bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulation of smoldering multiple myeloma (SMM) progression to multiple myeloma (MM) via modulation of AKT kinase, proinflammatory cytokines, and insulin-like growth factor-1 (IGF-1) in human immunodeficiency virus-1 SMM ( HIVSMM ) patients treated with adjuvant selenomethionine (Se-Met) ritonavir-based HAART.
Authors: McPherson Eugene , Mejia Ervido , Tassy Philippe
Published: March 2020

e19540

Background: Multiple myeloma is a B-cell malignancy involving germinal center B cells characterized by urinary monoclonal proteins, osteolytic bone lesions and infiltration of bone marrow with plasma cells and pathology involving aberrant chromosomal translocation with increased glucose uptake as glucose transporter (GLUT-4), AKT kinase activation, overexpressed proinflammatory cytokines produced by bone marrow stromal cells (BMSC) in smoldering multiple myeloma and multiple myeloma, These biomarkers are antiapoptotic and control growth, prognosis and survival. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) are major growth factors in MM. IGF-1 binds to IGF-1 receptor (IGF-1R) as a strong prognostic indicator. Dysregulation and modulation of IGF-1, proinflammatory cytokines, AKT kinase and IL-6 in HIVSMM patients with RTV-based HAART and selenomethionine (Se-Met) adjuvant therapy may suppress NF-kb and abrogate GLUT-4 HIVSMM progression. Methods: We evaluated several HIVSMM patient's biomarkers over four years: CD4, HIVRNA, beta-2-microglobulin, LDH, soluble interleukin -2 receptor (sIL-2R), CRP, SFLC ratio, selenium, bone survey, and bone marrow aspiration/biopsy. Results: CD4 increased to 456/cumm from < 80/cumm, HIVRNA was undetectable from > 1 million copies/ml, beta-2-microglobulin 2.24 mg/L from 14.40 mg/L, LDH 155 IU/L from 432IU/L, sIL-2R 75 pg/ml from 45,752 pg/ml, CRP 1.49 mg/L from 87.4 mg/L, SFLC ratio 0.93 from >2.08, selenium kept >140 mcg/L (high normal level), bone survey negative X 2, and bone marrow aspiration/biopsy plasmacytosis with plasma cells < 5% from > 10% and CD 138 positivity. Conclusions: Dysregulation and modulation of HIVSMM biomarkers with adjuvant Se-Met and RTV-based HAART may suppress AKT kinase and NF-kb activation preventing HIVSMM progression to HIVMM via IGF-1 recruitment of GLUT-4. Overall improved prognosis and survival may be extrapolated to non-HIVSMM patients with concommitant immunomodulary therapy.
A retrospective risk assessment of patients (pts) with high grade upper (UE) and lower extremity (LE) sarcoma: Predictors of survival.
Authors: Kneisl Jeffrey , Crimaldi Anthony Joseph , Symanowski James Thomas , Ahrens Will , Patt Joshua , McCall Bradley , Bates Michael , Ferguson Chad , Livingston Michael B. , Kim Edward S.
Published: March 2020

e21504

Background: Patient outcomes of high grade extremity soft tissue sarcomas (STS) are dependent upon grade and size of the primary tumor and extent of surgical resection. Poorer overall survival (OS) has been associated with specific anatomic sites (e.g. head and neck, retroperitoneum) but OS has not been evaluated for UE vs LE. We investigated the relationship of tumor size and anatomic sites with OS in our pts with high grade extremity STS. Methods: A retrospective review of all pts diagnosed with a high grade STS of the UE and LE was performed from 1992-2010 via an IRB approved protocol at Levine Cancer Institute. Pts were included if they had sufficient medical records, limb-sparing surgery, age greater than 18 years, no stage IV disease. All cases were centrally reviewed by a single pathologist. Overall survival was analyzed with Cox proportional hazards models and tumor size was analyzed using ANOVA techniques. Results: 93 pts were identified. 61 pts had LE sarcomas and 32 had UE. Demographics: 52% male, 67% Caucasian, 60% >50 years of age. Disease characteristics included 88% deep and 66% >5cm STS. 13% of pts received chemotherapy and 86% received radiation therapy, consistent with NCCN guidelines and institutional protocol. Median baseline tumor size was 7.0 cm with a range of 1.7-40 cm. LE STS were generally larger than UE; medians 8.5 cm (range 1.7-40 cm) vs 5.0 cm (range 2.0-17 cm), p=0.005. When analyzed quantitatively, larger tumor size correlated with an increased risk of death (p=0.001). 28 total deaths occurred (0.3-5.4 yrs). Death rates were 27.9% (17 deaths) with LE STS vs 34.4% (11 deaths) with UE. LE disease had an overall reduced risk of death (HR=0.543). Pts with tumors >5cm had an increased risk of death (HR=3.235 overall) for both LE (HR=3.042) and UE (HR=3.453) sarcomas. Conclusions: To our knowledge, this is the largest reported cohort of high grade STS that stratified on upper and lower extremities. Larger size was associated with higher risk of death. Additionally, we observed a higher risk of death in patients with UE sarcomas vs. LE sarcomas. Strong consideration should be given to UE vs. LE STS when assessing risk and treatment.
Reversal of acquired resistance to pazopanib in soft tissue sarcoma with addition of an mTOR inhibitor: A case report.
Authors: Katz Daniela , Zick Aviad , Cohen Jonathan E. , Sonnenblick Amir , Fridman Evgeniya , Shaham Dorith , Peretz Tamar
Published: March 2020

e21508

Background: Pazopanib (P) is a multikinase inhibitor targeting the VEGF and PDGF receptors capable of controlling soft tissue sarcoma for several months. Acquired resistance to P usually leads to chemotherapy resumption. We present a case of reversal of acquired resistance to P by addition of an mTOR inhibitor. Methods: A 46 year old female, completed five cycles of adjuvant treatment with epirubicin and ifosfamide followed by radiotherapy for a fully resected gluteal pleomorphic undifferentiated sarcoma. Ten months later, a single lung metastasis was resected, followed by trabectedin, then switched to gemcitabine and docetaxel after five cycles due to progression. Seven cycles were given with stable disease as best response. Upon progression, P 800mg/d was initiated as part of a compassionate program and continued for six months with a partial response. When disease progressed, treatment was switched to doxorubicin, dacarbazine and cyclophosphamide with rapid progression after two cycles, both complicated by febrile neutropenia. Uncontrolled disease after stopping P, limited response to chemotherapy in the past and worsening myelosupression led us to reintroduce P at 400mg/d in combination with sirolimus 2mg/d with the intention of overcoming acquired resistance to P by inhibiting downstream intracellular mediators. Results: One week after P and sirolimus initiation, pain in a paracostal protruding lesion subsided with softening and a decrease in mass size. After six weeks a CT scan demonstrated a partial response by Choi criteria with an 18% tumor shrinkage and decreased enhancement. Most of the lesions were previously of mixed density and became predominantly necrotic. Treatment was very well tolerated. Conclusions: We report a renewed response to P with addition of an mTOR inhibitor in advanced pleomorphic undifferentiated sarcoma. Crosstalk between pathways, upregulation of PI3K/mTOR signaling along with a rebound effect stirred by cessation of VEGFR blockade may have all contributed to more aggressive disease at the time of progression and may explain reversal of resistance by the addition of a downstream inhibitor such as sirolimus. A study designed to prove this concept is underway.
Adjuvant chemotherapy in patients with malignant fibrous histiocytoma: Single center experience.
Authors: Sekhina Olga , Bulanov Anatoly , Fedyanin Mikhail , Bokhyan Beniamin , Bliznukov Oleg , Aliev Mamed
Published: March 2020

e21510

Background: There is controversy information about efficacy of adjuvant chemotherapy (ACT) for treatment of Soft Tissue Sarcomas (STS) due to histological heterogeneity of these tumors. Whereas STS are heterogeneous group with different sensitivity to chemotherapy (CT), we conducted retrospective study to assess efficacy of adjuvant chemotherapy in patient with high-grade malignant fibrous histiocytoma (MFH). Methods: From 2000 to 2010, 56 patients with localized malignant fibrous histiocytoma were treated in Russian Cancer Research Center named after N.N. Blokhin. Main features: median age 61 years (range: 16–83 years); III stage 37/56, 66%; II stage 19/56, 34%, median tumor size 10cm (range: 2-25 cm); ACT received 18/56, 32%; ACT not received 36/56, 64%; doxorubicin-based CT 16/18, 88%; ifosfamid-based CT 2/18, 12%. Median follow-up was 59 month. Results: Median disease free survival (DFS) was 30 month. Median overall survival (OS) not reached. Median DFS in patients receiving CT was 30 month versus 10 month in patients without CT (p=0.02, HR=2.5; 95% CI 1.09-5.3). In patients with ACT disease progression was observed statistically significantly less often, then without it (39% versus 69%, p=0.04). Three-year OS in patients with ACT was 95% versus 65% in patients control group (p=0.05). We conducted univariate analysis of features, which influence the risk of disease progression disease. Features of favorable prognosis were T1 (p=0.05) and ACT (p=0.04). In multivariate analysis these features remained statistically significant: T (p=0.01, OR 6.7; 95% CI 1.3-34.1), ACT (p=0.02, OR 0.2; 95% CI 0.05-0.7). Conclusions: ACT improved DFS and OS in patients with high-grade localized resectable MFH. These benefits require confirmation in larger studies.
Interesting antitumor activity of lenalidomide in a patient with hepatic epithelioid hemangioendothelioma (HEH).
Authors: Pallotti Maria Caterina , Pantaleo Maria A. , Lolli Cristian , Nannini Margherita , Saponara Maristella , Mandrioli Anna , Gatto Lidia , Di Scioscio Valerio , Pileri Stefano A , Bolondi Luigi , Biasco Guido
Published: March 2020

e21511

Background: Epithelioid hemangioendothelioma (HEH) is a rare malignant vascular soft tissue tumor occurring mostly in the liver. The molecular background is still unkonwn and therefore the medical treatment has not been established. Some case reports treated with angiogenesis inhibitors are described. Lenalidomide has anti-proliferative and cytotoxic effects, immunomodulatory properties but also anti-angiogenic activity. In literature there are few case of patient with solid tumors treated with lenalidomide.We report a patient affected by HEH treated with lenalidomide for long time. Methods: In 2010, a 73 year old man arrived our attention with multiple hepatic lesions diagnosed with contrast computed tomography (CT), abdominal magnetic resonance (MR) imaging and contrast enhanced ultrasound (CEUS) of the liver. An ultrasound guided biopsy of an hepatic lesion was made and histopathology exam deposed for the diagnosis of HEH. We decided to treat the patient with lenalidomide 25 mg daily on 1- 21 every 28 days, because a liver transplantation was not inidcated for the age of the patient. The follow up of disease was made by abdominal ultrasound and MR every three/four months. Results: The patient was treated with lenalidomaide for thirty months totally. After six months the imaging showed a stable disease and after ten months MR also demonstrated an intralesional structure modification as colliquative necrosis. In February 2012, after 24 months of continuos therapy, we decide to stop the treatment for fatigue and for other comorbidity of the patient. After five months of suspension, the ultrasound showed a dimensional increase of a target hepatic lesion & so we restarted lenalidomide for other six months. MR imaging demonstrated a stable disease and abdominal ultrasound showed a decrease of the dimension of a target hepatic lesion. The patient is still under treatemnt with a control of disease. Conclusions: HEH is a rare tumors with probably an indolent natural history but this case report suggests an interesting activity of lenalidomide and antiangiogentic drugs in the treatment of this solid tumor. More patients treated with lenalidomide are encouraged and a small phase II study should be proposed.
Effects of temozolomide combined with bevacizumab in patients with relapsed uterine sarcoma.
Authors: Sasaki Naoki , Kouta Hiroko , Ikeda Yuji , Takano Masashi , Kikuchi Ryoko , Kudoh Kazuya , Kita Tsunekazu , Furuya Kenichi , Kikuchi Yoshihiro
Published: March 2020

e21520

Background: Common treatment for patients with unresectable relapsed uterine sarcoma is anthracycline-based combination chemothersapy, but the response is not satisfactory. We evaluated the effects of temozolomide combined with bevacizumab in patients with relapsed uterine sarcoma. Methods: From 2009 to 2012, nine patients with relapsed uterine sarcoma were treated with weekly bevacizumab (2mg/kg; days1,8, and 15, q4 weeks) and temozolamide (80mg/body, daily), and treatment continued until disease progression. The response and adverse effects were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: In RECIST evaluation, 1 (11%) of 9 patients had complete response (CR) and 1 (11%) had partial response (PR). Four patients (44%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD) were 22% and 66%, respectively. The median progression-free survival was 9.8 months (range from 3 to 32 months). There were no treatment-related deaths or CTCAE grade 4 toxicities, and no patients were dose-reduced due to toxicity. Conclusions: Temozolomide combined with bevacizumab provided disease stabilization in some patients with relapsed uterine sarcoma with tolerable toxicities. These results suggested that this combination would offer another option in the treatment of unresectable relapsed uterine sarcoma.
Oxidative modification of proteins of blood plasma in the development of ovarian cancer relapse.
Authors: Surikova Ekaterina Igorevna , Nerodo Galina , Goroshinskaya Irina Aleksandrovna , Kachesova Polina Sergeevna
Published: March 2020

e22002

Background: Comparative analysis of oxidative modification of proteins of blood plasma level in patients with ovarian cancer in a state of remission and during the formation of tumor relapse with various intensity of bloodstream in it. Methods: The research includes 61 patients with ovarian cancer, from whom 11 women were in a state of remission, and 50 had local relapse in the cavity of the lesser pelvis. With the help of ultra-sonic scanner we evaluated the intensity of vascularization and the speed of bloodstream in relapsing tumors. We also studied the level of blood plasma spontaneous metal catalyzed oxidative modification of proteins (OMP), spectrophotometrically registering 2, 4-dinitrophenylhydrazines. Results: In remission there was noted the increase of OMP products level by 74.4% under 530 nm (p<0.05) in blood plasma as compared with the its level in healthy women. During the progress of avascular relapse there was noted the increase of OMP products level by 63.3% under 370 nm (p<0.001) and decrease of OMP products level by 32.2% under 530 nm as compared with the level in remission. In the group with hyper intensive bloodstream in relapse tumor the level of OMP products increased by 37.4% under 370nm (p<0.05) and the level of products decreased by 24% under 530 nm as compared with the group with avascular relapse. In case with metal catalyzed OMP the low level of OMP products under 370 nm (by 18-28% lower than the level of OMP of healthy women, p<0.01), the high level of OMP products under 530 nm (by 24-47% higher than the level of OMP of healthy women, p<0.01) remained, and the level of OMP under 430 nm was increasing as compared with healthy women. Conclusions: The increase of OMP products of neutral character registered under 370 nm, and the decrease of the products of the basic character registered under 530 nm take place during the progress of cancerous process and intensification of the bloodstream in a tumor. The dynamics metal catalyzed OMP products shows the heightened formation of the products of the basic character (430 and 530 nm), being the markers of proteins fragmentation.
RACGAP1 overexpression in uterine carcinosarcomas.
Authors: Mi Shijun , Lin Mingyan , Heim Jennifer , Isani Sara , Brouwer-Visser Jurriaan , Cossio-Poblete Maria , Smotkin David , Gunter Marc J. , Zheng Deyou , Huang Gloria S.
Published: March 2020

e22009

Background: Uterine carcinosarcomas, also known as malignant mixed mullerian tumors (MMMT), are rare and highly aggressive neoplasms that carry a poor prognosis even when diagnosed at an early stage. A better understanding of the molecular mechanisms underlying the development of uterine carcinosarcoma may lead to specific targeted therapies for these refractory tumors. Methods: Using a next generation sequencing approach and bioinformatic analysis, we compared the whole transcriptomes of 6 histologically normal endometrial tissues and 6 uterine carcinosarcoma tissues from patients. Quantitative real-time PCR and immunoblotting were done to validate the differentially expressed genes. Lentiviral transfection with short hairpin RNAs was performed to achieve targeted gene silencing in a carcinosarcoma cell line. p53 and survivin levels were monitored by immunoblotting. Results: We identified 27 dramatically differentially expressed genes between normal endometrial tissues and uterine carcinosarcoma tissues from patients. We confirmed the differential expression of these genes between normal tissues and uterine carcinosarcoma tissues by qRT-PCR. Of these, we found that RACGAP1 is significantly overexpressed in all of the uterine carcinosarcoma tissues at the mRNA level and at the protein level, compared to normal endometrial tissues. Silencing of RACGAP1 by shRNA in a carcinosarcoma cell line remarkably reduces cancer cell proliferation and leads to p53 upregulation and survivin downregulation. Conclusions: Our data demonstrate that RACGAP1 may represent a novel biomarker and therapeutic target for uterine carcinosarcomas.
Salmonella typhimurium A1-R prolongs survival of aggressive pancreatic cancer in orthotopic nude mouse models.
Authors: Maawy Ali , Zhang Yong , Bouvet Michael , Hoffman Robert M. , Zhao Ming
Published: March 2020

e22013

Background: Salmonella typhimurium A1-R has been previously shown to target multiple tumor types in various mouse models. The aim of this study was to test the efficacy of S. typhimurium A1-R against a high aggressive pancreatic cell line in an orthotopic nude mouse model. Methods: Human MiaPaCa2 pancreatic cancer cells, expressing red fluorescent protein (RFP), were implanted subcutaneously in nude mice. After tumor engraftment, the mice were subjected to intravenous therapy with S. typhimurium A1-R (5×107 CFU) once a week for 3 weeks. The tumors were harvested and weighed after the treatment period. MiaPaCA2-RFP was subsequently surgically implanted orthotopically and S. typhimurium A1-R treatment was initiated 2 weeks later. Mice were treated with intravenous A1-R (5×107CFU) once a week for 6 weeks, after which survival and tumor growth were recorded. Results: In the subcutaneous tumor model, significant decreases in the rate of tumor growth (p = 0.049) and tumor size (p = 0.004) were observed upon termination. In the orthotopic model, a significant decrease in the rate of tumor growth (p = 0.01) and increased survival was observed (p = 0.014). None of the mice showed any adverse events or weight loss from bacterial therapy. Conclusions: The results suggest further investigation S. typhimurium A1-R, including in combination with chemotherapy, with the goal of cure of pancreatic cancer.
Transcriptional gene expression profile in hepatocarcinoma cells induced by acetylsalicylic acid (ASA) in hepatitis C virus (HCV)-subgenomic replicon system.
Authors: Rios Ibarra Clara Patricia , Verduzco Garza Barbara , Ortiz Lopez Rocio , Grondin Yohann , Lozano Sepulveda Sonia , Quintanilla Guzman Arturo , Rivas Estilla Ana Maria
Published: March 2020

e22016

Background: It has been demonstrated that ASA treatment could down-regulate in vitro HCV expression in hepatocarcinoma cells (~50%, p 0.05). However, the signaling pathway induced during ASA antiviral effect has not been elucidated. We analyzed the transcriptional expression profile of Huh-7-HCV-subgenomic replicon cells in presence or absence of ASA in order to identify the signaling pathway and the molecular mechanisms involved in the antiviral effect induced by ASA on HCV expression. Methods: Huh-7-HCV-replicon cells (hepatocarcinoma) were exposed to 4 mM ASA from 24 to 72 hours. Total RNA was isolated, quantified and validated by capillary electrophoresis. After that, we performed a retrotranscription in vitro. Synthesized transcripts were marked with biotin, purified, fragmentized and hybridized in HG-U133 Plus 2 Gene Expression. Hybridization signals were captured with Gen Chip 3000 7G Scanner and analyzed by Expression Console and Dchit Software. Results: After normalization, we obtained hierarchical maps with differentially-expressed genes. Among genetic targets over-expressed, the following stood out CCAAT-enhancer-binding proteins (C/EBP), interleukine-8 (IL-8), cytochrome P450 (CyP450) and methallothioneins (MT) genes were found. Among down-regulated genes we identified ribonucleotide reductase (RR) and superoxide dismutase (SOD) genes. Some of these genes have been previously associated with oxidative stress regulation. All results were validated by real time PCR. Conclusions: We observed that ASA modulates the expression of genes associated with antioxidant role as SOD and methallothioneins. Antioxidant agents can inhibit virus proliferation. HCV decreased antioxidant defense, which promotes the development of hepatic complications caused by HCV infection, including liver cancer. Therefore, ASA could be inducing an antioxidant environment regulating HCV replication. This study provides a tool for identifying novel host factors in hepatocarcinoma cells involved in the antiviral effect regulated by ASA against HCV and improves our understanding of the regulatory mechanism of HCV replication.
Using certain indices of fibrinolytic system for forecasting the efficiency of neoajuvant chemotherapy in ovarian cancer.
Authors: Frantsiyants Yelena , Moiseyenko Tatiana , Komarova Yekaterina , Kozlova Larisa
Published: March 2020

e22022

Background: Using cell markers that characterize biological properties of a tumor, the relevance of treatment used can be determined for each patient, further ways of surveillance of the patients can be selected, and individual forecasts of the illness can be made. Methods: After 1 course of neoajuvant chemoterapy according to the scheme CAP, in the malign tumor tissue of 21 patients (T3a-c N0-1M0-1), the activity of plasminogen and plasmin was determined by ELISA. Then the ratio K of plasminogen (PG) and plasmin (P) was calculated. As a blank, tumor tissue of 18 patients having ovarian cancer without chemotherapy administered has been studied. On all patients, operations in full or cytoreductive surgery were performed. Results: With efficient treatment, ratio K increased (К=1,4±0,2) relative to indices in patients without neoajuvant chemotherapy (К=0,3±0,17), while it remained the same (К=0,2±0,09) or decreased relative to initial data if there was no clinical effect, which is confirmed by further development of ovarian cancer. Conclusions: Thus, determining of plasminogen and plasmin – fibrinolytic system indices – in the tumor tissue and calculating of their ratio allows detecting the patients who have effect from treatment and good forecast and ones without effect, having bad forecast, who need aggressive ajuvant treatment. It also allows determining individual sensitivity or resistance of malign tumors in patients to certain regimens of chemotherapy. At the same time, there is an opportunity to objectify the results of specific therapy.
Effect of p53 gene transfection on proliferation, apoptosis, and radiosensitivity of cervical cancer cells.
Authors: Li Xiaofan , Wen Shao , Zhang Shanwen
Published: March 2020

e22024

Background: To investigate the effects of p53 gene transfection on proliferation, apoptosis and radio-sensitivity of cervical cancer cells. Methods: Two cervical cell lines: Siha with wild-type p53 gene and C33a with mutant p53 gene, were transfected with human wild-type p53 gene. Un-transfected cells and transfected cells were exposed to 6 Gy of radiation. Cell proliferation, apoptosis, and protein expressions of p53, MDM2, p21, and bax in the un-treated, p53- transfected, and irradiated cells were analyzed. Results: The protein expression of p53, MDM2, p21, and bax in the untreated Siha cells is very low; High level p53 and MDM2 proteins and low level of p21 and bax proteins were found in the untreated C33a cells. When transfected with recombinant adenoviral human wild-type p53 gene (rAd-p53) the protein levels of p53, MDM2, p21, and bax in both Siha and C33a increased. Highest levels of these proteins were detected at 48 hours after transfection. The increased protein expressions were accompanied with inhibition of cell proliferation. At 72 hours after transfection, 12.3% and 5.5% of Siha and C33a cells became apoptotic, respectively. When exposed to 6 Gy of radiation after 48 hours of the transfection, 46.2% and 38.3% apoptotic Siha and C33a cells were detected, respectively; but only 5.6% and 6.3% of apoptotic cells of their un-transfected counterparts detected at 24 hours after the radiation treatment. Conclusions: Wild-type p53 gene transfection can inhibit cell proliferation, promote apoptosis, and sensitize to radiation of both Siha and C33a cells. The effects on Siha cells are stronger.
A phase II clinical trial of neoadjuvant therapy with zoledronic acid for operable breast cancer.
Authors: Nakayama Yoshie , Takahashi Shunji , Ito Yoshinori
Published: March 2020

e22027

Background: The neoadjuvant use of bisphosphonates has been reported to increase rates of pathological response in patients with operable breast cancer. We conducted a study to determine whether treatment with zoledronic acid (ZOL) would improve outcomes in such patients when it was added to standard neoadjuvant chemotherapy (NAC). Methods: From April 2010 to June 2012, 30 patients with HER2-negative operable breast cancer were eligible for the study. The patients received NAC (4 cycles of CEF: intravenous epirubicin 100mg/m2, cyclophosphamide 500mg/m2, and fluorouracil 500mg/m2 on day 1, then 12 cycles of weekly paclitaxel 80mg/m2) with ZOL. The ZOL was administered after each cycle of NAC in a 4-mg dose by intravenous infusion every 3 to 4 weeks. The primary end point of the study was pathological response (pPR) rate. The secondary end points were pathological complete response (pCR) rate, adverse effects (AEs) and the changes in the numbers of disseminated tumor cells (DTC), circulating tumor cells (CTC), and circulating endothelial cells (CEC). We evaluated the efficacy and safety of ZOL in the NAC in patients by use of Fisher’s exact test. Results: 29 patients completed surgery after NAC, and pathological analyses and the numbers of CTC and CEC were assessed. Two patients had progressive disease during NAC, with brain metastasis and bone metastasis, respectively. The pPR rate, pCR rate, was 31.0%, 10.4%, respectively. CTC were detected in 3 patients at baseline, and CTC had changed to positive in one patient in D15 of the first cycle, then after NAC, all four patients changed to negative. CTC were negative in two patients at baseline, but after NAC, changed to positive. There were no factors associated with the change rates of CTC. CEC after NAC increased from baseline significantly (p<0.001). The increase rates of CEC were not significantly different among premenopausal and postmenopausal, PR and non-PR, and luminal and triple negative patients. There were no severe AEs associated with ZOL to discontinue treatment. Conclusions: These data suggested ZOL in combination with NAC might not have a significant direct anti-tumor effect. Change of CEC would be a biomarker for NAC, but further analyses would be necessary. Clinical trial information: 000003498.
3D morphometric analysis to yield high sensitivity and specificity enumeration of circulating tumor cells.
Authors: Meyer Michael , Neumann Thomas , Katdare Rahul , Presley Chris , Hayenga Jon , Hawthorne Ben , Nelson Alan
Published: March 2020

e22031

Background: The enumeration of circulating tumor cells (CTCs) has become a common method to assess cancer treatment efficacy. In this study, we propose to test our ability to detect and enumerate CTCs using a morphometric classifier based on 3D cell features to distinguish normal cells from lysed blood and breast cancer cells. Methods: Commercially available normal whole blood was lysed to destroy red blood cells, leaving white blood cells and some cell debris. These cells and breast cancer cells from the SK-BR-3 cell line were studied. The cells were stained with hematoxylin, then were automatically imaged using VisionGate’s 3D cell imaging system (Cell-CT) that unambiguously renders individual cells with isometric, sub-micron resolution. Image libraries of cells were created. For each cell, 683 morphology features were computed. Features characterize various aspects of the cell such as chromatin distribution in the nucleus, nuclear volume and shape and nuclear to cell volume ratios. The true cell diagnosis for each cell was determined by a cytotechnologist and added to the feature set. Cross-validated classifiers were created using the technique of adaptive boosting that combines a sub-set of the features into a single score that best correlated with the binary cell diagnoses. Results: 3,256 normal cells or other normal objects and 1,843 breast cancer cells were studied. A classifier that distinguished normal cells from cancer cells was created that used the strongest 25 3D morphology features. The morphometric classifier had an area under the ROC curve that measured 0.9998. This classifier could be operated with near perfect specificity and a cancer cell sensitivity of 95%. Conclusions: Performance of automated, 3D morphometric classifiers for cancer cell detection suggests highly accurate CTC enumeration with implications for patient management and prediction of cancer progression.
The impact of sex on ropporin expression in multiple myeloma patients.
Authors: Wade Raymond , Radhi Saba , Chiriva-Internati Maurizio , Hardwick Fred , Mer Jesse , Aulakh Amardeep , Saadeh Charles , Yu Yuefei , Mirandola Leonardo , Zepeda Kristopher , Chiaramonte Raffaella , Colombo Michela , Platonova Natalia , Nguyen Diane Duyen Thuy , D'Chuna Nicholas , Konala Venu , Jenkins Marjorie , Figueroa Jose A. , Cobos Everardo
Published: March 2020

e22052

Background: Multiple myeloma (MM) is a cancer of plasma cells wherein aberrant cells accumulate in the bone marrow leading to bone damage and interference with normal blood cell production. Although MM remains incurable, it is treatable. As with most forms of cancer, early detection is the key to improving prognosis and avoiding permanent damage. Cancer Testis Antigens (CTAs) are a class of proteins that are expressed in male gametogenic tissue but generally not in the somatic tissue of healthy adults. However, a number of cancer types have been shown to produce these proteins, and their expression has been correlated with malignancy. Ropporin is a specific CTA shown to be associated with MM, and this protein represents a potential target for MM diagnosis as well as immunotherapy. In this study, we examine the impact of sex on the expression of Ropporin, in MM patients. Methods: The expression of this particular CTA in MM patients was analyzed using PCR, ELISA, and immunohistochemistry in a cohort of 59 MM patients (37 male and 22 female). Results: 61% of MM patients were positive for Ropporin expression. When the data were broken down by sex, it was revealed that Roporrin expression was 81.8% in females and 48.6% in males. Interestingly, 50% of female patients as well as 78% of males expressing Ropporin were deceased. In addition, 100% of the deceased subjects in the cohort were Ropporin positive. Conclusions: Our results provide indications that sex can shift the expression of CTA in multiple myeloma. Furthermore, the data indicate CTA expression may affect the prognosis in MM patients. Further studies in a large cohort of patients are warranted to validate the correlation of CTA/ropporin in MM patients and sex.
Can serum thioredoxin levels predict sensitivity to platinum in lung cancer?
Authors: Dinh Vy Thuy , Wangpaichitr Medhi , Nguyen Dao M. , Matsangou Maria , Wu Chunjing , Ahn Eugene , Savaraj Niramol
Published: March 2020

e22062

Background: Our laboratory has found that cisplatin resistant lung cancer cells possess high levels of ROS (reactive oxygen species). Low intracellular TRX1 (thioredoxin) levels due to increased secretion of the thioredoxin-1 (TRX1) is the primary reason for high intracellular ROS levels. We have further shown that reconstituting TRX1 protein in cisplatin-resistant cells can restore sensitivity to cisplatin. Conversely, silencing TRX1 in parental cells reduced the sensitivity to cisplatin (MCT11:604, 2012). Thus, it is possible that serum TRX1 levels may be a useful marker to predict sensitivity to platinum containing regimens. Methods: Serum samples were obtained before, during, and after platinum chemotherapy. TRX1 was determined by sandwich ELISA with two TRX1 antibodies. Samples, standards, and reagent blank were incubated with precoated plate (IBL). Labeled antibody solution was added followed by Chromagen substrate and subjected to plate reader. The value on normal healthy individual is less than 5 ng/ml. The lowest limit of detection is 1 ng/ml. Results: 11 patients (pts) were entered into the study. 6 pts had small cell lung cancer (SCLC) and 5 had non small cell lung cancer (NSCLC). 2 SCLC pts died before treatment and couldn’t be assessed and 2 pts are too early to assess response. In these lung cancer pts, the baseline levels ranged from 0 to 96.5 ng/ml. Thus far, 4 pts (1 SCLC and 3 NSCLC) who had baseline TRX1 levels of 0, 0, 0 and 3 responded to chemotherapy. An additional SCLC pt with very high levels of TRX1 (96) also responded to chemotherapy. However, this pt also had a recent operation for NSCLC and the baseline blood sample was obtained after the operation, which may not be the appropriate baseline. 2 pts with baseline TRX1 levels of 31.1 and 6.5 did not respond to treatment. TRX1 levels increased during chemotherapy, especially when given concurrently with radiation. However, in pts who responded, TRX1 levels decreased at the end of treatment. Conclusions: The study is currently ongoing. Our initial results suggest that low TRX1 levels may indicate possible future response to platinum containing regimens. While TRX1 levels may increase during treatment, in pts who respond to treatment, TRX1 levels often decrease back to baseline.
Prevalence and quantity of circulating tumor cells (CTCs) after adjuvant chemotherapy in patients with HER2-negative early breast cancer (EBC).
Authors: Schochter Fabienne , Andergassen Ulrich , Neugebauer Julia Katharina , Friedl Thomas W. P. , Pestka Aurelia , Jueckstock Julia Kathrin , Jaeger Bernadette , Salmen Jessica Christine , Hepp Philip Gm , Heinrich Georg , Camara Oumar , Decker Thomas , Ober Angelika , Fehm Tanja N. , Pantel Klaus , Fasching Peter A. , Schneeweiss Andreas , Beckmann Matthias W. , Janni Wolfgang , Rack Brigitte Kathrin
Published: March 2020

e22075

Background: Prevalence of CTCs after adjuvant chemotherapy in patients with EBC might indicate both treatment response and prognosis. Here we present data on CTC prevalence and quantity assessed after chemotherapy in correlation with tumor characteristics and chemotherapeutic treatment in patients with Her2-negative EBC from the German SUCCESS C study. Methods: The SUCCESS C trial is a randomized, open-label, Phase III study comparing disease free survival (DFS) in patients with HER2-negative EBC treated with either 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC) followed by 3 cycles of Docetaxel(DOC), or 6 cycles of a anthracycline-free regimen with Docetaxel-Cyclophosphamide(DOC-C). The CTC status at chemotherapy cycle 6 was prospectively evaluated using the FDA-approved CellSearch System (Veridex, USA). Results: Valid data on CTC status after chemotherapy were available for 2,336 patients (78% estrogen receptor positive, 6% pT3 or pT4, 12% pN2 or pN3). CTCs were found in 278 (11.9%) patients (median 1, range 1 – 69 CTCs). One CTC was detected in 164 (59%), two CTCs in 57 (21%), three to five CTCs in 45 (16%), and more than five CTCs in 12 (4%) of these patients. CTC prevalence was not significantly associated with tumor size (pT1, pT2, pT3, pT4), nodal stage (pN0, pN+), grading (G1, G2, G3), histological type (invasive ductal, invasive lobular, other), estrogen receptor status, progesterone receptor status, or treatment arm (FEC-DOC, DOC-C), as revealed by both univariate analyses (Chi-square tests, all p > 0.1) and a logistic regression with CTC prevalence as dependent variable. Conclusions: In about 12% of patients with Her2-negative EBC, CTCs in the peripheral blood were detected at the end of adjuvant chemotherapy treatment. However, neither CTC prevalence nor quantity of CTCs were related to tumor characteristics or type of chemotherapeutic regimen. The low rate of CTC-positive patients might be attributed to the negative HER2 status and reflects therefore the relatively low risk of these patients to develop metastatic relaps. Clinical trial information: NCT00847444.
Relationship between EGFR Intron-1 CA SSR 1 polymorphism and skin rash in patients treated with cetuximab.
Authors: Nawrocki Sergiusz , Rucinska Monika
Published: March 2020

e22087

Background: EGFR inhibiting drugs do not work equally effectively in cancer patients. We were looking for potential genetic factors which could help to select patients who benefit from treatment with cetuximab. One of established clinical factors is skin rash, which correlate with clinical response to EGFR inhibitors. Our hypothesis was that rash intensity depends on genetic polymorphisms of gene encoding EGFR, especially on Intron-1 CA SSR 1 polymorphism. The number of CA repeats in Intron-1 may affect the level of preRNA synthesis. Methods: The prospective study included 62 patients (colon cancer, head and neck, non-small cell lung cancer and gastric cancer) who were treated with cetuximab together with chemotherapy. 4 weeks after the start of treatment with cetuximab, rash intensity was assessed according to NCI CTAEv.3.0. criteria. DNA for analysis was isolated from 5 ml of peripheral blood. Using the PCR reaction with specific primers (polymorphic DNA segment was amplified. The obtained DNA fragments were analysed by GenScan to determine their lengths. Results: Patients with 15-18 “CA” repetitions were classified as having a short allele “S”, while patients with 19-22 “CA” repetitions have been marked as having a long allele “L”. The relationship between the rash intensity and the CA-polymorphism was assessed (Table). The analysis showed that there is tendency to more intensive rash in patients with pair of “short” alleles (SS), than in patients with “short-long” (SL) and “long” (LL) allelles (p<0,1 chi-square test). Conclusions: There is a relationship between the EGFR Intron-1 CA-polymorphism and the rash intensity in patients treated with cetuximab which warrants further prospective clinical investigation. [Table: see text]
Molecular subtyping of breast cancer using dedicated breast PET-CT.
Authors: Pinker-Domenig Katja , Magometschnigg Heinrich , Mayerhoefer Marius , Dubsky Peter Christian , Bartsch Rupert , Bago-Horvath Zsuzsanna , Karanikas Georgios , Weber Michael , Helbich Thomas
Published: March 2020

e22090

Background: Recently dedicated breast 18FDG breast PET-CT has emerged as an additional imaging tool for assessment and staging of primary breast cancer. Expression of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status, has direct prognostic and therapeutic implications in patient management. This study aimed to determine whether correlations exist between 18FDG up-take of the primary breast cancer lesions and these predictive and prognostic factors. Methods: Before undergoing surgery 114 patients with primary breast cancer underwent 18FDG breast PET-CT. The maximum standardized uptake value (SUVmax) of the primary breast cancer was measured in each patient and standard immunohistochemistry was performed on a surgical specimen to characterize the receptor state of tumor cells. Appropriate statistical tests were used to test for any association that may exist among ER, PR, and HER2. Results: A significant association was found between a triple negative status and the SUVmax (p < 0.001) of breast tumors. ER-negative tumors (mean SUVmax, 10.4) demonstrated a significantly higher SUVmax than did ER-positive tumors (median SUV, 5.1) (p= 0.045). No statistical significant difference was found for SUVmax of PR-negative vs. PR-positive lesions with a mean SUVmax of 8.6 and 4.9 (p=0.15) respectively. No statistical significant difference was found for SUVmax of HER2-negative vs. HER2-positive lesions with mean SUVmax of 6.4 and 5.3 respectively (p=0.55). If either ER or PR was positive, then the other tended to be positive as well (chi2 = 84%, P < 0.01). No such significant relationship was detected between PR or ER and HER2 (P > 0.05). Conclusions: ER-negative breast cancer tumors display higher 18FDG uptake than ER-positive tumors. Triple-negative breast tumors are associated with increased 18FDG uptake commensurate with their aggressive biology. The data suggest that SUVmax measurements of 18FDG breast PET-CT can provide valuable information about the state of ER, PR, and HER2 and the associated glucose metabolism of the primary breast cancer lesions. Such an association may be of importance to treatment planning and outcome in these patients.
Targeting angiogenesis driven by fibroblast growth factor using RPT835, an FGFR2 inhibitor.
Authors: Stepanova Evgenia , Solomko Eliso , Ryabaya Oxana , Peretolchina Nina , Tsimafeyeu Ilya , Tjulandin Sergei
Published: March 2020

e22097

Background: The fibroblast growth factor (FGF)/FGF receptors (FGFR) signaling axis plays a key role in driving tumor angiogenesis. There is little data on the targeting of FGF-induced angiogenesis. We describe here the targeting angiogenesis driven by FGF using RPT835, novel inhibitor of the FGFR2 extracellular domain (received from RusPharmTech, LLC). Methods: To assess the efficacy of RPT835 on FGF-mediated endothelial cells proliferation, the human umbilical vein endothelial FGFR-expressing cells (HUVEC) were incubated in a 96-well microculture plate and were treated with serially diluted RPT835 or Brivanib as a control. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. In vivo angiogenesis was measured with subcutaneously implanted Matrigel plugs containing bFGF (100 ng/ml) or bFGF (100 ng/ml) + bevacizumab (10 mg/kg) or bFGF (100 ng/ml) + RPT835 (15 mg/kg). Control group was without stimulation and treatment. Each group included 3 mice. Number of endothelial cells/vessels was calculated. Results: Basic FGF significantly increased proliferation of the HUVEC cells (P=0.001) in untreated control group. RPT835 significantly inhibited FGF-triggered endothelial cell proliferation when compared with control (P<0.001) or brivanib (P<0.001, IC50=289 nmol/L) with IC50 of 11 nmol/L. In vivo, bFGF induced proliferation of endotheliocytes and mature vessels formation (P<0.001). There were no vessels in FGFR2 inhibitor group. Bevacizumab did not decrease number of vessels in comparison with FGF-stimulated angiogenesis (P=0.9). Conclusions: Inhibition of bFGF/FGFR2 pathway resulted in effects on endothelial cells proliferation andmature vessels formation. Bevacizumab had no activity in FGF-induced angiogenesis.
Association of tumor-specific GPR87 overexpression with poor prognosis in non-small cell lung cancer.
Authors: Nii Kazuhito , Liu Dage , Tokunaga Yoshimasa , Zhang Xia , Ishikawa Shinya , Haba Reiji , Kakehi Yoshiyuki , Yokomise Hiroyasu
Published: March 2020

e22108

Background: GPR87 is a member of G-protein-coupled receptors (GPCRs). Recently, GPR87 was suggested to contribute to the viability of human tumor cells, and the overexpression of GPR87 mRNA was found in many malignant tumors including lung cancer. However, the clinical significance of GPR87 expression in non-small cell lung cancer (NSCLC) has not been well studied. Methods: 127 NSCLC patients who underwent surgery from 1999 to 2004 were investigated. There were 59 adenocarcinomas, 55 squamous cell carcinomas and 13 others. The intratumoral expression of GPR87 was evaluated by immunohistochemistry. The Ki-67 proliferation index was also evaluated. Results: A tumor-specific expression of GPR87 was found in NSCLC in comparison with the surrounding normal tissue. Fifty-nine tumors (46.5%) were found to be high-GPR87 tumors. The high-GPR87 tumors were more frequently found in squamous cell carcinoma than in adenocarcinoma (60.0% versus 37.3%, p=0.02). Regarding the tumor proliferation, the Ki-67 index was significantly higher in high-GPR87 tumors than in low-GPR87 tumors (p=0.04). There was a tendency that the overall survival was worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.22). For the patients with adenocarcinoma, the overall survival was significantly worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.04). Conclusions: GPR87 expression may become a poor prognostic predictor for patient with NSCLC, especially for those with adenocarcinoma. GPR87 may contribute to the cell viability by promoting cell proliferation, has a potential to become a novel therapeutic target for cancer treatment.