tbuckley/cabot-search huggingface dataset:
Serum insulin to predict time to castration-resistant progression and overall survival in metastatic androgen-dependent prostate cancer (mADPCa).
Authors: Farshid Dayyani, Graciela M. Nogueras-Gonzalez, Rebecca Slack, Randall E. Millikan, Amado J. Zurita, John C. Araujo, Gary E. Gallick, Christopher Logothetis, Paul Gettys Corn
Journal: Journal of Clinical Oncology (2013)

e16038 Background: Duration of response to androgen-deprivation therapy (ADT) is highly variable in patients with mADPC and prognostic markers are needed. Insulin resistance and hyperinsulinemia may contribute to prostate cancer progression. We hypothesized that pretreatment serum insulin levels would predict time to castration-resistant progression (PFS) and overall survival (OS). Methods: Sera from men treated on a randomized phase 3 trial of first line ADT vs. ADT plus chemotherapy were retrospectively analyzed using a multiplex ELISA for cytokines and angiogenic factors (CAFs). Univariate and multivariate Cox proportional hazards regression models were used to identify associations between CAFs and PFS/OS. Results: 66 pts were evaluable, 86% Caucasian, median age 72 yrs, median PSA 31.5ng/mL, 77% Gleason score of ≥8, and 53% high volume metastatic disease (HVM). Thirty-five pts received ADT; 31 pts received ADT+chemo. In univariate analysis, higher pretreatment insulin and C-peptide were positively correlated with PFS, whereas higher hepatocyte-growth factor (HGF), osteopontin (OPN) and HVM were negatively correlated with PFS. In multivariate analysis, only higher insulin was associated with longer PFS (HR=0.72, 95%CI 1.32 -0.87; p&lt;0.001), whereas higher HGF and OPN were associated with reduced PFS (HR=1.82, 95%CI 0.59-2.83, p&lt;0.01 and HR=1.81, 95%CI 1.18-2.47, p&lt;0.001, respectively). Higher Insulin and Program Death 1 (PD1) were associated with longer OS on multivariate analysis (HR=0.78 p&lt;0.02 and HR=0.55 p&lt;0.02, respectively), whereas HVM and higher OPN were associated with reduced OS (HR=2.28 p&lt;0.01 and HR=1.60 p&lt;0.02). Using low insulin, high HGF and high OPN as 3 independent risk factors (RF), 3 distinct risk groups could predict PFS: good (zero RF), intermediate (1 or 2 RF) and poor risk (3 RF), with median PFS of 6.90, 1.97, and 0.86 years, respectively (p&lt;0.001). Conclusions: Higher pretreatment insulin was associated with prolonged PFS and OS in men with mADPC treated with ADT. Our data suggest that insulin levels are a biomarker for sensitivity to ADT and highlight the complex interactions between metabolism and PCa progression.
Baseline diagnostic imaging in early breast cancer—Five-year analysis of a large cohort
Authors: P. G. Morris, J. Gray, C. O' Rafferty, M. O' Connor, M. J. Kennedy
Journal: Journal of Clinical Oncology (2007)

17059 Background: Many patients with newly diagnosed breast cancer undergo multiple investigations as part of baseline staging, although the evidence base for this is poor. To assess the use of baseline diagnostic imaging and its benefit a review of practice was carried out. Methods: A retrospective review of all patients diagnosed with breast cancer in St James's Hospital in Dublin, Ireland over a five-year period was carried out. Baseline demographics and the appropriateness of baseline diagnostic imaging were assessed. Results: Between 01/01/2001 and 12/31/2005 781 patients were diagnosed with breast cancer in St James's Hospital, of whom 776 were women and 5 were men, with a mean age of 56.7 years. At diagnosis 266 patients (34%) underwent a bone scan, which showed evidence of skeletal metastases in 42 (15.8%). Of the patients with positive bone scans 26 (61.9%) were symptomatic with bone pain, and 16 (38.1%) were not. In the 16 patients without bone pain a diagnostic workup for metastatic disease was undertaken in 5 patients because of clinical findings, in 4 patients because of abnormal liver blood tests and in 5 patients because of radiological findings. Only two patients out of 266 who underwent a bone scan were found to have an incidental finding of metastatic bone disease, of whom one had a bone scan as part of a clinical trial. At diagnosis 261 patients (33.4%) underwent a liver ultrasound, which showed evidence of metastases in 23 (8.8%). Of these, 19 patients had abnormal liver blood tests. Four patients had metastatic disease on liver ultrasound with normal liver blood tests and of these, one patient had a malignant pleural effusion and one patient had inflammatory breast cancer and was considered high risk for metastatic disease. Only two patients out of 261 who underwent a liver ultrasound had incidental findings of liver metastases. Conclusions: Over a five-year period, occult metastases were discovered in only two patients on bone scans and in two patients on liver ultrasounds. The routine use of these imaging modalities to detect metastases in early breast cancer is not justifiable. No significant financial relationships to disclose.
The importance of early treatment to decrease therapy-related complications in Burkitt lymphoma (BL), Burkitt-like leukemia/lymphoma (BLL), and acute lymphocytic leukemia (ALL) treated with disease-specific systemic therapy.
Authors: Alaa Muslimani, Adewale Fawole, Hamed Daw, Timothy Peter Spiro, Hong Ye, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2013)

6577 Background: BL, BLL and ALL are highly aggressive malignancies. We conducted a study to determine the relationship between the time to start of disease-specific systemic therapy and the frequency of various complications during treatment. Methods: A multi-center chart review was conducted for a total of 175 patients (pts) from Cleveland Clinic and Beaumont Health System, who received thearapy between Jan 2000 and Oct 2012. Pts were classified into two groups based on time to start of disease-specific systemic therapy. The first group started therapy within 1 week of the presenting symptoms and the second group started therapy in ≥ 1 week. Pts characteristics, stage of disease, incidence of acute renal failure (ARF) [Am J Med. 1983;74(2):243], Tumor lysis syndrome (TLS) [Cairo-Bishop definition], major bleeding [requiring transfusion, drop in hemoglobin &gt; 2 g/dL, or bleeding in critical sites], venous thrombotic events (VTEs) [documented by imaging], neutropenic fever (NF) [Clin Infect Dis. 2011;52(4):e56], and mortality rate were retrieved from the records. Results: Of 175 pts (66 BL, 13 BLL, 96 ALL), 67 % were males, 92.6 % had stages III or IV disease. Chi-Square test analysis showed pts treated with disease specific systemic therapy within 1 week as compared to those whose treatment began ≥ 1 week after symptoms onset had less incidence of ARF (16.7% vs 38.5% p=0.001), less TLS (3.6% vs 16.5% p=0.006), less VTEs (8.3% vs 16.6% p=0.007), less NF (3.6% vs 24.2% p=0.001) and most importantly had a lower mortality rate during the therapy (1.2% vs 8.8% p=0.036). Further analysis of the data showed no significant difference in the incidence of major bleeding between the two groups (9.5% vs 17.8 p=0.129), although there was a trend toward fewer episodes in pts started on therapy within 1 week. Conclusions: This study confirmed an increased risk of therapy related complications including higher mortality in pts with BL, BLL and ALL when the therapy was initiated ≥ 1 week after symptoms onset. These findings indicate that clinicians should start disease specific therapy within 1 week.
Abstract 80: Accumulation of Mitochondrial DNA in Autolysosome Causes Inflammation and Heart Failure Through Toll-Like Receptor 9 (TLR9) Signaling
Authors: Takafumi Oka, Osamu Yamaguchi, Issei Komuro, Kinya Otsu
Journal: Circulation Research (2012)

Backgrounds Nuclear DNA in apoptotic cell is digested by lysosomal deoxyribonuclease II (DNase II) in macrophages. Improper DNA digestion can lead to inflammation. We previously reported that cardiac-specific DNase II-deficient mice (CKO) exhibited heart failure after transverse aortic constriction (TAC). We observed inflammatory response and DNA accumulation in autolysosome in TAC-operated CKO heart. They were considered to be mitochondrial DNA (mtDNA). In present study, we elucidated the mechanism of inflammation integrated by DNA accumulation in TAC-operated CKO hearts. Furthermore we investigated the pathogenesis of inflammation and heart failure in wild-typeTAC-operated mice. Methods &amp; Results First, we identified the origin of accumulated DNA in lysosome. To label cardiac mtDNA, EdU (5-ethynyl 2’ deoxyuridine) were injected into mice before TAC. In TAC-operated CKO mice, EdU- and LAMP2a (lysosomal marker) or LC3 (autophagosome marker) positive deposits were observed, indicating that mtDNA accumulated in autolysosome. Then, we examined the mechanism how the mtDNA accumulation leads to inflammation. mtDNA has similarities to bacterial DNA, which contains inflammatogenic unmethylated CpG motif. TLR9, localized in the endolysosome, senses DNA with unmethylated CpG motifs. Therefore, we hypothesized that undigested mtDNA is sensed by TLR9. We administrated the inhibitory oligodeoxynucleotides against TLR9 to TAC-operated CKO mice. They attenuated the development of cardiomyopathy in CKO mice. Ablation of Tlr9 also canceled the cardiac phenotype of CKO mice. Next, we examined the involvement of DNA accumulation and TLR9 signaling in wild-type TAC-operated mice. DNase II activity was up-regulated in hypertrophied hearts, but not in failing hearts. LAMP2a- or LC3- positive DNA accumulation was observed in failing hearts. To determine the significance of TLR9 signaling pathway in the pathogenesis of heart failure, we subjected TLR9-deficient mice to TAC. They showed significant resistance to pressure-overload. TLR9-inhibitory oligodeoxynucleotides also improved the mortality in wild-type TAC-operated mice. Conclusion mtDNA-TLR9 axis is involved in inflammation in failing hearts in response to pressure overload.
A comparative study of circulating biomarkers of anti-VEGF therapy in phase II trials in advanced hepatocellular carcinoma (HCC) patients (pts).
Authors: Lipika Goyal, Marek Ancukiewicz, Rakesh K. Jain, Andrew X. Zhu, Dan G. Duda
Journal: Journal of Clinical Oncology (2014)

2543 Background: Sorafenib, a multikinase inhibitor of VEGFR, remains the only approved systemic therapy in HCC. Several other anti-VEGFR agents have either failed or continued in phase III trials. Despite the extensive efforts in developing antiangiogenic agents in HCC, no biomarker currently exists for appropriately selecting patients with HCC for antiangiogenic therapy. We performed a comparative study of circulating biomarkers in single arm, phase II studies of sunitinib, cediranib and ramucirumab in pts with advanced HCC. Methods: Clinical trial design and outcomes have been previously reported (PMID 19470923, 23362324, 24088738). Peripheral blood was obtained prior to and at various time points after treatment and was analyzed for circulating biomarkers using multiplex ELISA. Results: A total of 54 pts were analyzed in this study: sunitinib (S) (n=33), cediranib (C) (n=12), and ramucirumab (R) (n=9). Compared to baseline, monotherapy with all three agents increased the Day 14 circulating levels (Day 14 level/baseline level) of PlGF (S, 3.1; C, 3.4; R, 3.5) and VEGF (S, 2.1; C, 1.3; R, 2.0) and decreased those of soluble VEGFR2 (S, 0.7; C, 0.8; R, 0.7). In exploratory correlative studies, high baseline and on-treatment levels of soluble VEGFR1 – an endogenous inhibitor of VEGF and PlGF – were associated with poor outcomes for all three treatments. Other biomarkers, including angiogenic molecules and inflammatory cytokines, showed differential kinetics and no significant associations with clinical outcomes. Conclusions: Exploratory studies from phase II trials of pts with advanced HCC who received sunitinib, cediranib, or ramucirumab suggest that circulating PIGF, VEGF, and sVEGFR2 are potential pharmacodynamic and response biomarkers of anti-VEGF therapy. They also show that soluble VEGFR1 may be a useful biomarker of resistance to anti-VEGF therapy. These biomarker candidates need to be validated in large prospective studies.
A report of cardiac events in a phase II clinical study using trastuzumab combined with pertuzumab in HER2-positive metastatic breast cancer (MBC)
Authors: C. C. Portera, J. M. Walshe, N. Denduluri, A. W. Berman, U. Vatas, D. R. Rosing, C. K. Chow, S. M. Swain
Journal: Journal of Clinical Oncology (2007)

1028 Background: T and P are humanized recombinant monoclonal antibodies (MoAB) that target different epitopes of HER2 extracellular domain. P blocks HER2’s ability to heterodimerize with other HER/ErbB receptors. Methods: This Ph II trial evaluates the efficacy and safety of T with P in patients (pts) with HER2+ (FISH +) MBC who had progressive disease (PD) on T-based therapy. Eligible pts must have had = 3 T-based regimens, normal (nl) left ventricular ejection fraction (EF=55%) and without significant cardiac history. Pts received IV T (6mg/kg) and P (420 mg) every 3 weeks (wks). EKG plus echocardiogram (ECHO) or cardiac MRI and tumor response were assessed every 3 and 6 wks, respectively. Results: Eleven pts received 39 (1 to 13) cycles, 1 pt achieved a partial response (PR) and 3 pts had stable disease. A total of 68 ECHOs and 8 cardiac MRIs were performed. Left ventricular systolic dysfunction (LVSD) with nl EKG was seen in 5 pts; Grade (Gr) 1 (n = 2) (EF 50–55%), Gr 2 (n = 2) (EF 40–50%) and Gr 3 (n = 1) (EF20–40%). Gr 2–3 events were associated with global hypokinesis. Gr 3 event was associated with symptomatic CHF. All 5 pts had received 240mg/m 2 cumulative dose of doxorubicin, 2 pts (Gr 2–3) received chest wall radiation, and 1 pt (Gr 1) had HTN. Two pts with Gr 1–2 LVSD had a history of reduced EF during prior T-based treatment, which reversed to nl upon stopping T. Reduced EF appeared within 1–2 cycles, which returned to nl in 3 pts within 1wk to 3 months (mo) post discontinuing T/P. One pt had persistent Gr 2 LVSD 3 mo after the initial event. The pt with Gr 3 LVSD had extensive chest wall disease and died of PD and possibly CHF 2 mo after treatment termination. Conclusions: We observed Gr 1–3 LVSD in patients with HER2+ MBC who received dual MoAB treatment directed at HER2, in which very strict cardiac surveillance guidelines were required. One of 11 pts achieved PR and 1 pt had symptomatic CHF thus far. It is unknown whether the other events would have become symptomatic if treatment had continued. Further evaluation of the efficacy of combination T with P is required to define the overall risk and benefit. No significant financial relationships to disclose.
Assessment of the prognostic and predictive utility of the breast cancer index (BCI): An NCIC CTG MA.14 study.
Authors: Dennis Sgroi, Paul Edward Goss, Judy-Anne W. Chapman, E. Richardson, Shemeica N. Binns, Yi Zhang, Catherine A. Schnabel, Mark G. Erlander, Kathleen I. Pritchard, Lei Han, Lois E. Shepherd, Michael N. Pollak
Journal: Journal of Clinical Oncology (2012)

561 Background: Breast Cancer Index (BCI), a continuous risk index, combines the ratio of HOXB13 to IL17BR (H/I) and the molecular grade index (MGI) (Jerevall et al., British J Cancer, 2011). Here, the prognostic and predictive performance of BCI for BC relapse in MA.14 trial was examined. Methods: MA.14 randomly assigned 667 hormone receptor positive (HR+) women to 5 years of tamoxifen (TAM) +/- 2 years of octreotide LAR (TAM-OCT). A representative subgroup of 299 patients was profiled by RT-PCR for BCI. The primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS) with median 9.8 years follow-up. Association of BCI was assessed with step-wise forward stratified Cox regression. Pre-defined categories of low (L), intermediate (I) and high (H) BCI risk groups were used to provide adjusted 5- and 10-year RFS. Results: 292 of 299 patient samples passed internal analytical quality control. The 292 patients contained 49% LN+ patients and had 19.9% BC relapses. Both continuous and pre-specified BCI risk groups were significant multivariate factors (p&lt;0.0001; p=0.007) with higher BCI associated with shorter RFS. Adjusted univariate hazard ratios and 95% CI were 2.53 (1.36 – 4.71) for BCI-H vs -L and 1.28 (0.65 – 2.52) for BCI-I vs -L. With both LN- and LN+ included, BCI-L had 5- and 10-year RFS of 94.0% and 87.5%; -I, 91.8% and 83.9%; and -H, 81.5% and 74.7%. No significant difference in BCI’s ability to stratify patients into 3 risk groups was observed between LN-/no chemotherapy subgroup vs balance of MA.14 patients (p=0.26). Higher pathologic T-stage was multivariately associated with shorter RFS (p=0.01). Interactions between trial therapy and BCI was not significant (p=0.40). Conclusions: This study confirmed the strong prognostic effect of BCI on breast cancer recurrence. BCI was prognostic in both LN- and LN+ patients. The lower 10-year RFS in the BCI-L group than in our previous studies reflected the mixed LN-/LN+ population examined. Like the parent MA.14 trial, BCI did not predict benefit of adding OCT to TAM therapy (Pritchard et al., J Clin Oncol, 2011). This retrospective study is an independent validation of the prognostic performance of BCI within a prospective trial.
Prognosis of lung cancer patients with a past history of colorectal cancer.
Authors: Aritoshi Hattori, Kenji Suzuki, Keiju Aokage, Takahiro Mimae, Kanji Nagai, Masahiro Tsuboi, Morihito Okada
Journal: Journal of Clinical Oncology (2014)

e18537 Background: Due to the increasing number of lung cancer patients complicated with a previous history of colorectal cancers, there has been an urgent need for a study on its clinicopathological significance and the prognosis for these patients. Methods: For the period 2000 to 2013, we designed a retrospective multicenter study at 3 institutes in Japan to evaluate the prognostic factors in lung cancer patients with a previous surgery for colorectal cancer. Results: The study cohorts consisted of 123/4,431 lung cancer patients with/without a history of surgery for colorectal cancer. The median follow-up period was 6.1 years after lung cancer surgery. Lung cancer patients with colorectal cancer showed a higher age (70 y vs. 66 y, p<0.001) and male predominance (74% vs. 61%, p=0.004) compared to those without colorectal cancer. The 5-year overall survival (OS) in lung cancer patients with colorectal cancer (71.3%) was slightly inferior to that in patients without colorectal cancer (74.7%), but this difference was not significant (p=0.1426). Based on a multivariate Cox regression analysis in 4,554 lung cancer patients, gender (p<0.001), age (p<0.001), presence of any cancers other than those of the lung and colorectum (p=0.004), and p-stage of lung cancer (p<0.001) were significant prognostic factors, whereas a history of surgery for colorectal cancer was not a significant (p=0.5335). Among the 123 lung cancer patients with colorectal cancer, age and use of adjuvant chemotherapy for colorectal cancer were significant prognostic factors based on a multivariate analysis (p=0.0001 and 0.0236). Regarding the prognostic factors in 66 lung cancer patients with p-stage I colorectal cancer, age and the recurrence of colorectal cancer were significant in these populations based on a multivariate analysis (p=0.0298 and 0.0285). Furthermore, there was no difference in the OS of lung cancer patients according to the stage of colorectal cancer (stage I; 74.7%, stageII/III; 66.5%, p=0.7239). Conclusions: A history of surgery for colorectal cancer may not contribute to the prognosis in patients with subsequent lung cancer, if the patients are an appropriate age and the postoperative status for the previous colorectal cancer was well-controlled only by surgery.
Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies.
Authors: Tian Zhang, Rengasamy Boominathan, Brad Foulk, Mark Carle Connelly, Chandra Rao, Gabor Kemeny, John H. Strickler, James L. Abbruzzese, Michael Roger Harrison, Daniel J. George, Herbert Hurwitz, Mariano A. Garcia-Blanco, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2015)

11024 Background: Genetic alterations in the MET oncogene exist in many GI and GU malignancies. MET amplification is associated with poor prognosis and can arise as a resistance mechanism to EGFR targeting therapies. We aimed to capture and identify CTCs expressing c-MET. Methods: We modified the Cellsearchplatform by using nanomagnetic particles conjugated to antibodies against c-MET to capture c-MET-expressing CTCs and stained for c-MET-PE, DAPI, and pan-CK-FITC. CD45 + cells were excluded. The method was validated by spiking MET-amplified gastric cancer cells, c-MET-overexpressing, nonamplified cancer cells, and MET-negative cancer cells into peripheral blood from healthy volunteers (HVs). Peripheral blood samples were obtained from patients (pts) with refractory metastatic gastric, pancreatic, colorectal, bladder, renal, and prostate cancers. CTC enumeration with c-MET capture was compared to EpCAM capture. After CTC isolation, DNA FISH for MET amplification was performed. Results: The novel c-MET CTC assay was 80% sensitive for MET-amplified cells, 40-80% sensitive for c-MET-overexpressed cells, and 100% specific for c-MET negative cells and in 20 HVs. Of 50 pts tested thus far, we captured c-MET CTCs in duplicate samples from 3 pts, with gastric adenocarcinoma (90 and 52 c-MET CTCs), colorectal adenocarcinoma (7 and 2 c-MET CTCs), and renal cell carcinoma (RCC; 3 and 1 c-MET CTCs). CTC FISH demonstrated polysomy 7 and MET amplification in both gastric and colorectal cancer pts and trisomy 7 with gain of MET gene copies in the RCC pt. Conclusions: The c-MET CTC assay is rapid, non-invasive, sensitive and specific. c-MET expressing CTCs can be detected in gastric, colorectal, and renal cancers but not negative controls. MET amplification can be detected using FISH after CTC capture, leveraging this technology as a potential minimally invasive liquid biopsy. This approach may be clinically useful to identify and follow patients who may be candidates for c-MET directed therapies.