bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label trial of SMK treatment of advanced metastatic cancer.
Authors: Hoffman Steve , Bruckner Howard , Del Priore Giuseppe , Gurell Daniel , Mull Ruslan , Stega Damian , Goodwin Gail , Demurjian Mike , Malanowska-Stega Jeanetta 
Published: March 2020

e22095 Background: SMK is a novel therapy that creates alteration in defenses to oxidative stress and increases free radical availability to the cancer cell. SMK is designed to penetrate the living cancer cells and introduce multiple mechanisms to kill the cell. Inducing transfer of electrons in the cancer cells allow catalyzed external free radicals to react and stress the cell. SMK is a combination of low dose agents used for non-cancer treatment. Methods: IRB approved study for metastatic cancer. No additional chemotherapy allowed. First 30 subjects meeting criteria were consented. SMK given orally and SQ, 5 days/wk, 6 weeks (1 cycle). Eligible subjects had cycles 2 and 3. Results: Average age 57.5 (30-81); 70% female; 30% Male. 90% Caucasian, 3.3% each- Asian, Hispanic, Native American. Cancer type: 43% breast, 20% lung, 10% pancreatic, 6.6% each: bile duct and prostate with bone metastasis, 3.3% each: colon, tongue, appendix and thyroid. 100% Breast cancer subjects had metastasis: 15% each: bone, lung, bone/lymph 8% each: lung, lymph, bone/brain/lung, bone/brain/spine, bone/liver, bone/brain, liver/bones/lymph. 10% treated for 1 cycle, 90% 2 -3 cycles. 13.3% maintained same ECOG rating. 76.6% had 1 pt, 6.6% had 2 pt, and 3.3% had 3 pt improvement. 13.3% had 1 pt decrease, 23.3% maintained the same, 63.3% had 1-3 pt improvement in health on EORTC (1-7) rating. 13.3% had a 1 pt decrease, 20% maintained the same, 66.7% had 1-4 pt improvement in quality of life on EORTC (1-7) rating. 56.6% gained 1-13lbs. 16.6% same weight, 26.6% lost 1-4 lbs. 73.3% had 1-8 pt. pain reduction (scale 1-10). 19.9% had minimal or moderate pain and maintained. 6.6% had minimal pain and had a 1 pt increase. 46.6% were on pain medication. 43% no longer needed pain medication after study. 100% Health and quality of life significantly improved: 16.6% show no uptake on a PT scan; 16.6% have significant reduction in quantity and/or size of the tumor; 26.8% have reduction in quantity/size of the tumor; 40% have a stable disease; 90% -Alive, median survival 257 days to date. 10% died, median survival 163 days.Total median survival 247 days (from first day of treatment). 100% had hyperpigmentation. No SMK related adverse events reported. Conclusions: SMK is a very promising treatment for metastatic cancer.
Is tryptase a novel serum bio-marker predictive of radical surgery in colo-rectal cancer patients?
Authors: Ammendola Michele , Sacco Rosario , Donato Giuseppe , ZuccalÃ Valeria , Goffredo Veronica , Patruno Rosa , Brandi Mario , Sammarco Giuseppe , Ruggieri Eustachio , Montemurro Severino , Gadaleta Cosmo Damiano , Ranieri Girolamo 
Published: March 2020

e22104 Background: Data from experimental tumour models suggest that mast cells (MCs) accumulate near tumour cells before the onset of angiogenesis. Tryptase is a serin protease stored in mast cell granules that plays a role in tumour angiogenesis. Mast cells (MCs) can release tryptase following c-Kit receptor activation. Here we aims to assess tryptase serum levels in CRC patients before and after radical surgery resection and c-Kit expressing cells in primary tumour tissue. Methods: In this study patients with stage B and C CRC (according to Astler e Coller staging system) were selected. Samples of blood were taken from CRC patients between 7 and 9 a.m. 1 day before and 1 day after tumour surgical resection. Venous blood was dispensed into a tube for serum (Becton Dickinson Hemogard Vacutainer Systems, Plymouth, UK). Serum blood samples were centrifuged at 1,500g for 10 minutes and then aliquoted and frozen at -80 °C. Tryptase levels were measured using the UniCAP Tryptase Fluoroenzymeimmunoassay (Pharmacia,Uppsala, Sweden). In addition primary tissue section were immunostained with a primary anti c-Kit antibody (A4502; Dako, Glostrup, Denmark) by mean of immunohistochemistry. Results: Mean ± s.d. tryptase level pre-tumour surgical resection was 6.38 ± 4.49 μg/L, and mean ± s.d. tryptase level post tumour surgical resection was 5.11 ± 3.81 μg/L. A statistically significant difference between pre-tumour surgical resection and post-tumour surgical resection tryptase level concentrations was found: p=0.000 by t-test. A strong correlation between pre-tumour surgical tryptase level and c-Kit expressing cells was also found (r=0.81, p=0.000). Conclusions: This is the first report that analyzes the possible significance of serum tryptase levels changes in CRC patients who underwent radical surgical resection. Our results demonstrated higher serum tryptase levels CRC patients suggesting the release of tryptase from c-Kit expressing cells CRC tissue. We suggest that tryptase may play a role as a novel serum tumour bio-marker predictive of radical surgery in CRC patients. In this context tryptase inhibitors might be evaluated in adjuvant clinical trials as a new antiangiogenetic approach.
Brightness analysis in contrast-enhanced ultrasound using sonazoid for breast cancer.
Authors: Masumoto Norio , Kadoya Takayuki , Akimoto Etsushi , Kajitani Keiko , Emi Akiko , Shigematsu Hideo , Haruta Rumi , Kataoka Tsuyoshi , Okada Morihito 
Published: March 2020

e22113 Background: We evaluated the contrast effects of Sonazoid in tumor tissue according to brightness intensity, in cases pathologically diagnosed with breast cancer. Methods: Six cases of ductal carcinoma in situ (DCIS) and seven cases of invasive ductal carcinoma (IDC) diagnosed with needle or Mammotome biopsy between September and December 2012 were examined. The mean ages of the DCIS and IDC cases were 51.7 ± 11.8 years and 62.5 ± 15.7 years respectively. In the IDC cases, tumor diameter was 6-10 mm in three cases, 11-20 mm in three cases and over 50 mm in one case. Two IDC cases were of the luminal A subtype, three cases were luminal B and two cases were triple negative. The ultrasound equipment used was HI VISION ASCENDUS (Hitachi Medical Corporation). The contrast agent, Sonazoid, was administered intravenously at 0.01ml/kg, and for approximately 50 seconds, the tumor sections were fixated and underwent imaging. Sonazoid brightness in the tumor was digitized and a time intensity curve was created based on brightness intensity and time changes. Early and peak contrast brightness was then compared in order to objectively examine changes in contrast effects. Results: Peak brightness was 1.6 ± 0.3 times and 4.8 ± 3.2 times the early brightness in DCIS and IDC cases respectively, indicating a more significant increase in IDC cases (P < 0.05). Comparison according to subtype in IDC cases also revealed a strong increasing trend in triple negative cases, with results showing that peak brightness compared to early brightness was 9.1 times greater in triple negative cases, 2.7 times greater in luminal A cases and 3.3 times greater in luminal B cases. Classification of IDC cases according to nuclear grade (NG) found that peak brightness was 6.2 times greater than early brightness in NG3 cases, 5.7 times greater in NG2 cases and 1.7 times greater in NG1 cases. Conclusions: Brightness intensity, when digitized and analyzed, could be applied to the differential diagnosis of DCIS and IDC. Brightness intensity may also exhibit correlations with subtypes and NG, suggesting that it could be applied to malignancy grading, as well as the prediction of effects of drug therapy and effect measurement.
Impact of deviated balance of regulatory and cytotoxic T cells on release and reseeding of circulating tumor cells in hepatocellular carcinoma.
Authors: Yang Xin-Rong , Sun Yun-Fan , Xu Yang , Jian Zhou , Fan Jia 
Published: March 2020

e22133 Background: Our previous data showed that a preoperative CTC ≥2 was significantly related with relapse of hepatocellular carcinoma (HCC) after surgery. However, how CTCs managed to evade immune surveillance, invade into circulation and reseed in the original organ still remains largely unclear. In this study, we illustrated the pro-tumor effect of Treg infiltration in the context of CTC releasing and reseeding. Methods: Using CellSearch system, 115 HCC patients were tested for CTCs prior to resection. Foxp3+, CD8+ and Granzyme B-positive (GrB+) tumor -infiltrating lymphocytes were evaluated by immunohistochemistry (IHC) in tissue microarrays. For IHC markers, the cutoff for stratification subsets was the median value. The pro-invasiveness properties of Tregs were analyzed in both in vitro and vivo assays. Results: Twenty-two patients with high Tregs and low activated CTLs in tumoral tissues had increased number of CTCs compared to 22 patients with low Tregs and high activated CTLs (6.68 vs. 0.91, P<0.001). In 77 patients with detectable CTC, high Tregs and low activated CTLs in peritumoral tissues was significantly associated with an increased incidence of HCC recurrence (80.5% vs. 19.4%, P<0.001), and was an independent prognostic factor for HCC early recurrence (P=0.007). Further in vitro study showed Tregs-derived TGF-β promoted HCC cell migration and invasion; down-regulated E-cadherin and up-regulated N-cadherin, vimentin, fibronectin and snail. The data in human tumor sample also showed that the TGF-β level had positive relationships with Treg count, N-cadherin level and CTC count; and had inverse relationship with E-cadherin (all P values <0.05). In mice, depletion of Tregs by neutralizing antibody abolished intrahepatic colonization and lung metastasis. Conclusions: Local immune contexture in HCC orchestrates with biological behavior of CTCs. High intratumoral Tregs may promote the release of CTCs through inducing tumor cells EMT transition via TGF-β secretion. High peritumoral Tregs created an immune-subversive microenvironment by suppressing CTL to favor colonization of CTCs, which led to recurrence after HCC resection.
Bevacizumab as maintenance therapy (mBev) in metastatic breast cancer (MBC).
Authors: Militello Loredana , Carli Paolo , Di Lauro Vincenzo , Spazzapan Simon , Scalone Simona , Lombardi Davide , Tuzi Alessandro , Talamini Renato , Quitadamo Daniela , Turchet Elisa , Crivellari Diana 
Published: March 2020

e22149 Background: Preclinical models suggest that the anti-VEGF may improve the efficacy of anti-estrogen therapies in Hormonal Receptor positive (HR+) breast cancer, but there is lack of informations about the maintenance therapy with Bev (mBev) and Hormonal Therapy (HT). Methods: sixty-one pts with HER-2 negative MBC were treated, at our institution from 2007, with Bev+Taxanes (BT) as 1stline chemotherapy and with HT in HR+ pts as maintenance therapy. Primary endpoints were the evaluation of Progression Free Survival (PFS) and Overall Survival (OS). Secondary endpoint was the safety with HT in HR+ pts. Results: Hormonal status was positive in 52/61 (85%). Antracyclines were administered as adjuvant therapy in 26 pts (42%), antra+tax in 26 (42%) pts, no adjuvant therapy in 9 pts (14%). At the time of first relapse, median age was 50 y/o (range 33-72). First line HT was given to 12 pts. Metastatic sites were only bone in 20 pts (32%), visceral in 15 pts (25%), bone + visceral in 19 pts (31%), lymph nodes in 7 pts (11%). ECOG PS was 0 in 56 pts and 1 in 5. Median number of cycles of BT was 7 (1-14). All pts were evaluated for PFS and OS and 45 pts were evaluated for objective response: complete response (CR) was achieved in 5/45 pts (11%) (duration 12 months), partial response (PR) in 34/45 pts (75%) (duration 6-7 months), stable disease (SD) in 6/45 pts (14%) (6 months). After the assessment of the response, 34/61 pts received maintenance Bev (mBev); among this group, 24/34 pts with HR+ were also treated with HT until disease progression. The median number of cycles of mBev was 8 (1-42). Median PFS was 13.5 months (95%CI: 10.2-18.2) and median OS was 36 months (95%CI: 22-51). The BT regimen was well tolerated: 2 pts experienced cardiotoxicity with a reduction in left ventricular ejection fraction (LVEF); the most common side effects were hypertension (grade 1 in 11 pts e grade 2 in 16 pts), bleeding in 8 pts, proteinuria in 7 pts (grade 1 in 5 pts and grade 2 in 2 pts). Conclusions: Hormonalmaintenance and Bev can extend the overall benefit of therapy and it is well tolerated and associated with long-term clinical outcome. Our results are encouraging for prolonging Bev in association with HT as maintenance therapy until disease progression.
The claudin expression signature of BRCA1-deficient breast cancer.
Authors: Heerma van Voss Marise R. , van der Groep Petra , Smolders Yvonne H. C. , Bart Joost , Van Der Wall Elsken , van Diest Paul J. 
Published: March 2020

e22174 Background: Unraveling the biology of BRCA1 related breast cancers may help to improve early detection methods in mutation carriers and patient tailored therapy. Claudins constitute a family of integral membrane proteins, forming the backbone of tight junctions. Altered claudin expression has been linked to oncogenesis in several ways. Decreased cellular polarity increases nutrient and growth factor supply to the rapid expanding tumor cells and decreased intercellular attachments might increase metastatic potential. The discovery of a claudin-low intrinsic subtype of breast cancer has further increased the interest in claudin expression. This study searched for distinct claudin expression profiles that characterize BRCA1 related breast cancers. Methods: 40 BRCA1 related breast cancers and 40 age-matched sporadic breast cancers were immunohistochemically stained for claudin 3, claudin 4, claudin 6 and claudin 7. Cytoplasmic and membranous expression were scored. In addition, a score was given for the overall expression (cytoplasmic and membranous combined) in comparison to the surrounding normal breast tissue. Results: Distinct claudin expression profiles were observed in BRCA1 deficient breast cancers. The hereditary cases had significantly more overexpression of claudin 3, when compared to the tumor surrounding tissue (45.7% vs 17.9%, p=0.03). Membranous claudin 6 expression was seen in 28% in BRCA1 related, compared to only 2.9% in sporadic cases (p=0.007; OR 13.2 95% CI 1.50-116). Claudin 6 was also more often overexpressed, when compared to the normal surrounding tissue in BRCA1 cases (62.5% vs. 19.4%). For claudin 7 an interesting pattern was observed. Membranous expression was observed more often in sporadic (80.0%) than hereditary (42.0%) carcinomas (p=0.001; OR 0.19 95% CI 0.07-0.50), whereas cytoplasmic expression was more abundant in BRCA1 related tumors (85.0% vs. 66.7%; p=0.06; OR 2.83 95% CI 0.95-8.46). Conclusions: Distinct claudin expression profiles characterize breast cancer in BRCA1 mutation carriers. Therefore, claudins may serve as biomarkers for diagnosis of BRCA1 related breast cancer. The mechanism of cytoplasmic relocalization of claudin 7 in BRCA1 deficient tumors deserves to be further studied.
Approaching individualized care with a clinical tissue proteomics methodology.
Authors: Johann Donald Joseph , Mukherjee Sumana , Prieto DaRue , Blonder Josip 
Published: March 2020

e22180 Background: The vast majority of therapy plans for cancer patients are derived categorically. Currently, large and time lengthy clinical trials supply the oncology community with aggregate population and survival statistics. Although this approach has been successful there are known shortfalls. More specifically, since the inherent molecular heterogeneity of the solid tumor under study has not been examined, it is not surprising that results may vary widely across individual patients. Therefore, what is needed is a rationally-based molecular profiling of an individual patient's tumor, in a timely manner. The aim is to link the best drug(s) to the individual patient's cancer based on objective molecular data, thus maximizing therapeutic efficacy and minimizing toxicity. Methods: Presented is a new form of a protein-based molecular profiling approach developed utilizing LC/MS-MS. Importantly, this method has the same tissue and time requirements as IHC. A total of 30 breast tumors and 10 normal breast samples were analyzed. Tumors consisted of 10 ER+, 10 HER2+, and 10 triple negative. Custom software was developed. First, to better illustrate the molecular circuitry of the tumor, proteomic data was rendered as a virtual wiring diagram. This was done on a per tumor basis thus graphically illustrating the molecular traffic intensities. Second, computationally deriving a numeric similarity score to allow for easier comparison of molecular circuitry. Results: Biologically relevant proteins (p53, ER, HER2, Ki67) including driver oncoproteins were found. Effective molecular profiling of breast cancer at the protein level was achieved and the established clinical tumor subtypes were discriminated by unsupervised clustering. A visualized simulation of an estrogen carcinogenesis network was also developed. Experimentally identified proteins and expression levels were mapped and objectified onto known cancer pathways contained in the network. Conclusions: Since the tissue quantity and time requirements are the same as IHC the approach is clinically practical. The approach is discovery based and complementary to IHC but is not dependent on antibodies. This method shows promise as a research tool in a clinical trial.
Quantitative test of mutant EGFR and its effect on efficacy of EGFR TKI in advanced NSCLC.
Authors: Zhou Caicun , Li Xuefei , Ren Shengxiang , Yang Guohua , He Wei 
Published: March 2020

e22186 Background: It is reported that abundance of EGFR mutation is related with efficacy of EGFR TKI in advanced NSCLC patients with positive EGFR mutations. This study was designed to investigate influence of EGFR mutations and their abundance on efficacy of EGFR TKI. Methods: 141 advanced NSCLC treated with EGFR TKI and available tissue for EGFR mutations were enrolled into the study. EGFR mutation was detected with the kit of AmoyDx ARMS and concentration of mutant EGFR was detected with the method of a quantitative competitive allele specific Taqman PCR technology (qCAST). In this assay, copies from EGFR mutants were calibrated by standard curve respectively, and the mutation rates were estimated through normalizing by copies of a conserved sequence in EGFR exon2. The relationship between abundance of EGFR mutations and efficacy of EGFR TKI was analyzed. Results: The median age of patients was 59 years old, and in which 54.3% were male, 71.7% ex-somkers. Among all of the patients, adenocarcinoma accounted for 57.7%, squamous cell carcinoma 27.2%, adeno-squamous cell carcinoma 7.6%, and others 7.6%. 46.7% of patients harbored EGFR mutations, and in which 48.7% existed more than 20% abundance of EGFR mutations. Overall response rate was 31.4% and progression free survival was 5.0 months. The final analysis data will be reported at the conference. Conclusions: The abundance of EGFR mutations might affect the efficacy of EGFR-TKI, and quantitation of mutant EGFR may better predict for efficacy of EGFR TKI in advanced NSCLC.
Assessing factors for predictive response to ADC targets in clinical tissue for companion diagnostic development.
Authors: Potts Steven James , Krueger Joseph , Lange Holger , Eberhard David , Young George David 
Published: March 2020

e22187 Background: One premise of antibody-drug conjugates (ADC) is that the bound mAb-antigen complex on the cell surface will internalize and be metabolized by lysosomal proteases to release the free drug. Thus, the efficacy of an ADC is dependent not only on the presence of cell surface antigens, but also intact delivery of the conjugated drug. In most cases, the biological mechanisms behind these processes have not been elucidated. Furthermore, the extracellular stability of the ADC may be affected by the activity of the target proteases in the tumor microenvironment outside of the lysozome. These concepts are especially important for CDx approaches, which would ideally account not only for the degree of cell surface expression of the target, but also receptor internalization and potential effects of tumor microenvironment. Although in vitro approaches exist to measure these attributes, there are no clinically amenable approaches to measure these critical parameters. Methods: Flagship Biosciences has invented several proprietary approaches for measuring critical properties of the therapeutic target on the cell surface or inside the cell, as well as properties of the TME which could be used to predict efficacy to an ADC using FFPE biopsies. These image analysis approaches have been designed specifically in context of ADC CDx programs to: 1) Accurately define cell surface target expression independent of cytoplasmic expression; 2) Assess critical factors in the TME which may affect delivery of the drug to the intracellular target; and 3) Multiplex these evaluations for an integrative answer to be derived from a typical clinical biopsy. Results: The measurement of cytoplasm/membrane localization was evaluated on several hundred tissue sections, and the methodology was found to be highly reproducible, with coefficients of variation lower than that observed by manual pathologist accessment. Conclusions: Our approach discretely measures endpoints of cell surface biomarker prevalence, biomarker membrane/cytoplasmic ratio, heterogeneity, stromal contribution, inflammatory environment, and other important cell-by-cell outputs from a single FFPE slide in the context of typical drug discovery.
Using a program that computes tumor decay (d) and regrowth (g) rates and the fraction (Φ) of tumor killed to assist in clinical trials and improve patient survival.
Authors: Wilkerson Julia , Bates Susan Elaine , Stein Wilfred Donald , Fojo Tito 
Published: March 2020

e22213 Background: Clinical trials collect much data on tumor quantity as therapy proceeds. From this data progression endpoints and response rates are reported and used to evaluate efficacy. But there is much information contained therein that allows us to understand mechanisms of drug action and how to best administer therapies. Methods: We have developed mathematical equations that enable extraction of the rates of tumor decay (d) and regrowth (g) and also the fraction (Φ) of tumor killed. Results: We have analyzed data from >3,000 cases of various tumor histologies including prostate, breast, renal, and medullary thyroid cancers as well as multiple myeloma (MM). These malignancies have been treated with “cytotoxic” and “targeted” therapeutics as well as vaccines. Across all treatment modalities, overall survival does not correlate with the rate of decay, d, but correlates strongly with the growth rate, g. In some drug/tumor combinations, Φ can also be extracted and its role in the drug’s action ascertained. Most therapies developed in metastatic cancers such as ixabepilone in breast cancer and sunitinib in renal cancer are “g therapies”. Such therapies reduce g, impact survival favorably and could further impact survival if administered beyond conventional endpoints for progression. In contrast, “Φ therapies”, such as bortezomib in MM and ATTP in prostate cancer kill a larger fraction of tumor and are proposed to be effective as adjuvant and neo-adjuvant treatments, with little benefit from extending treatment in the metastatic setting. Furthermore, the data suggest resistance in most is likely intrinsic since tumor growth rates on therapy do not change appreciably over time. Conclusions: We have developed an analytical method that characterizes a tumor’s response to a therapy and enables extraction of tumor decay (d) and regrowth (g) rates and the fraction (Φ) of tumor killed. Both g and Φ, but not d, determine the effectiveness of a therapy. Use of these parameters should allow for the conduct of smaller trials and may also help improve patient survival. A stand-alone computer program has been built, is available to the research community and will be demonstrated.