tbuckley/cabot-search huggingface dataset:
Implementing a CTC-based clinical trial assay for selecting AR-V7+ patients for enrollment in a pivotal phase 3 study (ARMOR3-SV).
Authors: Daniel T. Dransfield, Glyn Ball
Journal: Journal of Clinical Oncology (2016)

348 Background: ARMOR3-SV is a randomized phase 3, multi-center study comparing galeterone to enzalutamide in men with metastatic (M1) castrate resistant prostate cancer (CRPC) expressing androgen receptor splice variant-7 mRNA (AR-V7) who have not yet received chemotherapy, or other second generation androgen signaling inhibitors. AR-V7 is a truncated, constitutively active splice variant of the androgen receptor (AR) that lacks the ligand binding domain (LBD) and has been implicated in prostate cancer progression. Recently, the presence of AR-V7 in circulating tumor cells (CTCs) has been associated with a lack of responsiveness to both abiraterone and enzalutamide, whereas galeterone, a selective small molecule that potently degrades the androgen receptor, has demonstrated activity in preclinical model systems expressing AR-V7 and clinically in patients with C-terminal loss, of which AR-V7 is the most common form. Methods: Utilizing the lab test developed at JHU as a model system, we sought to develop a clinical trial assay utilizing immunomagnetic bead isolation of CTCs followed by mRNA isolation and cDNA generation. We then developed a duplexed PCR assay using Taqman chemistry to detect the full-length AR (AR-FL) and AR-V7. Negative patient samples were used to establish the limit of blank and assay cut-off and synthetic oligonucleotides to establish the limit of detection. Results: The AR-FL and AR-V7 assay shows linear response to template dilution to the assay cut-off Ct. Blood spiked with LNCaP and LNCaP95 cells were used to demonstrate assay suitability and sensitivity. We have successfully detected AR-FL and AR-V7 in select CRPC patient samples. We have also demonstrated assay reproducibility and have shown that the assay remains consistent in the presence of select interfering substances. Conclusions: For the ARMOR3-SV trial, this clinical trial assay is being utilized globally at central laboratories to screen patient blood samples for AR-V7 expression in evaluable CTCs as the first criterion for inclusion in this study. Clinical trial information: NCT02438007.
Analysis of tegulatory T cells in renal cell carcinoma
Authors: A. J. Schrader, A. Jeron, S. Pfoertner, P. J. Olbert, A. Hegele, J. Buer, R. Hofmann
Journal: Journal of Clinical Oncology (2008)

16074 The frequency of peripheral CD4CD25 regulatory T-cells (Treg) is increased in many malignancies. Depletion of Treg cells can lead to increased antitumor immune response demonstrating their involvement in tumor immune tolerance. Therefore, the combination of standard therapies with the Treg depletion/modulation might be a promising new therapeutic option. Since this requires a more detailed understanding of Treg biology and its role in cancer we aimed to further characterize Treg from pts. with renal cell carcinoma (RCC) in comparison to healthy controls. We collected peripheral blood from 11 healthy donors and 8 pts. with RCC and isolated CD4CD25 Treg using AutoMACS. Purity of isolated CD4CD25 T cells was >90%, as confirmed by FACS. After total-RNA isolation we applied the “Human Treg Chip” which is a self-developed customized oligonucleotide microarray paticularly designed for expression analysis of 350 Treg associated genes. After data normalization we compared the obtained expression profiles using unsupervised hirarchical clustering algorithms. We were able to demonstrate a significant increase in CD4+CD25+ and particularly CD4+CD25high frequencies (mean, 11.5% vs. 6.8%) in RCC pts. vs. healthy donors. In addition, we revealed significant differences in the expression levels of 57 genes between Tregs of RCC pats. and healthy controls. Gene ontology identified functional association of significantly regulated genes to 11 functional classes, particularly apoptosis with genes such as LGALS1, LGALS3 and BAX, as well as genes coding for cytokines, chemokines or their receptors (e.g. TNFRSF1B and CCR4). Selected array results were confirmed by real-time RT-PCR. As several anti-apoptotic genes were upregulated in RCC pts. we conclude that Treg derived from RCC pts. might be less responsive to apoptotic stimuli, which could promote their accumulation in the periphery and subsequently tumor immune escape. Results of current immunohistochemisty test (CD4/FOXP3) in tumor and normal kidney will be presented at the meeting. No significant financial relationships to disclose.
Prediction of a potential lethal phenotype in testicular nonseminomatous germ cell tumor.
Authors: Mehmet Asim Bilen, Sue-Hwa Lin, Rosale General, Lance C. Pagliaro, Christopher Logothetis, Ivan Gorlov, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2013)

e15575 Background: Cancer is a heterogeneous disease. The nature of heterogeneity provides clues about the biologic origin of cancer. Studying cancer heterogeneity may enable us to elucidate the various subtypes of a particular cancer, and improve the diagnosis, prognostication, and therapy of cancer. Nonseminomatous germ cell tumor (NSGCT) is a prime example of a heterogeneous disease. We determined the lethality of NSGCT by characterizing the histological makeup of primary testicular tumors (proportion of embryonal carcinoma [EC], choriocarcinoma, seminoma, yolk sac tumor [YST], and teratoma) and their tumor burden. Methods: From November 1997 to October 2012, 142 consecutive patients diagnosed with a NSGCT were included for this study. Predictors significant in univariate analysis: tumor stage, tumor size, percentage of YST component, and percentage of EC component were used as predictors of cancer specific death or incurability in a multivariate binary logistic regression model. The outcome of the model is probability of death or incurability. Results: Patient characteristics: age, median (range) – 25 (12-53); race – Caucasians 65%, Hispanics 28%; pathology – embryonal carcinoma 15%, teratoma 6%, mixed NSGCT 79%; stage – I 43%, II 33%, III 24%; size of primary tumor, median (range) – 3.8 cm (0.9-27); HCG&lt;5,000 95%, &gt;5,000 4%; AFP&lt;1,000 85%, &gt;1,000 13%; therapy – salvage chemotherapy 15%, RPLND 34%, HD chemotherapy w/ SCT 1%, WBRT 1%. Univariate analysis showed that clinical stage (p=.0001), presence of YST (p&lt;.005), size of primary tumor (p=.005), and absence of EC (&lt;.01) have prognostic significance. We developed a nomogram to identify patients who are most likely to succumb to their NSGCT based on the histologic makeup of their primary tumor, size of the primary tumor, initial tumor markers, and appropriate surgeries after chemotherapy. Conclusions: Presence of YST in advanced NSGCT predicts chemotherapy resistance in a potentially lethal phenotype. Early diagnosis and timely treatment with chemotherapy and surgery may improve the clinical outcome of these patients. Results of this study need to be validated in another data base or a prospective clinical trial.
Changing characteristics and improved outcome of early breast cancer in low- and middle-income countries.
Authors: N. S. El-Saghir, H. Mikdachi, Z. Nachef, N. El Asmar, H. Sibai, F. Boulos, J. Abbas, M. Hussein, F. Jamali, G. Berjawi, K. J. Bikhazi, T. Eid
Journal: Journal of Clinical Oncology (2011)

e11044 Background: Reports from low and middle income countries, including Arab countries (El Saghir NS, et al. Int J Surg. 2007 Aug;5(4):225-33) show an increased proportion of women below 50y with breast cancer, advanced stages at presentation (60-80%), high mastectomy rates (60-80%) and poor survival. Such data provided background for widespread awareness campaigns led by local practicing physicians and health authorities, and helped by a concerned international community. Methods: We reviewed the records of all patients treated in the general oncology practice at the American University of Beirut Medical Center (AUBMC) between1997-2007. Patients (pts) were staged according to AJCC 7th edition. Data was entered and analyzed using PASW. Disease-free survival (DFS) was calculated from time of diagnosis till time of distant recurrence. Overall survival (OS) was calculated from time of diagnosis till time of last follow-up or death. The study was approved by IRB of the AUB. Survival analysis was done according to Kaplan-Meier method. Results: Of a total of 386 breast cancer pts, 83 had Stage I, 161 Stage II, 106 Stage III and 36 Stage IV. Early stages (I and II) constituted 63.2% (244/386 pts), while advanced stages (III and IV) constituted 36.8%. Clinical characteristics, treatment and survival data are presented in the table. Data on stage III patients was presented at SABCS (El-Saghir NS, et al. SABCS 2010, abstract P1-11-17). Number of patients with stage IV is too small to analyze. Conclusions: Two-thirds of patients seen had early stages at presentation rather than late ones as was reported in earlier years. Early diagnosis and multimodality therapy resulted in excellent long-term survival. Awareness campaigns and early detection have changed the stages at presentation and outcome of breast cancer as evident from this study from Lebanon. Stage I Stage II Number 83 pts 161 pts Med. age 49y 48y Average T size 1.44 cm 2.87cm ER/PR + 89.2% 75.2% Her2 + 15.7% 18.6% Triple negative 10.8% 16.1% Partial mastectomy 85.5% 52.8% MRM 22.9% 55.7% Adjuvant chemotherapy 67.5% 94.4% Adjuvant hormone therapy 88% 72% RT 75.9% 64.5% Median survival Not reached Not reached DFS at 5y 95% 86.8% OS at 5y 98% 89% DFS at 10y 92.8% 74% OS at 10y 94% 76.5%
Building platforms for collaborative care and clinical research in testicular cancer (TC): New approaches for care delivery for a model neoplasm.
Authors: Craig R. Nichols, Christian K. Kollmannsberger, Victoria Demchak, Ellen Cigan
Journal: Journal of Clinical Oncology (2012)

308 Background: TC is a “model of a curable neoplasm.” In expert centers, more than 95% of patients are cured and enjoy long, high quality survivorship. Unfortunately, emerging data demonstrate variations in quality outcomes seen in high volume centers. Result are not fully replicated in U.S. community settings, low resources countries or in settings of uneven access. We hypothesize that real time, electronic information exchange in TC can influence favorably clinical decision making, patient-centered outcomes, value and quality of survivorship across business and geographic boundaries. Further, we speculate that aggregated, de-identified clinical/ biological information will serve as a template for a rapid learning system to refine clinical management and advance biological understanding. Methods: Our primary objectives were to (1) Build organizational/administrative capacity. (2) Engage patients/local providers. (3) Develop the information infrastructure to accomplish real time exchange of live patient-permitted clinical data (patient reported inputs, laboratory, imaging) and timely transmission of clinical decision support and ongoing oversight of care delivery in the community. (4) Establish a proof-of-principle demonstration in a community-based, electronically organized care delivery system. Results: Organizational: TC Commons, a nonprofit organization, was founded to house this effort. Leading academic institutions form the knowledge base, initial data sharing network and administrative structure for this electronic cooperative group. Early implementation has utilized cloud-based resources and telepresence. Community Engagement: We are utilizing organized social media efforts and partnering with patient advocacy groups. IT Infrastructure: We are creating public/private collaboratives to house the electronic capacity with appropriate privacy concerns. Proof of Principle: We are selecting community partner organizations and planning grant submissions. Conclusions: Expert platforms to enhance care delivery, patient value and experience, and clinical research can be built using a “bootstapping,” cost-sensitive approach.
Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification
Authors: Shailesh Agarwal, Shawn J. Loder, Christopher Breuler, John Li, David Cholok, Cameron Brownley, Jonathan Peterson, Hsiao H. Hsieh, James Drake, Kavitha Ranganathan, Yashar S. Niknafs, Wenzhong Xiao, Shuli Li, Ravindra Kumar, Ronald Tompkins, Michael T. Longaker, Thomas A. Davis, Paul B. Yu, Yuji Mishina, Benjamin Levi
Journal: Molecular Therapy (2017)

Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).
Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with <i>ErbB</i> alterations: Results of a phase II trial.
Authors: Noura Choudhury, Alexa Campanile, Tatjana Antic, James Lloyd Wade, Walter Michael Stadler, Yusuke Nakamura, Peter H. O'Donnell
Journal: Journal of Clinical Oncology (2016)

459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb &lt; 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p &lt; 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.
Peripheral non-small cell lung cancer treated in stereotactic conditions: A prospective medico-economic French study.
Authors: L. Claude, B. Prevost, P. Boisselier, F. Gassa, C. Carrie, S. Dussart
Journal: Journal of Clinical Oncology (2010)

TPS289 Background: Stereotactic radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) T1-2 N0 M0 is considered as a good therapeutic option for patients noneligible for surgery. This study is a prospective French multicentric nonrandomized medico-economic study. Methods: 120 patients (pts) are to be included within 3 groups of treatment (approximately 80 pts treated in SBRT with Linac, 20 pts treated using Cyberknife and 20 pts treated in conformal conditions [RC3D] without SBRT), coming from 15 institutions. The type of treatment depends on the choice of the physician, according to the local availabilities. Main inclusion criteria are pts with good performans status, treated for nonoperated proven peripheral CBNPC or non proven CBNPC with strict criteria (positive PET scan, progression on 2 successive scans, …), ≤ 5 cm, N0, M0. Written informed consent is collected. Primary objective of the study is the local control rate at 2 years. Secondary objectives are (1) economic study of the different modalities of RT (CK vs. SBRT on Linac vs. RCTD), (2) acute and late toxicity study, (3) overall survival and disease free survival as well as (4) quality of life study. Sixteen patients have been included till now (6 months of inclusion) and about 30 patient's data should be available at the time of the congress. First results concerning local control, cost of treatment, acute and subacute toxicity as well as quality of life in the three groups will be given and open to discussion. No significant financial relationships to disclose.
Conditional survival probability of long-term survival after resection of peri-hilar cholangiocarcinoma.
Authors: Stefan Buettner, Cecilia Grace Ethun, Shishir Kumar Maithel, George A. Poultsides, Thuy Tran, Kamran Idrees, Chelsea A Isom, Ryan C. Fields, Bradley Krasnick, Sharon M. Weber, Ahmed I. Salem, Robert C. G. Martin, Charles Raben Scoggins, Perry Shen, Harveshp Mogal, Carl Richard Schmidt, Eliza W Beal, Ioannis Hatzaras, Rivfka Shenoy, Timothy M. Pawlik
Journal: Journal of Clinical Oncology (2016)

212 Background: Traditional survival analyses focus on factors determined at the time of surgery and may not be accurate over time. Conditional survival (CS) estimates future prognosis based on survival time accrued following treatment. We sought to define differences between actuarial and CS among patients after resection of peri-hilar cholangiocarcinoma (PHCC). Methods: 242 patients who underwent resection for PHCC between 2000-2014 were identified from 10 major HPB centers. Cox regression models were used to evaluate factors associated with overall survival. CS was calculated as the probability of surviving an additional 3 years at “x” years after surgery using the formula CS 3 =S (x+3) /S x . Results: Median patient age was 67 yrs (IQR:57-73) and the majority (73.6%) of patients had a major hepatic resection. Surgical margin status was R0 (n=160; 66.1%) or R1 (n=82; 33.9%). Tumor grade was well- (n=43; 19.1%), moderate- (n=131; 58.2%) or poorly- (n=51; 22.6%) differentiated. Most patients had T1 (13.8%) or T2 (66.4%) disease, while a smaller subset had T3 (17.3%) or T4 (2.6%) disease. Lymph node metastases were present in 79 (32.6%) patients. While actuarial survival decreased over time from 46.3% at 2 years to 18.2% at 5 years following surgery, 3-year CS increased over time among those patients who survived. The CS 3 at 2 years (i.e. the probability of surviving to postoperative year 5 after having already survived to year 2) was 39.3% and increased to 54.4% at year 5 (Table). Factors associated with worse OS included lymph node metastases (HR 1.71; 95%CI, 1.24-2.36) and perineural invasion (HR 1.54; 95%CI, 1.02-2.33) (both P&lt;0.05). CS 3 for high-risk patients exceeded the actuarial survival, e.g. patients with perineural invasion had an actuarial survival of 15.4% at 5 years vs. a CS 3 at 2 years of 37.6% (Δ=22.2%). Conclusions: CS provides a more dynamic means to estimate future survival among patients who have accrued survival time, especially in high-risk patients who were predicted to have short survival times. [Table: see text]
Does “low risk” muscle invasive bladder cancer actually exist?
Authors: Eugene J. Pietzak, S. Bruce Malkowicz, Thomas J. Guzzo
Journal: Journal of Clinical Oncology (2015)

308 Background: Despite level one evidence demonstrating improved survival with neoadjuvant chemotherapy (NAC), studies suggest that many eligible patients with muscle invasive bladder cancer (MIBC) never receive it prior to radical cystectomy (RC). Our objective was to determine if the absence of known pre-operative risk factors can indeed stratify for low risk of extravesical disease with RC alone. Methods: We identified consecutive NAC-naive patients with clinical stage cT2N0M0 urothelial type bladder cancer treated with RC at our center. cT2 patients with either hydronephrosis, transurethral resection (TUR) specimens containing lymphovascular invasion (LVI), or mixed variant histology were grouped as high risk. Clinicopathologic and survival outcomes were compared to cT2 patients without these adverse features, who were grouped as low risk. Results: Of 251 cT2 patients, 119 (47.4%) were high risk [LVI=31, hydronephrosis=69, mixed histology=54; ≥2 risk factors=70]. High and low risk cohorts did not differ in age, gender, race, BMI, smoking, co-morbidities, prior intravescial therapy, or treatment delay. At time of RC, high risk patients more often had lymph node metastasis (38.6% v. 26.7% p=0.04) &amp; tumor upstaging to pT3/4 (53.7% v. 40.2 p&lt;0.001), with significantly less achieving pT0 (2.5% v. 12.1% p=0.004). There was no difference in adjuvant chemotherapy rates (26.4% v. 25% p=0.8). Two and five year cancer-specific survival (CSS) was 84.8% and 62.3% for low risk patients, but only 59.5% and 42% for high risk patients (p=0.008), with competing risk analysis revealing worse bladder cancer specific mortality (BCSM) (sub HR=2.08 [95%CI=1.36 – 3.2]). Odds Ratio for BCSM was 1.29 (95%CI=0.68-2.5) if one risk factor was present, &amp; 3.2 (95%CI=1.7-5.8) if two risk factors. Only hydronephrosis (2.2 [95%CI=1.2-4.2]) and mixed histology (2.4 [95%CI=1.2-4.8]) were independently associated with worse BCSM on multi-variable analysis. Conclusions: Good cancer control is provided by RC alone to many patients with cT2 MIBC without adverse risk factors, particularly if hydronephrosis &amp; mixed variant histology is absent. However, tumor upstaging and lymph node involvement is not trivial even in low risk patients, which must be included in informed decision making on NAC.