tbuckley/cabot-search huggingface dataset:
Low cytolytic T-cell CD8 expression in mesenchymal triple negative (TN) breast cancers and overexpression of the adhesion protein CD24 in ER+ breast cancers that recur within 3 years of adjuvant chemotherapy.
Authors: Joyce O'Shaughnessy, Timothy R. Wilson, Maren K. Levin, Maria W Crockett, Jill M Spoerke, Yuanyuan Xiao, Carol O'Brien, Heidi Savage, Teiko Sumiyoshi, Ling Fu, Hartmut Koeppen, Mark R. Lackner
Journal: Journal of Clinical Oncology (2014)

582 Background: The phase III trial USON 01062 (O’Shaughnessy J, et al Proc SABCS, 2010, abstract S4-2) showed that the addition of capecitabine to docetaxel following doxorubicin/cyclophosphamide adjuvant chemotherapy did not improve 5-year disease-free survival (DFS) (HR 0.84, p=0.125). We evaluated molecular biomarkers to identify genomic predictors of early recurrence in ER+ and TN breast cancers in USON 01062. Methods: 817 FFPE primary breast cancers had good quality gene expression data for PCR-based identification of PIK3CAsomatic mutations (MT), as well as for Nanostring assessment of 800 breast cancer-related genes encompassing published breast cancer signatures and pathways. IHC for Ki67 and PTEN was also performed. Results: Intrinsic subtypes of the 817 cancers: 320 luminal A (Lum A); 124 Lum B; 296 basal (82% TN, 9% ER+ and 8% HER2+); and 69 HER2-enriched (60% HER2+, 33% TN, 7% ER+). Nonsignificant improvements in DFS with capecitabine were seen in the basal cancers with central Ki67 < 70%, and in luminal cancers with Ki67 > 25%. In Lum A pts, exons 9 or 20 PIK3CA MT predicted for favorable DFS; there was no difference in DFS outcome in Lum B PIK3CAMT vs wild type pts. CD24 and CDCA5 (which encodes the sister chromatid cohesion protein, sororin) were significantly overexpressed in ER+ cancers that recurred within 3 yrs of beginning adjuvant therapy (p=0.0086 and 0.045, respectively), and expression of ESR1 and its regulated genes such as RERG were associated with a low risk of recurrence. For the TNBCs, 42% were basal 1/2, 21% were immunomodulatory (IM), 15% were mesenchymal stem-like, 13% were mesenchymal and 9% were luminal AR. The mesenchymal subtype showed the highest rate of recurrence and low CD8 expression, while expression of IM genes including CD8 was associated with more favorable 5-year DFS outcome. Conclusions: Mesenchymal TNBC has low CD8 expression and a poor prognosis with adjuvant chemotherapy. Rapidly recurring ER+ breast cancers have low levels of ESR1 and overexpress CD24 which adheres to activated platelets and interacts with c-src/FAK to stimulate motility (Baumann P, Ca Res 65:10783, 2005).
Dendritic cells immunotherapy for patients with malignant bone and soft tissue tumors.
Authors: Hideji Nishida, Norio Yamamoto, Akihiko Takeuchi, Hiroaki Kimura, Shingo Shimozaki, Takashi Kato, Yu Aoki, Kentaro Igarashi, Takashi Higuchi, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2014)

10539 Background: We evaluated the safety and feasibility of autologous dendritic cell (DC) immunotherapy for patients with malignant bone and soft tissue tumors. Methods: Forty one patients were enrolled and immunized with DCs. Patient tumors comprised twenty one malignant bone tumors, seventeen malignant soft tissue tumors, and three metastases. 1st generation of DC immunotherapy was started in 2008. Autologous DCs were generated ex vivo and pulsed with original tumor lysate and OK-432. For the 2nd generation, we added TNF-α- pulsed with tumor lysate. 3rd generation was DC immunotherapy incorporated low dose cyclophosphamide. Each patient received 2-5 x 106cells one time a week for 6 weeks. Results: Immunizations were well tolerated by patients with only local redness at the injection site in 9 cases. Levels of interferon-gamma and interleukin-12 cytokines were increased after DC immunotherapy in twenty six patients (65%), eighteen of whom (44%) subsequently developed delayed-type hypersensitivity. At the final follow-up, one patient had partial response, eight patients had stable disease and thirty two patients had progressive disease. Conclusions: Although improvement of clinical efficacy requires further research, toxicity-free immunization by tumor lysate- and OK-432-pulsed DCs is safe and feasible in patients with malignant bone and soft tissue tumors.
Feasibility study of personalized peptide vaccination for advanced non-small cell lung cancer patients previously treated with two or more chemotherapy regimens.
Authors: Shunichi Sugawara, Teppei Yamada, Satoko Matsueda, Koichi Yoshiyama, Shinjiro Sakamoto, Osamu Ishimoto, Nobukazu Komatsu, Akira Yamada, Shinzo Takamori, Tetsuro Sasada, Kyogo Itoh
Journal: Journal of Clinical Oncology (2014)

e19116 Background: Personalized peptide vaccination (PPV) could offer a novel approach to cancer vaccines that boost anticancer immunity. We conducted non-randomized controlled study to investigate the potential of PPV combined with chemotherapy as third or further line for advanced non-small cell lung cancer patients (NSCLC). Methods: Patients diagnosed as advanced NSCLC patients who failed in at least two chemotherapy regimens were eligible for this study. A maximum of four HLA-matched peptides showing higher peptide-specific IgG responses in pre-vaccination plasma were selected from 31 pooled peptide candidates. They were subcutaneously administered weekly, bi-weekly thereafter, tetra-weekly finally. The primary endpoint was immunological responses to the injected peptides. This was evaluated by the frequency of cytotoxic T lymphocyte (CTL) or IgG responses to those peptides. Results: Among 58 patients enrolled, 23 or 16 patients received PPV with chemotherapy or targeted therapy, whereas 19 patients were not tolerable for either therapy and received PPV alone. Median treatment regimens before PPV in each group of PPV/chemotherapy, PPV/targeted therapy, or PPV alone were 4, 3, or 4, respectively. No severe adverse events associated with PPV were observed in any patients. Median survival time was 692, 468, or 226 days in the group of PPV/chemotherapy, PPV/targeted therapy, or PPV alone, respectively. There was no significant difference among the three groups with regard to the positive frequency of CTL or IgG responses to the injected peptides, but IgG responses to non-vaccinated peptides after the vaccination in the PPV/chemotherapy group were significantly stronger than those in the PPV alone group. Conclusions: PPV combined with chemotherapy might be feasible for advanced NSCLC as third line treatment because of the safety, immune responses, and possible clinical benefits. Further evaluation by prospective randomized trial is warranted. Clinical trial information: 000001839, 000002984, 000005631.
Simplified application of the model prognosis GERCOR group patients with metastatic colorectal cancer treated with bevacizumab.
Authors: Inmaculada Gallego Jimenez, Amelia Lopez Ladron, Eva Fernandez Parra, Javier Salvador Bofill
Journal: Journal of Clinical Oncology (2014)

e14631 Background: The variability in survival of colorectal cancer is defined by different parameters. Our goal is to assess whether the simplified model group GERCOR forecast predicts mortality in patients with stage IV colorectal cancer in first-line treatment with chemotherapy associated with bevacizumab. Methods: Prospective cohort study with the following inclusion criteria: 1) age> 18 years, 2) stage IV colon cancer, 3) first-line treatment with chemotherapy including biological therapy (bevacizumab). Three prognostic groups based on performance status (PS ) and blood values of LDH : 1 ) Good prognosis : PS 0 , LDH < 230, 2 ) Intermediate Prognosis : PS 0 , LDH > 230 or PS 1-2 LDH < 230, 3) Poor prognosis: PS 1-2, LDH > 230. Primary endpoint was death from any cause during follow-up. Survival was analyzed according to the risk group according to the forecast model GERCOR group. This survival analysis was carried out following the methodology of Kaplan-Meier, comparing different groups using the log-rank test. Results: 29 patients were included. 27.7 % of patients received regimen based on FOLFOX- bevacizumab. 17.2 % of patients, FOLFIRI bevacizumab. 44.8 % XELOX - bevacizumab. Bevacizumab-XELIRI was used in 6.9%. Capecitabine - bevacizumab was used in only 3.4%. At baseline, 6 ( 20 % ) were classified as good prognosis according GERCOR score, 13 (45%) as intermediate risk and 10 (34 %) as poor prognosis. Median survival in patients with good prognosis according to the score was 49 ( ± 9) months , whereas it was 37 ( ± 9) months in the intermediate prognosis and 29 ( ± 7) months in poor prognosis (p = 0.28 ) . The probability of death at 1, 2 and 3 years depending on the baseline score category was as follows: patients with good prognosis : 17 %, 17% and 37 %, patients with intermediate prognosis : 31 %, 54 % and 71 % , poor prognosis patients 20%, 60% and 80% respectively. Conclusions: The simplified model forecast GERCOR group seems to predict overall mortality in patients with stage IV colorectal receiving treatment regimens including biological therapies cancer. These preliminary results should be confirmed with a longer follow and the inclusion of new patients in our cohort.
Therapeutic implications of perivascular invasion in the context of high-density brain microvascular networks: A study on recursive pattern formation in malignant glioma.
Authors: Gregory Joseph Baker, Viveka Nand Yadav, Sebastien Motsch, Carl Johannes Koschmann, Anda-Alexandra Calinescu, Yohei Mineharu, Sandra Ines Camelo-Piragua, Daniel Orringer, Serguei I. Bannykh, Wesley S. Nichols, Ana C. deCarvalho, Tom Mikkelsen, Maria Castro, Pedro R. Lowenstein
Journal: Journal of Clinical Oncology (2014)

2057 Background: Malignant glioma cells use distinct brain structures for tumor growth and invasion. However, the cellular mechanisms and biological consequences of malignant glioma growth patterning remain poorly understood. Methods: We utilized multiple experimental imaging modalities (i.e. confocal-, multi-photon-, epifluorescence-, and electron- microscopy) to examine the routes of intracranial malignant glioma invasion using implantable and genetically-induced glioma models; we also examined brain tissue specimens from patients affected by primary human glioblastoma and brain metastasis. The clinical implications of our findings are discussed. Results: Mouse, rat, and human experimental malignant glioma cells commonly utilized the dense brain microvascular network as a scaffold for tumor invasion. Perivascularly invading brain tumors became vascularized as they engulfed brain microvessels at the invasive margin over the entire course of tumor progression. Macroscopic tumor formation occurred as a consequence of recursive inter-vessel displacement of normal brain tissue by mitotic glioma cells localized within the perivascular space. Based on these observations, we implemented a computational model that recapitulates this pattern of brain tumor growth. Notably, a parameter for neoangiogenesis was not required to obtain continued in-silico perivascular growth and recursive space filling. Treatment of perivascularly invading brain tumors with anti-VEGF (bevacizumab) or anti-VEGFR-2 antibodies (DC101) did not prolong animal survival, yet potentiated long distance glioma cell invasion, especially in a model of human glioma stem cells. Conclusions: Perivascular invasion, high brain microvascular network density, and recursive inter-vascular space filling is a common pattern of malignant brain tumor growth that supports tumor progression independently of VEGF-A signaling.
Prevalence of epidermal growth factor receptor (EGFR) mutation in an Ecuadorian population with non-small cell lung cancer (NSCLC).
Authors: Carmen Rivas, Luis A. Martinez, Enrique Eduardo Teran
Journal: Journal of Clinical Oncology (2014)

e19157 Background: Non-small cell lung cancer (NSCLC) when treated by cytotoxic chemotherapy had a response rate of 20-35 % and a median survival time of 10-12 months. In 2004, it was found that activated mutations of the epidermal growth factor receptor (EGFR) gene were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR tyrosine kinase inhibitors. In Ecuador, the real incidence of lung cancer is not establish, however, by 2008 it represented 1.1% of all deaths and was ranged as the fifth cause of mortality. No data about EGFR mutation is available. Methods: Guayaquil is the biggest city in Ecuador and the objective of the present study was to investigate the prevalence of EGFR mutation in patients diagnosed of lung cancer during 2011 at the Hospital Abel Gilbert Ponton in Guayaquil, which provides oncological attention for an important population. Results: A total of fifty one patients were recruited with an average age of 59.0±14.0 years old. There was no statistical difference in gender, although 55% (n=28) were women. 80.4% (n=41) of these patients did not refer familiar history of cancer and only 23.5% (n=12) were smokers. Histopathologic analysis confirmed adenocarcinoma in all cases and after molecular testing the mutation of EGFR was present in 17 patients (33.3%). Interestingly, mutation was more frequent in males (58.8%) than in females (41.2%) although was no significant (p=0.23; RR=1.538 [IC 95%: 0.8581 a 2.758]). In smokers mutation was found more frequently (88.2%) than in non-smokers (70.6%) but no significance was found (p=0.2934; RR=0.40 [IC 95%: 0.09840 a 1.626]). Conclusions: In our knowledge, this constitutes the first report for EGFR mutation rate in Ecuadorian population with lung cancer but seems to be in good agreement with publishing data in other series.
Molecular factors regulating clear cell renal cancer cells' fate: Implications for tyrosine kinase inhibitors responsiveness and toxicities.
Authors: Anna Malgorzata Czarnecka, Damian Matak, Wojciech Solarek, Mohammed Imran Khan, Lukasz Szymanski, Anna Kornakiewicz, Karolina Czarnecka, Robert Zdanowski, Magdalena Krol, Slawomir Lewicki, Cezary Szczylik
Journal: Journal of Clinical Oncology (2014)

e15577 Background: Cancer cell proliferation is regulated by its genomic and epigenetic abnormalities on one hand and by tumor microenvironment on the other. A complex network of different cell-cell interactions, paracrine and endocrine signals, extracellular matrix forces and physical factors influence ccRCC cells. These molecular factors are also responsible for tyrosine kinase inhibitors resistance and disease progression. Aims of this study included pooled analysis of hypoxia, triiodothyronine, insulin and insulin-like growth factors impact on the proliferation and metastatic potential of ccRCC cells. The second aim was to measure the effect of above mentioned tumor niche factors on sunitinib activity on ccRCC cells. The study was initiated as triiodothyronine receptor (TRβ) was indicated as a ccRCC tumor suppressor, hypothyroidisms was defined as biomarker of sunitinib treatment efficacy and obesity with diabetes (DM2) was also considered a risk factors for ccRCC. The goal of this research was to enable understanding of molecular events responsible for clinically relevant observations. Methods: ccRCC cells from primary and metastatic tumors (ATCC, MSKCC collection) along with ccRCC cancer progenitor cells (CD133+) were cultured in normoxic or hypoxic conditions; cells were cultured in defined media and induced by T3, IN or IGF; and/or inhibited by TRβ antagonist, sunitinib, sorafenib and axitinib. Cell proliferation and TKI activity were evaluated using Alamar Blue and MTT. Colony formation potential was evaluated under all conditions. TRβ gene expression was evaluated with RealTime-RT PCR. Normal kidney proximal tube cells were used as negative control. Results: ccRCC cells proliferation may be promoted by T3, IN and IGF in primary tumor and metastatic sites. Cancer progenitor cells are targeted by TKI, but hypoxia promote their proliferation. Conclusions: Multiple micro-environmental factors modify the proliferation of ccRCC cells and their response to TKI. Understanding of the complex interactions between cancer cells and the surrounding microenvironment should aid the identification of novel treatment targets and improve TKI treatment.
Predictors of response to abiraterone acetate in men with metastatic castrate resistant prostate cancer: Retrospective analysis of a large number of clinical and laboratory variables.
Authors: Vassilis Aggelis, Michelle Hutchinson, Satinder Jagdev, Christy Ralph, Catherine Siller, Naveen Vasudev
Journal: Journal of Clinical Oncology (2014)

e16073 Background: A number of effective treatments exist for men with metastatic castrate resistant prostate cancer. Predicting response to a given drug is desirable. We retrospectively reviewed patients treated with abiraterone acetate (AA), to identify clinical or laboratory variables associated with response. Methods: All patients who received AA at our institution between November 2011 and August 2013 were identified using our electronic prescribing system. Individual electronic patient records were retrospectively reviewed. A large number of clinical and laboratory parameters were collected including: Gleason score, site of metastases, time from start of first-line hormone therapy to start of AA, time from start of chemotherapy to start of AA, serum Hb, WBC, neutrophil, lymphocytes, neutrophil:lymphocyte ratio (NLR), platelets, Na, K, urea, creatinine, calcium, alkaline phosphatase, ALT and bilirubin. Each parameter was tested for its association with PSA response and time on AA on a univariate level. Results: We identified 78 patients, of which 70 (90%) were treated with AA in the post-docetaxel setting. PSA response rate was 36%. Median time on drug was 4.37 months. PSA response was associated with time on AA (p=0.0163). A NLR ≤ 5 was associated with a longer median time on AA (median 4.80 vs 3.07 months), consistent with previous reports (Leibowitz-Amit et al. Annals of Oncology. 2014 Epub ahead of print), but did not reach statistical significance (p=0.082). No other parameters were associated with PSA response. In particular, time from start of first line hormone therapy to start of AA, time from start of chemotherapy to start of AA and site of metastases were not predictive of response to AA. Conclusions: In this retrospective analysis of patients treated with AA, we did not identify any clinical or laboratory parameters significantly associated with response. Importantly, time from starting first-line hormones to reaching a castrate-resistant state does not predict response to AA. Efforts to identify molecular predictors, beyond simple clinical and laboratory parameters, are warranted.
Effects of Liraglutide on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus With or Without History of Myocardial Infarction or Stroke
Authors: Subodh Verma, Neil R. Poulter, Deepak L. Bhatt, Stephen C. Bain, John B. Buse, Lawrence A. Leiter, Michael A. Nauck, Richard E. Pratley, Bernard Zinman, David D. Ørsted, Tea Monk Fries, Søren Rasmussen, Steven P. Marso
Journal: Circulation (2018)

Background: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. Methods: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. Results: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73–0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62–0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84–1.38, P interaction =0.11). Similar results were seen for secondary outcomes across risk groups. Conclusions: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01179048.
Hypogonadism in men treated with tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) as a clinical biomarker of response.
Authors: Mehran Afshar, Helen Clarke, Emilio Porfiri
Journal: Journal of Clinical Oncology (2014)

e15610 Background: A common adverse effect, and reason for dose reduction and drug withdrawal of TKI’s in mRCC is lethargy. No clear evidence exists for cause of lethargy in this setting, but a small number of case reports and series have suggested hypogonadism as a potential side effect of TKI’s, and possible contributory factor for lethargy in men. Given that male hypogonadism is not a widely recognised adverse event in this setting, and that other adverse events such as hypertension and hypothyroidism have been shown to be predictors of response to therapy, our aim was to assess the gonadal function of our male patients with mRCC receiving TKI’s and analyse potential relationships with response. Methods: We prospectively evaluated gonadal function of all male patients with mRCC receiving TKI’s at our institution. Variables analysed included total testosterone (TT), leutenising hormone (LH), and follicular stimulating hormone (FSH). We collected retrospective data on progression events, body mass index (BMI), thyroid function and symptomatology. Patients were treated with sunitinib (Sun) at an initial dose of 50mg 4 weeks on, 2 weeks off, pazopanib (Paz) at an initial dose of 800mg OD, and Axitinib (Axi) at an initial dose of 5mg BD. Those found to be hypogonadic were offered testosterone replacement. Results: Gonadal function was prospectively evaluated in 40 patients with mRCC (median age 63, range: 17-89). 19(47.5%) were receiving Paz, 14(35%) received Axi, and 7(17.5%) received Sun. 25 pts(62.5%) were hypogonadic with a median TT of 250ng/dL (range: 11.5-951). Both primary and secondary hypogonadism were noted, with only 5 pts(12%) having a completely normal hormone profile. Age and BMI were not found to correlate with TT levels in this cohort with Pearson’s coefficients providing R2=0 for both. Cox regression analysis provided a hazard ratio for PFS of 1.13 (95% CI 1.05-1.20, p=0.001). Conclusions: We observed a high incidence of hypogonadism in men receiving TKI’s for mRCC, and have shown hypogonadism to be a potential clinical biomarker of response to TKI therapy in this setting. The authors suggest further prospective analyses are required to validate this finding.