (3/17). Using the whole panel of antibodies we determined that 11 cases (64.7%) were of the ER+/luminal phenotype, 3 (17.6%) of the HER2 overexpressing, 2 (11.7%) of the normal breast like and 1 (5.9%) tumor of the basal phenotype (HER1+ and CK5/6-). Conclusions: Male breast carcinoma presents similar expression profiling frequencies to that of female breast carcinomas. To our knowledge, this is the largest series of male breast cancer ever studied in Brazil. Despite intrinsic gender differences, breast carcinoma may share common tumor biology characteristics in males and females.

No significant financial relationships to disclose.
Linking diet, religion and cancer
Authors: Yadav S. P. , Sachdeva A.
Published: March 2020

21172

Background: Consumption of onion and garlic has been shown to give protection against various cancers. Motivated by this observation we intended to look at the cancer incidence in a population belonging to Jain religion that does not consume garlic and onion due to religious belief. This study was done to see cancer incidence in children of Jain religion as compared to other religions at a single centre. Methods: It was a retrospective analysis of consecutive children less than 16 years of age diagnosed with cancer at Sir Ganga Ram Hospital from January 2005 to January 2007. We excluded adult patients with cancer as tobacco and alcohol consumption in this age group would have been confounding factors.Age, sex and religion were noted. Data from Census of India for year 2001 was used to know distribution of various religions in general population alongwith literacy rates and proportion in 0–6 years age. Results: As per 2001 Census of India , distribution of population in India as per various religions is Hindu 80.5%, Muslim 13.4%, Christian 2.3%, Sikh 1.9%, Buddhist 0.8% , Jain 0.4% and others 0.6%. Proportion of population in 0–6 year of age in India is 15.9% and as per religions Hindu 15.6%, Muslim 18.7% ,Christian 13.5%, Sikh 12.8%, Buddhist 14.4% and Jain 10.6%. Literacy rates of India is 64.5% and by religion is Hindu 65%, Muslim 59.1% Christian 80.3%, Sikh 69.4%, Buddhist 72.7% and Jain 94%. Distribution of population in Delhi as per various religions is Hindu 82%, Muslim 11.7%, Christian 0.9%, Sikh 4%, Buddhist 0.2% and Jain 1%. Total of 201 patients were diagnosed with cancer and distribution as per religions was Hindu 162 (81%), Muslim 15 (7.5%), Christian 3 (1.5%), Sikh 8 (4%), Buddhist 1 (0.05%) and Jain 12 (6%). Conclusions: Incidence of cancer in children of different religions is similar to that of proportions of population of different religions in Delhi except for Jain religion where incidence of cancer is 6 times higher despite lesser number children in 0–6 year in this population as compared to other religions . Major difference is the diet lacking in onion and garlic . Other reason could be increased literacy levels in Jain community . This link between diet ,religion and cancer in Jain population needs to be studied in a larger muticenteric setting as it has implications for the whole world.

No significant financial relationships to disclose.
Breast cancer HER-2 amplicon-associated targets for immunotherapy identified by gene array analysis
Authors: Kostyal D. , Shay T. , Lanning C. , Horton K. , Welt S. , Whelle S.
Published: March 2020

21174

Background: Gene array technology was used to investigate Trastuzumab (T) induced molecular expression patterns in HER/2 amplified breast cancer cell lines. A variety of over-expressed and aberrantly expressed proteins were identified. Further analysis of these data demonstrated potential candidate target proteins for T-cell immunotherapy. The advantages of utilizing gene array analysis to identify target proteins for immunotherapy include rapid data generation and analysis, statistical confidence and reproducibility. Methods: BT 474 and SK-BR3 breast cancer cell lines contain the HER/2 amplicon. Under growth conditions demonstrating inhibitory effects of T (0.25–50 micrograms/ml), RNA extracts from treated and untreated cells were analyzed and compared by whole human genome, gene array analysis. Results: Three sperm associated proteins were found to be expressed in these breast cancer cell lines. In comparison to the HER/2 expression, sperm associated antigen-1 (saa-1) was found to be expressed at very high levels, approximately 30–40% the level of HER/2. Furthermore, treatment of breast cancer cell lines with T did not reduce the level of saa-1 expression. Two other aberrantly expressed genes were also identified, sperm associated antigen 8 (saa-8) and sperm associated antigen-14 (saa-14). Unlike saa-1, both saa-8 and saa-14 expression were down regulated by T treatments. Conclusions: Breast cancer patients with HER/2 over expressing tumors have a poorer prognosis. T treatment is an important part of the clinical management of these patients especially early in their course. The immunotherapy targets described here may further improve outcomes of T treatments and for T resistant disease when utilized as vaccines. These proteins are components of sperm acrosomes and whether they play a role in invasion and metastases is under investigation.

No significant financial relationships to disclose.
Targeted immunotherapy with intentionally mismatched rIL-2 activated donor lymphocytes in an attempt to eliminate minimal residual disease in patients with high-risk metastatic cancer
Authors: Slavin S. , Or R. , Dray L. , Samuel S. , Ackerstein A. , Shapira M. Y. , Resnick I. B. , Bitan M. , Morecki S.
Published: March 2020

21175

Background: Graft-versus-leukemia and graft-versus-tumor (GVT) effects following stem cell transplantation are well established, however, procedure related toxicity and mortality are unavoidable. In addition to limited efficacy following stem cell transplantation (SCT), graft-versus-host disease (GVHD) is unavoidable. Our protocol was designed to induce more potent anti-cancer immunotherapy by rIL-2 activated intentionally mismatched donor lymphocytes (MDL) at the stage of minimal residual disease (MRD) outpatient procedure with no SCT avoiding GVHD. Methods: Optimizing MDL was accomplished by cyclophosphamide 1,500 mg/m2 and 2 injections of alpha interferon (3x106IU) for more effective immunotherapy, aiming for depletion of regulatory T cells, followed by infusion of haploidentically mismatched lymphocytes activated with rIL-2 (6,000 IU/ml) for 4 days. On the day of cell infusion, patients received rIL-2 6x106 IU subcutaneously outpatient for 5 days. Results: A total of 41 (age 5–73, median 52) high risk patients were included: metastatic breast 13; colorectal 3; gastric 3; pancreatic 3; melanoma 3; head & neck 3; glioblastoma 2; and 6 with other solid tumors. Five patients had resistant hematological malignancies: multiple myeloma 2; non-Hodgkin's lymphoma 2 and Hodgkin's disease 1. 6 patients received lymphocytes with bispecific antibodies for targeted cell-therapy (3 with catumaxomab against CD3 & epithelial cell adhesion molecule (EpCAM); 3 with ertumaxomab directed against CD3 & Her-2/neu WHO toxicity >grade 2 was noted. 14 of evaluable patients are alive. 10/32 with solid tumors are alive, 7 with no evidence of disease > 9–91 (median 17) months (4 breast; 1 squamous cell; 1 head & neck; 1 prostate). Of 5 patients with hematological malignancies 4 are alive and disease free >18–96 (median 46) months. Conclusions: Safe induction of GVT effects may be accomplished by MDL, preferably targeted with bispecific antibodies after cyclophosphamide conditioning lymphocytes are more potent and act faster than matched lymphocytes and GVHD is avoided by rejection of donor lymphocytes. When applied at a stage of MRD, such treatment may result in operational cure.

No significant financial relationships to disclose.
Symptoms or signs due to different chemotherapeutics and their relationship with serum cytokines/VEGF levels in patients with cancer
Authors: Demirkazik A. , Yilmaz H. , Akbulut H. , Yalcin B. , Icli F.
Published: March 2020

21176

Background: Several problems such as myalgia, arthralgia, fever, dyspnea, generalised edema and pleural effusion and rarely “systemic capillary leak syndrome” may appear following the chemotherapy in cancer patients. Although it is supposed that some cytokines are associated with the development of these problems, there is no clear evidence for the relation between the cause and the effect. In this study, the relation between some symptoms following the first chemotherapy in cancer patients and the serum levels of interleukin-2 (IL- 2), interleukin-11 (IL-11), tumor necrosis factor alpha (TNF-a) and vascular endothelial growth factor (VEGF) which are supposed to cause these symptoms was investigated. Methods: Forty-four (28 male and 18 female) patients with cancer who had no heart, lung or renal diseases were consecutively enrolled to this study. Twenty-nine patients (27 with lung cancer, 1 with locally advanced gastric and 1 with pancreatic carcinoma) had active tumors. Fifteen patients (11 with breast cancer, 2 with gastric carcinoma, 1 with colon carcinoma, 1 with ovarian cancer) had no tumor because they were just curatively operated. Patients’ symptoms and findings due to chemotherapy were noted just before the chemotherapy and 24 hours later following chemotherapy. Patients’ serum samples were taken for the measurement of VEGF, TNF, IL-2 and IL-11 levels. Results: Any relation between the chemotherapeutic drugs and the symptoms or findings such as edema, dyspnea, cough and flu-like syndrome in patients were not observed. Otherwise, there were no relation with response to the chemotherapy and serum levels of VEGF, TNF, IL-2 and IL-11. But, patients who were not treated with paclitaxel, docetaxel, gemcitabine and vinorelbine showed a significant decrease in their IL-11 levels (p: 0.006). Conclusions: There was no statistically important difference between chemotherapeutics in terms of cytokine related effects. Although, there was no relation with response to the chemotherapy and serum cytokine levels, serum IL-11 levels were stable in patients administered with paclitaxel, docetaxel, gemcitabine and vinorelbine when compared with other drugs.

No significant financial relationships to disclose.
Relevance of modified prognostic score for breast carcinoma on fine needle aspiration cytology in a resource-poor setting
Authors: Malami S. A. , Sahabi S. M.
Published: March 2020

21177

Background: Breast cancer is the commonest malignancy in premenopausal Nigerian women in whom it is almost uniformly fatal probably due to lack of access to early diagnosis and treatment. To enhance the value of fine needle aspiration cytology, a rapid and comparatively new technique in our center, we sought to verify if it is also a cost-effective test to predict biological behavior in breast carcinoma. We developed a modified grading system to compare the cytologic features of the cases in our series with known prognostic factors (tumours size, histologic grade and axillary lymph node status) in subsequently excised tissues. Methods: Fine needle aspirates obtained in 42 patients diagnosed as ductal cell carcinoma not otherwise specified (NOS) at the UDUTH Hospital, Sokoto, Nigeria were investigated. The three cytologic features used were nuclear grade (score 1–3), cellular dyscohesion (score 1–3), and bare atypical nuclei (score 0, 1). A cytological score of 3 and below was considered a low score, and a score of 4–7 was considered a high score. We also categorized each patient according to the Nottingham Prognostic Index (NPI) into: good prognostic group (GPG), moderate prognostic group (MPG) and poor prognostic group (PPG). The cases in GPG and MPG were considered to belong to a more favourable category. Results of cytoprognostic scores were compared with the respective pathological information calculated by the NPI. Results: Eighteen of the 20 cases that had a cytologically high score were confirmed to be PPG while 2 correlated with MPG. Among the 22 cases that had cytologically low scores 14 cases were not correlated with favourable NPI index (belonged to PPG category) while the remaining 8 correlated well (MPG = 4 and GPG = 4). The overall accuracy for cytologic grading was 62% (26 out of 42 cases). Conclusion: Tumour typing on FNA material correlates with the NPI in the poor prognostic group. However, this modified cytoprognostic score seems to have doubtful promise as a prognostic factor in our group of patients with favourable NPI. The importance of each cytological feature used in this grading system will be determined by regression analysis in a larger sample size.

No significant financial relationships to disclose.
Improvement in quality of life and symptom control with MYCOBACTERIUM W (CADI-05) in head and neck cancer
Authors: Dave R. I. , Tripathi U. B. , Parikh B. J. , Patel K. M. , Shukla H. K.
Published: March 2020

21186

Background: Recurrent, radiated and chemotherapy given patients are having many unmanageable symptoms and problems. This condition is worsened by malnutrion, infection, pain and immuno suppression. Modifying immune mechanism of the body is the last and best weapon to fight against such diseases. Role of immunotherapy in the treatment of malignant diseases is on experimental level. Dr George Thyphrontis & Michael Kousilers have produced good results in carcinoma of urinary bladder, melanoma & lung cancer with Immunotherapy. At GCRI, we have tried vaccine, prepared from mycobacterium-W in 100 cases of Head & Neck Cancer. Methods: As a prospective nonrandomized study, to see beneficiary effect on quality of life and symptom control, we have done a trial during Jan. 2004 to Dec.2005. Informed consent and ethical clearance was obtained. Study was made to find out any side effect or adverse reactions of the vaccine. After fulfilling the criteria of inclusion and exclusion the case was selected for study and 0.1 ml vaccine (CADI-05) was injected intradermally with all aseptic precautions. Four injections, weekly and later on four injections monthly were given. Patient was followed up for 6 months. Results: Total No. of cases -100. M / F - 89/11. age distribution - Maximum No. were in 5th decade -(34%) followed by 6th decade (21%)Site of primary - Commonest site was Buccal mucosa (29%) followed by tongue (17%). There was no major side effect. Only 5% Patients developed constitutional symptoms and infection at injection site. 27% patients had pain relief. Symptom control was seen in 15% patients. Improvement in quality of life was observed in 82% of patients. 4% of patients had no effect. The beneficiary effect lasted for three month in 27% patients and more than six months in 13% patients. The effect was more marked in dysphagia, ulcer and fistula. Effect was insignificant in strider, change in voice and metastatic nodes. Four patients are living with Immuvac in spite of disease symptom free for more than one year. Conclusions: Immunotherapy with Mycobacteium W can safely be used to improve quality of life and control of symptom in terminally ill Head & Neck cancer.

No significant financial relationships to disclose.
Evaluation of occurence of cancer of the lung among young people in six regions of the western Ukraine
Authors: Kitsera N. , Shparyk J.
Published: March 2020

21188

Background: Analysis of the cases of malignant lung tumors of young people (<34 yrs, born in 1963–2004) and diagnosed in 1997–2004 was made using the materials of the database of cancer registers of Volyn (V), Ivano-Frankivsk (IF), Lviv (L), Rivne (R), Ternopil (T) and Chernivtsi (C) regions. The population of young people <34 yrs of this region - 4.2 million/year. Results: Among 7541 cases of cancer in the six regions of the Western Ukraine malignant tumors of the lungs were diagnosed in 102 cases (1.4%). This pathology was registered in males in 57 cases, and in females in 45. The number of males with tumors of the lungs prevailed in V, IF, L, T. The number of young males and females with such pathology during the said period was the same - 11 cases in each gender group - in R. The youngest among the 102 individuals from the above said six regions were a boy aged 6 and a girl aged 16 from R. Combination with other tumors was observed in three females (C49, C53, C58) and one male (C81). In C among 766 cases of malignant tumors in young people <34 years lung cancer were detected in 5 (0.7%). Among 959 cases of cancer such tumors of the lungs were detected in 8 (0.8%) in V. Among the young people <34 years this pathology was detected in 14 (1.2%) in IF out of all 1156 cases of malignant tumors, in T - 947 tumor - 15 cases (1.6%). Among the six above regions in L there have been detected 2465 cases of malignant tumors, of which lung cancer were diagnosed in 38 - 1.5%. The highest frequency of occurrence of this pathology was registered in R (1.8%) - 22 cases in 1248 cases of malignant tumors. Conclusions: Fluctuation of frequency of this pathology in all these regions in various years during the investigated period had a wave-like character. As each of these regions is characterized by different geographic and climatic conditions, physical and chemical factors, exhausts of industrial enterprises, the study of frequency of malignant tumors in young people will permit to evaluated more objectively contribution of hereditary factor in the development of this pathology. The perspectives of further research in this field lie in the study of the role of genetic predisposition to the occurrence and development of malignant tumors in each patient, taking into account ecological zone of residence, occupational hazards and harmful habits.

No significant financial relationships to disclose.
A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion every 3 weeks in patients (pt) with refractory solid tumors
Authors: De Braud F. G. , Isambert N. , Curigliano G. , Spitaleri G. , Ferrant E. , Ramazeilles C. , Bolloni L. , Fumoleau P.
Published: March 2020

2518

Background: This phase I study of SSR244738, a G2-cell cycle inhibitor cytotoxic agent, was aimed to establish the dose limiting toxicities (DLT), the maximum administered dose (MAD) and to characterize the PK profile of the proposed schedule. Methods: SSR244738 was administered as one-hour IV infusion every 3 weeks in pts (selected according common phase I criteria) starting with a modified accelerated dose escalation scheme. PK profiles (up to day 8) were obtained in each pt after the 1st administration. CYP2C9 and CYP3A5 genotypes were analyzed to identify pts’ metabolizer status. Results: 2 centers enrolled 14 heavily pretreated pts: 5 females, 9 males, median age: 52 years (32–67), ECOG PS: 0 (93% pts); main tumor types: head and neck, lung, melanoma, and breast. 40 cycles (median = 2, range: 1–11) were administered in 6 dose levels (DL) ranging from 165 to 1,300 mg/m2. Accelerated dose escalation was stopped at 660 mg/m2 for non-proportionally increase of PK parameters respect to the dose administered . SSR244738 was well tolerated up to 1,300 mg/m2: one DLT (abnormal liver function tests ALFT) was reported in one breast cancer pt with liver metastases. Only one pt (hepatocarcinoma) was withdrawn from the study due to toxicity (ALFT) after 3 cycles at 1,000 mg/m2. 2 stable diseases were reported. PK data: mean T1/2 of 23h (range: 9.20–127), mean Vss: 11.1 L (6.43–15.8) and mean Clearance (CL): 0.71 L/h (0.041–1.43). This large variability of the CL (CV% =63%) could in part be explained by CYP2C9 genotype: so far CL is <0.4 in 2 poor metabolizers (PM) and >0.6 in extensive metabolizers. Conclusion: Due to the high CL variability, 1300 mg/m2 is considered as the MAD. 3 pts will be accrued at 1,300mg/m2 to complete the DL (a reduced dose will be given to CYP2C9 PM). Weekly and twice-weekly schedules will be tested.

No significant financial relationships to disclose.
Evaluation of Cockcroft-Gault (CG) and abbreviated modified diet in renal disease (MDRD) formulae in dosing of cancer drugs other than carboplatin
Authors: Jennings S. A. , de Lemos M. L. , Levin A. , Murray N.
Published: March 2020

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Background: Glomerular filtration rate (GFR) is often used to determine initial dosing of renally-excreted cancer drugs. Estimated GFR (eGFR) can be calculated using serum creatinine (SrCr) -based formulae such as CG and MDRD. MDRD is more accurate in non-cancer patients, does not require patient weight, and is reported automatically by all laboratories in British Columbia (BC). We previously showed that CG and MDRD have similar accuracy for carboplatin dosing in patients with gynecological malignancies. We now examine dosing of all renally-excreted cancer drugs in the general cancer population. Since this setting does not include routine measurement of GFR, we report the concordance of eGFR derived from CG and MDRD. Methods: Patient data were collected retrospectively at the BC Cancer Agency. The primary outcome was concordance of eGFR derived from CG and MDRD, using the method of Bland and Altman. A difference of ≥ 30% was assumed to be clinically significant because this difference would usually lead to dose adjustment based on reclassification of renal function. The secondary outcome was the proportion of patients who would have received a different initial dose due to difference in eGFR. Each patient’s dose was determined from dose adjustment tables stated in specific treatment protocols. Results: 313 patients were evaluated: 40% male, median 56y, 67.5kg, 166cm, SrCr 74micromol/L. Median eGFR derived from CG and MDRD were 86.8mL/min and 87.6mL/min, respectively. A difference of ≥ 30% in eGFR was found in 17.9% (56/313) of patients. 8.6% (27/313) of patients would have received a different dose due to difference in eGFR; of these, 67% (18/27) would have received a higher dose. Conclusions: There is good concordance of eGFR derived from CG and MDRD for most cancer patients, with less than 10% of patients expected to receive a different initial dose of chemotherapy. MDRD may be a reasonable alternative to CG for dosing of any renally-excreted cancer drug.

No significant financial relationships to disclose.
Use of tumor gene expression signatures and drug-induced changes to discriminate early response in human breast cancer
Authors: Lee S. , Watson M. , Xu X. , Wong C. I. , Iau P. , Sukri N. , Lim S. E. , Chuah B. , McLeod H. , Goh B. C.
Published: March 2020

2524

Background: To elucidate the genomics of tumor responses to different classes of chemotherapy, we analyzed breast cancer gene expression before and after in vivo treatment with adriamycin or docetaxel. Methods: Tumor biopsies were obtained before and 3 weeks after one chemotherapy cycle and tumor RNA amplified and hybridized on the Affymetrix HG-U133+2 array containing 33,000 genes. Results: Pre- and post-treatment tumors from 46 chemonaive patients with unresectable breast cancers were studied, of which 24 and 22 respectively received adriamycin and docetaxel in the first cycle, and 14 in each group had early response sensitive tumors (=25% shrinkage after 1 cycle). Comparison of our baseline gene signatures with drug-specific panels generated in vitro (Nevins, Nat Med 2006,12:1294) revealed 12 and 2 common genes (p<0.05) that predicted for adriamycin and docetaxel response respectively, with the 12 common adriamycin-response gene panel correctly predicting response in 76% of patients. Analysis of the relative change in tumor gene expression (ratio of post- and pre-treatment differential values to pre-treatment values) in our dataset revealed adriamycin to up- or down- regulate 209 transcripts (p<0.005) including genes that encode for nuclear protein, cell cycle regulation, aminopeptidases, and Ankyrin repeats, while docetaxel up- or down-regulated 469 transcripts (p<0.005) including genes that encode for extracellular matrix, transmembrane signaling, endocytosis, EGF-like calcium binding, tubulin and actin binding functions. Adriamycin and docetaxel concordantly up- or down-regulated 269 transcripts (p<0.01) that may be common response markers, including genes involved in cell cycle proliferation, mitosis, DNA damage, and carboxypeptidase activities. Adriamycin and docetaxel differentially induced 92 transcripts (p<0.01) that distinguished between the two drugs with 96% accuracy. 27 adriamycin- and 100 docetaxel-induced transcripts (p<0.005) predicted response to each drug with >90% accuracy. Conclusions: Drug-specific genomic changes can predict clinical response, and may yield insights to targets to overcome drug resistance.

No significant financial relationships to disclose.
Clinical impact of ERCC1 and TOPOIIα gene expression in small-cell lung cancer patients treated with platinum/etoposide
Authors: Selvaggi G. , Ceppi P. , Longo M. , Giaj Levra M. , Cappia S. , Volante M. , Novello S. , Papotti M. , Scagliotti G. V.
Published: March 2020

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Background: Platinum/etoposide is a commonly used regimen both in limited (LS) and extensive stage (ES) small-cell lung cancer (SCLC). The study was aimed at testing retrospectively the predictive role of mRNA quantification of genes correlated to platinum/etoposide therapy: ERCC1, RRM1 and TOPOIIa. Methods: Total RNA was extracted from microdissected sections of 103 formalin-fixed, paraffin embedded bronchial biopsies. Relative quantification for ERCC1, RRM1 and TOPOIIa and an internal reference gene (β- Actin) was performed by Real-Time PCR using intron-spanning primers. ERCC1 expression was also evaluated by immunohistochemistry using a semi-quantitative score. Results: Eighty-five samples (83%) were successfully amplified. Overall median survival (MS) was 9.9 months, 45 patients had LS (MS=13.1 months) and 40 had ES (MS=7.1 months). Fifty-six (65%) had an objective (complete or partial) response to treatment. Immunohistochemical staining of ERCC1 evidenced a positivity in 2 out of 85 patients with no correlation with clinico-pathological factors. By contrast, a gene expression level was detectable in all samples and a significant correlation between ERCC1 and RRM1 levels (Rs=0.34, p=0.0011) was found. By segregating patients according to response to treatment, it was found that lower TOPOIIa expression was associated to a better response in LS patients (p=0.025) and, more interestingly, those who had a complete response had low TOPOIIa levels than both partial and non-responsive patients (p=0.015). By adopting cut-offs according to median values, univariate analysis of survival by Kaplan-Meier method showed that LS patients with low ERCC1 had a significantly longer survival (MS 14.9 vs. 9.9 months, p=0.012), while RRM1 and TOPOIIa levels showed no influence on outcome. In multivariate analysis, ERCC1 was an independent prognostic factor for survival of LS patients, together with PS and response to therapy. No significant role was found for ERCC1, RRM1 and TOPOIIa in patients with ES. Conclusions: ERCC1 and TOPOIIa represent reliable candidate markers in predicting clinical outcome and response to treatment in LS SCLC patients, who may benefit from a better individualized therapy.

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Age and body composition related-effects on the pharmacokinetic disposition of STEALTH liposomal CKD- 602 (S-CKD602) in patients with advanced solid tumors
Authors: Zamboni W. , Maruca L. J. , Strychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Friedland D. M. , Stoller R. G. , Belani C. P. , Ramanathan R. K.
Published: March 2020

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Background: STEALTH liposomes (SL), which contain lipids conjugated to polyethylene glycol (PEG), prolong the circulation time of a drug in plasma, achieve high and extended drug exposure in tumor, and are eliminated via the reticuloendothelial system (RES). S- CKD602 is a SL formulation of CKD-602, a camptothecin analogue. CKD-602 released from S-CKD602 is eliminated by the kidney. There is significant interpatient variability in the pharmacokinetic (PK) disposition of S-CKD602. Thus, there is a need to identify factors associated with the PK variability. We hypothesize that older patients (pts) have a reduced capacity to eliminate SL agents due to age-related impairment of the RES and that body composition alters the disposition of SL. Methods: PK studies of S-CKD602 were performed in a phase I study of S-CKD602 at 0.1 to 2.5 mg/m2 IV q 21 d in pts with solid tumors. Concentrations of encapsulated (E), released (R), and sum total (E + R) CKD-602 in plasma and CKD-602 in urine were measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated and normalized by dose (AUC/dose). The ratio of total body weight to ideal body weight (TBW/IBW) was calculated as a measure of body composition. Results: Mean ± SD S-CKD602 sum total AUC/dose in pts < 60 (n = 13) and = 60 (n = 17) years of age (yo) were 4.5 ± 5.0 and 11.2 ± 11.0 (μg/ml·h)/(mg/m2), respectively (P<0.05). Controlling for age, there was a statistically significant inverse relationship between TBW/IBW and S-CKD602 AUC/dose where low TBW/IBW was associated with high AUC/dose in both age groups (P<0.05). The cumulative amount of CKD-602 recovered in the urine was 2.2-fold higher in pts < 60 yo compared with = 60 yo. Conclusions: These data suggest that pts = 60 yo have a reduced clearance of S-CKD602 and reduced release of CKD-602 from S- CKD602 compared with pts < 60 yo. In addition, pts < 60 and = 60 yo with a lean body composition may have a reduced tissue distribution and an increased plasma exposure of S-CKD602. The clinical significance of these differences and the factors associated with them need to be evaluated for S-CKD602 and other liposomal and nanoparticle anticancer agents.

No significant financial relationships to disclose.