tbuckley/cabot-search huggingface dataset:
Prognostic significance of carbonic anhydrase IX (CAIX), endoglin (CD105), and 8-hydroxy-2deoxyguanosine (8-OHdG) in breast cancer patients.
Authors: L. Beketic-Oreskovic, P. Ozretic, Z. N. Rabbani, I. L. Jackson, B. Sarcevic, S. Levanat, Z. Vujaskovic
Journal: Journal of Clinical Oncology (2010)

e21048 Background: The purpose of this study was to use immunohistochemical analysis of carbonic anhydrase IX (CA IX), endoglin (CD105) and 8-hydroxy-2′-J-deoxyguanosine (8-OHdG) to evaluate hypoxia, neoangiogenesis and oxidative stress markers as potential prognostic parameters for overall survival (OS) and relapse-free (RFS) survival in breast cancer patients. Methods: Immunohistochemistry was performed on paraffin-embedded tumor tissues from forty female breast cancer patients. Fisher's exact test, Spearman rank correlation coefficient, Kaplan-Meier univariate method and the Cox proportional hazards regression model were used for statistical analysis. Results: Occurrence of relapse was significantly higher in patients with high CA IX expression (above cut-off value) (p = 0.002). Univariate analysis showed that high CA IX expression was significantly associated with shorter OS (p < 0.001) and shorter RFS (p < 0.001). High expression of CD105 was significantly associated with shorter OS (p = 0.032). Multivariate analysis showed that high CA IX expression was a strong independent prognostic indicator for shorter OS (p = 0.018) and shorter RFS (p = 0.011). Among lymph node negative patients and those with grade II tumors, it was possible to differentiate patients with better or worse prognosis based on the expression level of hypoxia marker CA IX. Lymph node negative patients, but with high CA IX expression had both shorter RFS (p = 0.031) and OS (p = 0.005). Within the subgroup of patients with grade II tumors, those patients with high CA IX expression showed shorter OS (p = 0.046). The level of CD105 and 8-OHdG expressions did not correlate with prognosis in any subgroup of patients. Conclusions: Elevated expression of CA IX was an independant prognostic marker for decreased RFS and OS and a significant marker for tumor aggressiveness. CD105 had weak prognostic value; whereas, 8-OHdG, in this study, did not provide sufficient value as a prognostic indicator for RFS nor OS in breast cancer patients. No significant financial relationships to disclose.
HPV vaccination to prevent cervical cancer and other HPV-associated disease: from basic science to effective interventions
Authors: Douglas R. Lowy
Journal: Journal of Clinical Investigation (2016)

Identification of HPV infection as the etiologic agent of virtually all cases of cervical cancer, as well as a proportion of other epithelial cancers, has led to development of three FDA-approved multivalent prophylactic HPV vaccines composed of virus-like particles (VLPs). This essay describes the research and development that led to the VLP vaccines; discusses their safety, efficacy, and short-term effect on HPV-associated disease; and speculates that even a single dose of these vaccines, when given to adolescents, might be able to confer long-term protection. The HPV field exemplifies how long-term funding for basic research has lead to clinical interventions with the long-term potential to eradicate most cancers attributable to HPV infection. Although this essay is the result of my receiving the 2015 Harrington Prize for Innovation in Medicine from the Harrington Discovery Institute and the American Society for Clinical Investigation, this clinical advance has depended on the research of many investigators, development of commercial vaccines by the pharmaceutical companies, and participation of many patient volunteers in the clinical trials.
Inflammatory responses in pseudomyxoma peritonei and peritoneal mesotheliomas.
Authors: P. Thomas, V. Govindarajan, B. W. Loggie
Journal: Journal of Clinical Oncology (2010)

e14126 Background: Inflammatory responses have been observed clinically and histologically in patients with peritoneal neoplastic disease (PND). An association between Interleukin-6 (IL-6) and carcinoembryonic antigen (CEA) has been reported, and elevated serum IL-6 levels have been associated with poor prognosis in colorectal cancers. IL-6 also promotes high angiogenic activity through the STAT-3 pathway causing increased tumor vascularization. We looked for evidence of elevated IL-6 and a possible link with CEA in ascites from patients with PND. Methods: IL-6 levels were measured by ELISA in ascites fluid (n = 12) from patients with pseudomyxoma peritonei (PMP, n = 5), colorectal cancer (CRC, n = 3) and malignant peritoneal mesothelioma (MPM, n = 4). These were compared to peritoneal washings from patients with peritoneal disease but without ascites (PW, n = 4; PMP, 2; CRC, 2). Ascites CEA levels were also measured. Results: IL-6 levels were grossly elevated in all ascites samples from PMP (3/5 were > 20,000 pg/mL; min = 6085), CRC ascites (1/3 > 20,000 pg/mL; min = 3379), and MPM (1/4 > 20,000 pg/mL; min = 4,697). In PW, IL-6 was not detectable in 3/4 patients, and was 481 pg/mL for one case. Ascites CEA levels were also grossly elevated (> 180 ng/mL in all 8) in the colorectal and PMP groups but were normal or marginally elevated in the MPM (max = 12 ng/mL) and PW groups (max = 30 ng/mL). The ascites CEA levels for PMP and CRC groups reflected the elevated serum levels (mean 45, median 21) but were much higher in the ascites. Conclusions: IL-6 is grossly elevated in ascites fluid in PND. CEA has been shown to activate macrophages with production of IL-6 and other cytokines but because the MPM patients also showed elevated IL-6 with low or normal CEA levels it is unlikely that CEA production is the sole source of immune cell activation in PMP and peritoneal CRC. Inflammation may be an important component of the tumor microenvironment in PND and elevated IL-6 levels may contribute to tumor cell survival. No significant financial relationships to disclose.
Respiratory health and disease in a UK population-based cohort of 85 year olds: The Newcastle 85+ Study
Authors: Andrew J Fisher, Mohammad E Yadegarfar, Joanna Collerton, Therese Small, Thomas B L Kirkwood, Karen Davies, Carol Jagger, Paul A Corris
Journal: Thorax (2016)

<h3>Background</h3> People aged 85 years and older are the fastest growing age group worldwide. This study assessed respiratory health, prevalence of respiratory disease and use of spirometry in respiratory diagnosis in a population-based cohort of 85 year olds to better understand respiratory health and disease in this sector of society. <h3>Methods</h3> A single year birth-cohort of 85 year olds participated in a respiratory assessment at their home or residential institution including self-reporting of symptoms and measurement of spirometry. General practice medical records were reviewed for respiratory diagnoses and treatments. <h3>Findings</h3> In the 845 participants, a substantial burden of respiratory disease was seen with a prevalence of COPD in medical records of 16.6% (n=140). A large proportion of the cohort had environmental exposures through past or current smoking (64.2%, n=539) and occupational risk factors (33.6%, n=269). Spirometry meeting reliability criteria was performed in 87% (n=737) of participants. In the subgroup with a diagnosis of COPD (n=123), only 75.6% (n=93) satisfied Global Initiative in Obstructive Lung Disease (GOLD) criteria for airflow obstruction, and in a healthy subgroup without respiratory symptoms or diagnoses (n=151), 44.4% (n=67) reached GOLD criteria for airflow obstruction and 43.3% (n=29) National Institute of Health and Care Excellence criteria for at least moderate COPD. <h3>Interpretation</h3> Spirometry can be successfully performed in the very old, aged 85 years, and may help identify respiratory diseases such as COPD. However interpretation in this age group using current definitions of COPD based on spirometry indices may be difficult and lead to overdiagnosis in a healthy group with transient symptoms.
Abstract P1-07-19: Effects of JAK pathway inhibition in pre-clinical models of breast cancer bone marrow metastases
Authors: Alessia Bottos, Jason Gill, Thomas Radimerski, Alexandar Tzankov, Aleksandra Wodnar-Filipowicz, Nancy E Hynes
Journal: Cancer Research (2015)

Abstract Bone marrow (BM) metastases are an important problem in metastatic breast cancer. Metastatic-relapse occurs even decades after the first diagnosis and can show different clinical features compared to the primary disease. The cross-talk between cancer cells and the microenvironment influences tumor behaviour and impinges on therapeutic efficiency. To uncover new targets for the inhibition of BM metastases, we performed a transcriptional analysis of BM stromal cells using in-vivo models of breast cancer bone metastases. We identified IL6, and its downstream JAK kinases pathway, as major up-regulated signals in the bone stroma of tumor-bearing mice. Moreover, we found that a significant proportion of BM metastases from breast cancer patient biopsies are positive for pSTAT3 staining, attesting to activation of JAK-STAT signaling. These results provide a rational to investigate the therapeutic potential of a JAK inhibition in bone metastases. We evaluated the effect of two JAK inhibitors: the BSK805, a JAK2 inhibitor, and ruxolitinib a JAK1-JAK2 inhibitor currently in clinical trials for metastatic breast cancer. In pre-clinical models of breast cancer metastases (the triple negative MDA-MB231 SCP1833 and the ER+ EO771), treatment with the JAK inhibitors decreased pSTAT3 signaling in the bone, but surprisingly increased metastastic tumor burden. Considering the importance of the JAK-STAT pathway as a therapeutic target, we are investigating the possible bystander effects of blocking JAK kinases. Analysis of the BM stoma showed that JAK inhibition decreased TRAP+ osteoclasts and affected the mesenchymal compartment, with a significant increase in the BM fat compartment in tumor-bearing animals. The reasons for and the consequences of these changes in the bone stroma are under investigation. As the JAK-STAT signaling pathway is also a key regulator of the hematopoietic compartment, we are studying how JAK inhibitors influence the immune response in tumor bearing mice. Further dissection of the immunomodulatory effect of JAK inhibition and how this influences tumor dissemination and expansion is warranted. Citation Format: Alessia Bottos, Jason Gill, Thomas Radimerski, Alexandar Tzankov, Aleksandra Wodnar-Filipowicz, Nancy E Hynes. Effects of JAK pathway inhibition in pre-clinical models of breast cancer bone marrow metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-19.
Serum-Mediated Inhibition of Lymphocyte Stimulation by Autochthonous Human Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: F. Vánky, J. Stjernswärd, G. Klein, U. Nilsonne
Journal: JNCI Journal of the National Cancer Institute (1971)

Specimens from biopsies of human sarcomas and other tumors treated with mitomycin C stimulated autochthonous lymphocytes to increased DNA synthesis in the mixed lymphocyte target-interaction test. Autochthonous sera from patients with tumors inhibited the stimulatory effect. A collection of allogeneic sera was tested against one fibrosarcoma-lymphocyte combination that gave a regularly positive stimulatory interaction. The sera of patients with sarcomas blocked the lymphocyte-stimulating interaction significantly, but not of patients with other tumors, and of most healthy controls. The blocking effect of serum from a patient with fibrosarcoma diminished temporarily after the tumor was excised.
CD26 expression in donor stem cell harvest and its correlation with engraftment in human haematopoietic stem cell transplantation: Potential predictor of early engraftment.
Authors: K. Prabhash, N. Khattry, V. Alai, A. Joshi, A. V. Bakshi, S. Kannan, P. Sastry, P. M. Parikh, J. Kode
Journal: Journal of Clinical Oncology (2010)

6544 Background: The efficiency of Haematopoietic stem and progenitor cells (HSPC) is important when donor cell numbers are limiting. This study evaluates CD26/dipeptidylpeptidase IV expression on all cells of graft (mobilized peripheral blood stem cell- PBSC) including CD34+ stem cells and its correlation with engraftment kinetics in HSCT. Methods: Human G-CSF mobilized PBSC samples were collected from cancer patients (n = 24) selected for autologous stem cell transplantation or from allogeneic related healthy donors (n = 20). Nucleated cells were analysed for CD34hiCD45lo (HSPC) and CD26 expression by flow cytometry. Further CD26 expression and day of engraftment (WBC /platelet) in autologous and allogenic PBSC were compared using unpaired two-tailed t test. Correlations for association of CD34/CD26 expression with days of WBC and platelet engraftment were evaluated using Pearson's correlation. Results: This is the first study comparing CD26 expression on human PBSC harvest from cancer patients (46.3 ± 4.6%) and allogeneic donors (22.8 ± 5). CD26 expression was increased on PBSC harvest of autologous compared to allogenic cases (p < 0.0009).WBC engraftment was significantly faster in autologous cases (day 10 ± 0.3) compared to allogenic cases (day 12.4 ± 0.3; p = 0.00021).This demonstrated increased CD26 expression leads to early engraftment in transplanted patients.Correlation of CD26 expression with WBC engraftment was statistically significant (L gate: p = 0.0008; M gate: 0.0004; N gate: p = 0.0007 All populations: p = 0.0009).CD34 expression is a known engraftment predictor.However there was no correlation between CD34 and CD26 expression in these cases. Conclusions: This study provides important leads that CD26 peptidase is expressed significantly on PBSC harvest cells and shows negative correlation with WBC engraftment days in transplanted patients. Our study strongly suggests this can be considered as potential independent predictor of engraftment. No significant financial relationships to disclose.
Gastrointestinal neuroendocrine tumors: Concordance of SST2 and chromogranin A immunohistochemical staining in relation to primary site of tumor origin: A single-center retrospective analysis.
Authors: T. O'Dorisio, I. A. Onwere, M. O'Dorisio, B. DeYoung
Journal: Journal of Clinical Oncology (2010)

e21102 Background: Previous analyses have demonstrated that a neuroendocrine tumor's site of origin correlates with tumor biology, clinical presentation, and oftentimes prognosis. There is however limited data available on the concordance of SST2 and Chromogranin A immunohistochemical staining in relation to primary site of tumor origin. Methods: We sought to determine the concordance of IHC staining for SST2 and Chromogranin A, with site of tumor origin. We retrospectively analyzed 78 formalin-fixed, paraffin-embedded neuroendocrine tumor (NET) specimens that had undergone immunohistochemical staining (IHC) for SST2 and Chromogranin A (ChrgA). IHC staining was graded 1+ to 3+ for both SST2 and ChrgA. Results: There were a total of 78 gastrointestinal tumor specimens. The two sites of primary origin included small bowel (55/78), and pancreas (23/78). Conclusions: Our results obtained by the semi-quantitative assessment of SST2 and ChrgA by IHC staining, demonstrates the likelihood of concordance in SST2 and ChrgA in pancreatic NETs. Although small bowel NETs were most often ChrgA 2-3+, there was marked heterogeneity in terms of SST2 IHC staining and thus a lack of concordance between the two neuro-peptide markers. Immunohistochemical staining by site of primary origin Small bowel NETs 1+ 2+ 3+ Neg SST2 40% 29% 25% 6% ChrgA 4% 7% 89% 0% Pancreatic NETs SST2 13% 44% 35% 8% ChrgA 9% 13% 74% 4% No significant financial relationships to disclose.
PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the <i>MLL</i>-Rearranged Disease
Authors: Zejuan Li, Ping Chen, Rui Su, Chao Hu, Yuanyuan Li, Abdel G. Elkahloun, Zhixiang Zuo, Sandeep Gurbuxani, Stephen Arnovitz, Hengyou Weng, Yungui Wang, Shenglai Li, Hao Huang, Mary Beth Neilly, Gang Greg Wang, Xi Jiang, Paul P. Liu, Jie Jin, Jianjun Chen
Journal: Cancer Research (2016)

Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.
Bevacizumab (B) plus low-doses immunotherapy (IT) plus chemotherapy (CT) (BIC) in metastatic renal cell cancer (mRCC): Antitumor effects and variations of T-regulatory cells (Treg) and other T lymphocytes subsets. A study of the Italian Oncology Group for Clinical Research (GOIRC)
Authors: R. Passalacqua, S. Buti, L. Rivoltini, C. Castelli, C. Camisaschi, C. Simonelli, G. Lo Re, R. Mattioli, G. Mazza, M. Brighenti, S. Lazzarelli
Journal: Journal of Clinical Oncology (2008)

5121 Background: B is effective in mRCC and has a synergistic effect with CT in many tumors. The activity of B plus interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Aim of this study is to explore the efficacy of B+IT+CT and to correlate its efficacy with the variations in circulating T lymphocytes and Treg. Methods: Pts with histological diagnosis of mRCC, previous nephrectomy, PS 0–1, adequate organ function, no CNS metastases and 0–2 previous systemic regimens were treated with B (10 mg/kg d 1 and 15) plus CT (gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus d 1 and 8 every 28 d) plus IT (IL-2: 1 MUI/m2 bid sc d 8, 9, 15, 16 and 1 MUI/m2/die sc from d 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on d 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and IT until progressive disease (PD). In 30 pts, blood samples for Treg and other T lymphocytes subsets were evaluated on days: 1, 8, 15, 22, 29 and at the disease progression. Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 58 years; 49% pre-treated; 41 pts were evaluable for response (4 too early) and we observed 33% PR, 35% SD and 32% PD for an overall disease control rate (DCR) of 68%. Median TTP was 8.2 mos (95% CI: 6.9–9.4). In 21 not pre-treated pts DCR was 78%. In MSKCC poor risk group we observed 20% PR and a DCR of 80% with a TTP of 8.7 mos. Treatment was well tolerated, gr. 3–4 toxicity included neutropenia non-febrile 57%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 12%. Preliminary data show increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of IT (d 15) and a decrease after the treatment with B (d 22). Variation in Treg seems to be correlated with the response to treatment. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. The final analysis of its activity and Treg variations and correlations with clinical outcome will be presented at the meeting. No significant financial relationships to disclose.
Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: A phase II study of the DOD Prostate Cancer Clinical Trials Consortium
Authors: E. Small, A. Harzstark, V. K. Weinberg, D. C. Smith, P. Mathew, T. Beer, G. Liu, J. Sharib, J. Rosenberg
Journal: Journal of Clinical Oncology (2009)

5058 Background: Mitoxantrone (M) plus prednisone (P) and ixabepilone (Ix) each have modest, non cross-resistant activity as second line chemotherapy regimens in docetaxel-refractory patients with CRPC. These agents were therefore combined in a phase I study which demonstrated anti-cancer activity and defined the recommended phase II dose used in this trial. Methods: Patients with metastatic CRPC and progression after 3 or more cycles of docetaxel were enrolled in a phase II multicenter study of the combination of prednisone 5 mg BID, Ix (35 mg/m2) and M (12 mg/m2) administered intravenously on day 1 every 21 days, with pegfilgrastim (6 mg on day 2) support. Results: To date, 43 pts have been enrolled and have received a median of 4 cycles. Of 37 patients currently evaluable for response, 14 (38%; 95% CI: 22–55%) have had a confirmed ≥50% decline in PSA and 19 (51%; 95% CI 34–68%) have had a confirmed ≥30% decline in PSA. Two of 15 patients with evaluable measurable disease (13%) have had a RECIST-defined objective response. All 43 patients are evaluable for toxicity. Grade 3 or 4 neutropenia was seen in 6 pts (17%) and grade 3 or 4 thrombocytopenia was seen in 3 (8%). Nonhematologic grade 3/4 events possibly related to study drug have included grade 3 fatigue (3 pts), grade 3 pneumonia (2 pts), and grade 3 atrial fibrillation, grade 4 myocardial infarction, grade 4 prostatitis, grade 3 nausea/vomiting, grade 3 neuropathy, grade 3 elevated transaminases, grade 3 dizziness, grade 3 dehydration, grade 3 shortness of breath, and grade 4 vasovagal syncope (1 pt each). Grade 2 neuropathy has been seen in 4 patients. Conclusions: The Ix, M, P regimen is active as second-line therapy in CRPC patients with progressive disease after docetaxel therapy and is reasonably well tolerated. Further investigation of this regimen is warranted. This study was supported in part by CTEP/NCI and the DOD Prostate Cancer Clinical Trials Consortium. [Table: see text]