tbuckley/cabot-search huggingface dataset:
Relationship between serum HER2 level and histologic HER2 status in patients with advanced/recurrent gastric cancer.
Authors: Takahide Sasaki, Nozomu Fuse, Takeshi Kuwata, Mari Takahashi, Hiromichi Asano, Kazuhiro Kaneko, Toshihiko Doi, Takayuki Yoshino, Takashi Kojima, Atsushi Ochiai, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2012)

24 Background: The HER2 extracellular domain can be quantitatively measured in terms of the serum HER2 level by using a CLIA. Increased serum HER2 levels have been reported to be found in 20-25% of metastatic breast cancer patients and correlated with HER2 protein overexpression, increased tumor volume, and worse prognosis. However, the prevalence of HER2 expression in the serum of gastric cancer (GC) patients is not known. Methods: This study retrospectively analyzed the tumor tissue and serum samples of 100 patients who had histologically confirmed advanced/recurrent stomach adenocarcinoma, had started chemotherapy at National Cancer Center Hospital East during 2007–2011, did not have any other active malignancies, and whose serum and tumor tissue samples had been collected and stored at the baseline. HER2 protein expression was determined by immunohistochemistry (IHC; I-VIEW Pathway 4B5 kit) with the GC scoring system (Hofmann, 2008), and gene amplification was determined by fluorescence in situ hybridization (FISH; PathVysion HER2 DNA probe kit), with HER2:CEP17 ≥ 2.0 seen in tumor tissue. Serum HER2 levels were measured using a CLIA (ADIVA Centaur XP). HER2 positivity was defined as IHC 2+ with FISH positive or IHC 3+. Results: The baseline characteristics were as follows: men, 66; median age, 66 years (range, 29–85); advanced/recurrent, 96/4; and intestinal/diffuse/mixed, 38/41/21. An IHC score of 0/1+/2+/3+ was noted in 41/32/6/21 patients, respectively. Gene amplification in FISH was noted in 28 cases. The number of HER2 positive patients was 21. The median serum HER2 level was 9.3 ng/mL (range, 5.0–332.4). With a cutoff level of 15 ng/mL (mean + 2SD of 241 healthy control women), the sensitivity of serum HER2 levels with respect to HER2 positivity was 52.4%; specificity, 93.7%; positive predictive value, 68.8%; negative predictive value, 84.1%; and accuracy, 85.0%. The area under the receiver operating characteristic curve was 0.894. Conclusions: Increased serum HER2 levels were noted in GC patients and were associated with HER2 overexpression in tumor tissue. Further investigations of serum HER2 in terms of the clinical significance are warranted.
Dissecting the Hierarchical Level of Hematopoietic Progenitors' Involvement in AML with NPM1 Gene Mutation and Their Engraftment Potential in Immunocompromised Mice.
Authors: Maria Paola Martelli, Valentina Pettirossi, Christian Thiede, Elisabetta Bonifacio, Mauro Di Ianni, Ilaria Gionfriddo, Debora Cecchini, Roberta Pacini, Alessia Tabarrini, Federica Mezzasoma, Roberta Rossi, Linda Giunchi, Uta Oelschlägel, Lorenzo Brunetti, Marica Gemei, Raffaella Ciurnelli, Federica Cecchetti, Luca De Carolis, Arcangelo Liso, Francesco Di Raimondo, Massimo F Martelli, Brunangelo Falini
Journal: Blood (2009)
Frequency of Citogenetic Abnormalities and the BCR/ABL Fusion Gene In Adult Patients with Acute Lymphoblastic Leukemia (ALL). Multicentric Study From Mexico
Authors: Gregorio Ignacio, Rosa_Maria Arana, Juan_Carlos Solis, Christian Ramos, Mauricio Gonzalez, Oscar Perez, Rosa_Maria Jimenez, Yolanda Lugo, Lilia Aguilar, Jope DeDiego, Laura Guzman, Etha Rozen, Alejandro Limon, Manuel Lopez, Kevin Nacho
Journal: Blood (2010)
Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.
Authors: Jasmeet Chadha Singh, Stacy Stein, Matthew Volm, Julia Anne Smith, Yelena Novik, James L. Speyer, Marlene Meyers, Sylvia Adams, Coral Oghenerukevwe Omene, Franco Muggia, Robert Schneider, Silvia Formenti, Samantha Davis, Brian Beardslee, Amy Tiersten
Journal: Journal of Clinical Oncology (2012)

e11529 Background: Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of RAD001 (oral mTOR inhibitor) and Carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study was to estimate the clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) &gt;6 months) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0-3 prior chemotherapy regimens for metastatic disease. 25 subjects were to be entered into a single stage open label Phase II study. Prior Carboplatin is allowed. Treated brain metastasis are eligible. The null hypothesis that the clinical benefit rate is ≤10% could be rejected if number of CR/PR/SD &gt;6 months was ≥6. Originally, intravenous Carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia with this combination, the dose of Carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001. Results: 18 patients have been recruited thus far. Median age is 59. There have been 1 CR, 4 PR’s and 2 SD's lasting &gt; 6 months. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6-60 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). However, since amendment of Carboplatin dose to AUC 4 the regimen has been well tolerated. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 50% (95% C.I.: 24%, 76%). Median time to progression or death is 87.5 days from start of treatment; there is only 1 death to date on this study. Conclusions: The study has achieved it’s primary objective of demonstrating clinical benefit of RAD 001-Carboplatin combination in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment.
Pathology Results of Tissue Biopsy during Idelalisib-Associated Diarrhea/Colitis
Authors: Cecilia C.S. Yeung, David M. Hockenbery, Maria Westerhoff, Steven Coutre, Ruth H. Sedlak, Ronald L. Dubowy, A. Mario Marcondes, Veerendra Munugalavadla, Kerry Taylor, Francesc Bosch
Journal: Blood (2016)
Minimal Residual Disease (MRD) in Childhood Acute Lymphoblastic Leukemia (ALL). Correlation with Prognostic Factors and Outcome
Authors: Anna Paisiou, Georgios Paterakis, Nikolaos Tsagarakis, Nektaria Kentrou, Vassilios Papadakis, Stefanos I Papadhimitriou, Agapi Parcharidou, Vasillios Basdekis, Konstantinos Papadimitriou, Dimitra Skoumi, Konstantinos Tsitsikas, Sophia Polychronopoulou
Journal: Blood (2008)
Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles.
Authors: Stefan Frohling, Claudia Scholl, Ross L. Levine, Marc Loriaux, Titus J. Boggon, Olivier A. Bernard, Roland Berger, Hartmut Dohner, Konstanze Dohner, Benjamin L. Ebert, Sewit Teckie, Todd R. Golub, Marcus M. Schittenhelm, Benjamin H. Lee, James D. Griffin, Richard M. Stone, Michael C. Heinrich, Michael W.N. Deininger, Brian J. Druker, D. Gary Gilliland
Journal: Blood (2007)
Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors
Authors: Seraina Faes, Adrian P. Duval, Anne Planche, Emilie Uldry, Tania Santoro, Catherine Pythoud, Jean-Christophe Stehle, Janine Horlbeck, Igor Letovanec, Nicolo Riggi, Nicolas Demartines, Olivier Dormond
Journal: Molecular Cancer (2016)

Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.
New concepts for an old problem: the diagnosis of endometrial hyperplasia
Authors: Peter A. Sanderson, Hilary O.D. Critchley, Alistair R.W. Williams, Mark J. Arends, Philippa T.K. Saunders
Journal: Human Reproduction Update (2016)

Endometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterized by an increase in the endometrial gland-to-stroma ratio when compared to normal proliferative endometrium. The clinical significance of EH lies in the associated risk of progression to endometrioid endometrial cancer (EC) and 'atypical' forms of EH are regarded as premalignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and, as a consequence, standardized patient management can be challenging.EC is the most common gynaecological malignancy in developed countries. The incidence of EC is rising, with alarming increases described in the 40-44-year-old age group. This review appraises the current EH classification systems used to stratify women at risk of malignant progression to EC. In addition, we summarize the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis.PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. The following search terms were used: 'endometrial hyperplasia', 'endometrial intraepithelial neoplasia', 'atypical hyperplasia', 'complex atypical hyperplasia', 'biomarker', 'immunohistochemistry', 'progression', 'genomic', 'classification' and 'stratification'.Recent changes to EH classification reflect our current understanding of the genesis of endometrioid ECs. The concept of endometrial intraepithelial neoplasia (EIN) as a mutationally activated, monoclonal pre-malignancy represents a fundamental shift from the previously held notion that unopposed oestrogenic stimulation causes ever-increasing hyperplastic proliferation, with accumulating cytological atypia that imperceptibly leads to the development of endometrioid EC. Our review highlights several key biomarker candidates that have been described as both diagnostic tools for EH and markers of progression to EC. We propose that, moving forwards, a 'panel' approach of combinations of the immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role.EC has historically been considered a predominantly postmenopausal disease. Owing in part to the current unprecedented rates of obesity, we are starting to see signs of a shift towards a rising incidence of EC amongst pre- and peri-menopausal woman. This creates unique challenges both diagnostically and therapeutically. Furthering our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions.
Association of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinoma.
Authors: C. Xu, H. A. Ball, N. Bing, C. N. Sternberg, Z. Xue, L. McCann, K. King, C. F. Spraggs, V. E. Mooser, L. N. Pandite
Journal: Journal of Clinical Oncology (2011)

303 Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced renal cell cancer (RCC). Interindividual variability in response and survival is observed among advanced RCC pts treated with P. Our previous analyses showed that germline variants in angiogenesis (IL8, HIF1A, VEGFA)- and exposure (NR1IR)-related genes may predict progression free survival and/or response rate to P monotherapy (ASCO 2010 abstract 4520). This study sought to test the hypothesis that differences in overall survival (OS) can be explained, at least in part, by germline genetic variants in angiogenesis- and/or exposure-related genes. Methods: Twenty-seven functional polymorphisms within 13 genes were evaluated in 241 P treated pts with advanced RCC from a phase III study (ESMO 2010 abstract LBA22) and a single arm Phase II study. Genetic association with OS was analyzed using the Cox proportional hazards model. Results: Six polymorphisms in IL8, FGFR2, VEGFA, FLT4, and NR1I2 showed nominally significant association with OS (p≤0.05). A median OS of 29.6 months was observed in pts carrying wild-type IL8 2767 AA genotype (n=68, 31%), compared to 14.8 months in those with the TT variant genotype (n=36, 16%) (HR (95%CI) = 2.3 (1.4, 3.9) for TT vs. AA, p=0.002]. The median OS for pts who were heterozygous for this IL8 polymorphism was 23.9 months (n=119, 53%). The FGFR2 IVS2 + 906C&gt;T variant TT genotype was associated with inferior OS compared with the wild-type CC genotype (median OS, 21.4 vs. 28.0 months, HR (95%CI) = 2.0 (1.2, 3.2), p=0.009). Similarly, shorter OS was observed for the VEGFA −1154G&gt;A variant AA genotype compared with the wild-type GG genotype [median OS, 16.7 vs. 25.3 months, HR (95%CI) = 2.2 (1.3, 3.6), p=0.004]. The variant genotypes of the NR1IR (−25385C&gt;T) and FLT4 (1480A&gt;G) polymorphisms were also associated with reduced OS (p&lt;0.05). Conclusions: Germline variants in angiogenesis- and exposure-related genes may be associated with survival outcome for P monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset. [Table: see text]
Gemcitabine (G) and cisplatin (C) as first-line treatment of metastatic breast cancer (MBC): Results of phase II trial.
Authors: Meinolf Karthaus, Irina Poddubnaya, L. Churilova, R. Khazanov, T. Veremeychuk, E Rumyantzeva, M. Garin, O. Brichkova, Bernhard Heinrich, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

e11528 Background: G has been studied in combination with a variety of agents known to be active in cancer. G has a mild toxicity profile. GC is active in various advanced tumors. Splitting of C dose (d1 + d8) is better tolerated and can be a good alternative to once a cycle in pts with advanced breast cancer. This phase II trial evaluates G (1000 mg/m2) C (35 mg/ m2) d1+d8 repeated every 21 d in the 1st-line treatment of metastatic breast cancer (MBC). The primary objective of the study was to determine the objective tumor response rate (ORR) of 1st-line GC in patients with metastatic breast cancer. The one-stage design tested the null hypothesis that the true response rate for this population should be equal to 50% for efficacy. Overall survival (OS), time to progression (TTP) and toxicity were evaluated. Methods: 70 female MBC pts with the median age of 49.8 yrs (range 29.6-80.0) were enrolled. Tumor assessment was performed every other cycle by standard criteria including CT or MRI. 67 pts received a total of 310 cycles GC, out of these 54 pts were evaluable for efficacy. Results: Complete and partial responses were observed in 7/54 (13.0%) and 19/54 (35.2%) evaluable pts, respectively with an overall response of 48.1%. Disease stabilization was noticed in 19/54 (35.2%) pts. Progression was observed in 5/54 (9.3%) pts. Median TTP was 33.9 weeks (95% CI, 23.9-48.0). Median OS was 84.0 weeks (95% CI, 58.6-119.3). 1-year overall survival rate was 68.4% (95% CI, 53.6-79.3%). Hematological toxicity G4 was neutropenia in 14.9% (10/67), and no G4 thrombocytopenia. Hypotension G4 (1.5%) was the only severe non-hematological toxicity. Conclusions: GC in the first-line treatment of MBC demonstrated a substantial overall response rate and had a good toxicity profile. GC is a suitable option for first-line MBC in selected pts.
A phase II study of low-dose protracted irinotecan in patients with advanced sarcomas.
Authors: S. N. Dumont, J. C. Trent, S. Patel, D. M. Araujo, A. G. Dumont, R. S. Benjamin
Journal: Journal of Clinical Oncology (2011)

10064 Background: Irinotecan was designed in 1983 and showed activity in preclinical and Phase I trials in solid tumors including osteosarcoma and rhabdomyosarcoma. A wide variety of schedules were used, ranging from weekly to monthly administrations. Dose limiting toxicities were mainly diarrhea and myelosuppression. This IRB-approved phase II trial evaluated the efficacy and toxicity of irinotecan via a low-dose protracted schedule in adult patients with pretreated advanced sarcoma. Methods: Patients with inoperable locally advanced or metastatic sarcoma that had received or refused standard chemotherapy for their disease were treated by 16 mg/m2 of irinotecan daily, intravenously over one hour, for 5 days x 2 weeks, with a 2-day rest, repeated in 21-day cycles. The primary end point was tumor response, defined as complete or partial response at 6 weeks or stable disease lasting at least 12 weeks. Results: Between April 2003 and June 2007, 38 patients (25 males and 13 females) with a median age of 48 years (range, 21-71 years) entered the study. Patients received a median of 2 cycles (range, 0 to 8 cycles). 2 patients underwent surgery and 1 patient is still with no evidence of recurrent disease. 7 patients required early discontinuation of therapy due to toxicities, mainly diarrhea. 16 patients developed progressive disease after 2 cycles, 11 presented stable disease and 6 had partial response after 2 cycles. Among the patients with stable disease after 2 cycles, 3 achieved a partial response, 4 remained stable and 4 progressed after 4 cycles. The response rate was 26%. The median time to progression and overall survival for all 38 patients was 6 weeks and 41 months, respectively. 1 of the 2 chondrosarcoma patients responded to treatment while the other one had transient stable disease. 5 of 7 Ewing sarcoma patients responded to this therapy (71%). Conclusions: Irinotecan is an interesting therapy option in selected type of sarcoma in advanced and pretreated patient population. Its toxicity profile remains limiting due to diarrhea despite a low dose protracted-schedule delivery. However, myelotoxicity seems reduced on this regimen.
Occurrence of Neoplastic Diseases in a Large Cohort of Thalassemic Patients in Greece
Authors: Alexandra Kouraklis, Antonia Chatziliami, Antonis Kattamis, Efthimia Vlachaki, Evangelos Briasoulis, Ioannis Lafiatis, Polyxeni Lampropoulou, Christina Fragodimitri, Aggeliki Moira, Argiris Symeonidis
Journal: Blood (2012)
Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy
Authors: Masahiro Muto, Benoit Manfroi, Hitoshi Suzuki, Kensuke Joh, Masaaki Nagai, Sachiko Wakai, Christian Righini, Masayuki Maiguma, Shozo Izui, Yasuhiko Tomino, Bertrand Huard, Yusuke Suzuki
Journal: Journal of the American Society of Nephrology (2016)

The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD-CD38+/-CD19+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-α but also, the less frequent APRIL-δ/ζ mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.
The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9
Authors: Nabil G. Seidah, Marianne Abifadel, Stefan Prost, Catherine Boileau, Annik Prat
Journal: Pharmacological Reviews (2016)

The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues. In contrast, PCSK9 cleaves itself once, and the secreted inactive protease drags the low-density lipoprotein receptors (LDLR) and very LDLR (VLDLR) to endosomal/lysosomal degradation. Inhibitory PCSK9 monoclonal antibodies are now prescribed to treat hypercholesterolemia. This review focuses on the implication of PCs in cardiovascular functions and diseases, with a major emphasis on PCSK9. We present a phylogeny of the PCs and the analysis of <i>PCSK9</i> haplotypes in modern and archaic human species. The absence of PCSK9 in mice led to the discovery of a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR. PCSK9 inhibition may have other applications because it reduces inflammation and sepsis in a LDLR-dependent manner. Our present understanding of the cellular mechanism(s) that enables PCSK9 to induce the degradation of receptors is reviewed, as well as the consequences of its key natural mutations. The PCSK9 ongoing clinical trials are reviewed. Finally, how the other PCs may impact cardiovascular disease and the metabolic syndrome, and become relevant targets, is discussed.