tbuckley/cabot-search huggingface dataset:
Multicenter observational study of temsirolimus use records conducted under conditions of routine medical practice.
Authors: Martin Eduardo Richardet, Raul Sala, Luis Fein, Eduardo Arnoldo Richardet
Journal: Journal of Clinical Oncology (2013)

e15610 Background: Sometimes efficacy and toxicity reported in clinical trials differs from what is later found on everyday practice. Temsirolimus was approved in Argentine on 2009. We conducted a study to evaluate the safety profile in advanced renal cancer patients treated with Temsirolimus in everyday practice conditions. Methods: Descriptive, observational, retrospective study of medical records of patients treated with Temsirolimus from 2 Argentinian centers were analyzed at IONC and IOR from April to December 2010. All patients were high risk according to Memorial Sloan Kettering Cancer Center. 50 patients were included, 36% (18) women and 64% (32) men, average age 53.8 years old (20 - 78). Adverse events were assessed based on the NCI CTC v3. Results: No patient showed side effects during or immediately after the infusion, related with the administration of the drug. This study included patients with extensive metastatic disease and multiple factors of adverse prognosis together with short life expectancy. All centers used the standard premedication and dose and no serious adverse events were registered. The most frequent adverse events were anemia, asthenia and mucositis. In all cases adverse events were manageable with support measures or dose reduction. Although more than 80% of patients showed some type of adverse event, the quantity and severity of them were lower than the ones reported in the literature. Disease progression (67.3% of patients) was the most frequent cause of treatment discontinuation. All patients received a dose = 25mg. A total of 52 adverse events were registered. In Terms of efficacy, 46 patients were suitable for analysis. Our rate of clinical benefit (PR 13%+SD 47.8%) is 60.8% , higher than what was reported in the pivotal phase III study (32.1%), this difference could be attributed to our limited sample size. The ORR observed (13%) is similar to the rate reported in the pivotal phase III trial (8.6%. Range 4.8 – 12.4). Conclusions: The treatment with Temsirolimus in patients with advanced renal cancer with poor prognosis factors showed an acceptable safety profile and clinical benefit, taking into account the characteristics of the target population.
Outcome of 58 trimodality-eligible esophagogastric cancer (EC) patients who achieved clinical complete response (cCR) after preoperative chemoradiation but then declined surgery.
Authors: Takashi Taketa, Arlene M Correa, Akihiro Suzuki, Mariela A. Blum, Jeffrey H Lee, James Welsh, Steven H. Lin, Dipen M Maru, Jeremy J. Erasmus, Manoop S. Bhutani, Brian Weston, David C. Rice, Stephen Swisher, Wayne Lewis Hofstetter, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2012)

4078 Background: For patients with EC who can withstand surgery, the preferred therapy is trimodality. However, after achieving a cCR (defined as post-chemoradiation negative endoscopic biopsy for cancer and post-chemoradiation physiologic FDG uptake by PET), some patients are tempted to decline surgery. Literature is sparse on the outcome of such patients. Methods: Between 2002 and 2011, we identified 621 trimodality-eligible EC patients in our prospective database. All patients had to be trimodality-elgible and must have received preoperative chemoradiation and completed preoperative staging that included a repeat endoscopic biopsy and PET-CT prior to surgery among other routine tests. Results: Of 621 trimodality-eligible patients identified, 58 patients declined surgery after completing chemoradiation. All patients had a cCR. The median age was 69 (range, 47-85). Male (84.5%) and Caucasian (91.4%) were dominant. Baseline stage was II (44.8%) or III (51.7%) and histology was adenocarcinoma (67.2%) or squamous cell carcinoma (29.3%). 40 patients remain alive at a median follow up of 50.4 months (95% CI, 38.6-62.1). 5-year OS and relapse-free survival were 56.7±9.0% and 32.9±7.7%. Of 12 patients with local recurrence during surveillance, 11 had salvage resection. Conclusions: Although, the outcome of EC patients with cCR who declined surgery appears reasonable, in the absence of a validated prediction/prognosis model, only trimodality therapy must be encouraged for trimodality-eligible patients. Supported by UT M. D. Anderson Cancer Center grants and generous donors.
How do elderly cancer survivors fare? A comparison of characteristics, health status, health behaviors, and spending between Medicare beneficiaries with and without a cancer history.
Authors: Xuehua Ke, Ilene H. Zuckerman, Naimish B. Pandya, Thomas Shaffer, Claire Frances Snyder, Bruce C. Stuart, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2012)

6028 Background: Prior research on cancer (Ca) survivors has been limited to small cohorts or claims data with limited measures. In this study we used population-based survey data to characterize multiple dimensions of the survivor experience including socioceonomic status, health status and behaviors, and healthcare spending, comparing survivors to beneficiaries w/o a Ca history. Methods: Data were pooled from the 1997-2007 Medicare Current Beneficiary Survey (MCBS) including linked claims (3 yrs prior to MCBS enrollment to concurrent). Ca survivors were identified from ICD-9-CM codes on claims or self report of a prior Ca dx, survived 2+ yrs from observed Ca dx, and had no active treatment, hospice enrollment or death in the selected survivorship yr. Beneficiary characteristics and healthcare use were based on self report augmented by claims-based measures. Bivariate and multivariate analyses were used to compare survivors’ characteristics and spending to controls. Results: The study included 3,921 survivors and 7,056 subjects w/o Ca. Among survivors, breast (21%), prostate (21%), and colorectal (16%) were most common Ca sites. Compared to controls without (w/o) Ca, survivors had higher income and assets, were more likely to have supplemental medical and prescription drug coverage (74% vs. 70%), had more comorbid conditions as measured by Charlson Comorbidity Index score &gt;=2 (18% vs. 15%), and a smoking history (60% vs. 53%); survivors were less likely to avoid visiting doctors (22% vs. 30%), and more satisfied with the quality of medical care received (96% vs. 92%). Survivors had higher annual healthcare spending (mean $12,095 vs. $8,928) and outpatient drug spending ($2,205 vs. $1,898). All differences in healthcare use and spending remained significant after adjusting for socioeconomic status, health conditions, and behaviors. Conclusions: Elderly Ca survivorshad more supplemental insurance coverage, stronger preferences for medical care, used more preventive services, and had higher spending compared to beneficiaries w/o Ca. These patterns may reflect the effects of survivorship on need for healthcare and care seeking behaviors.
Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study).
Authors: Dung T. Le, Andrew H. Ko, Zev A. Wainberg, Vincent J. Picozzi, Hedy L. Kindler, Andrea Wang-Gillam, Paul Eliezer Oberstein, Michael Morse, Herbert Zeh, Colin D. Weekes, Tony R. Reid, Aimee Murphy, Katherine McDougall, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Sandy Ferber, Thomas Walter Dubensky, Dirk G. Brockstedt, Elizabeth M. Jaffee
Journal: Journal of Clinical Oncology (2017)

345 Background: GVAX is composed of irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and induce broad tumor antigen responses. Low-dose cyclophosphamide (CY) is administered with GVAX to inhibit regulatory T cells. CRS-207 is live, attenuated, double-deleted Listeria monocytogenes(LADD) engineered to express mesothelin. CRS-207 boosts T cell responses against mesothelin and stimulates innate and adaptive immunity. In an earlier Phase 2 study in patients with mPDA, CY/GVAX + CRS-207 resulted in a significant improvement in overall survival (OS) compared to CY/GVAX alone. Methods: Patients with previously-treated mPDA were randomized 1:1:1 to receive 2 doses of CY/GVAX + 4 doses of CRS-207 (Arm A), 6 doses of CRS-207 alone (Arm B), or physician’s choice of single-agent chemotherapy (Arm C). Two cohorts were included based on number of prior lines of therapy; the primary cohort (PC) represented those with ≥ 2 prior lines. The primary objective was to compare OS between Arms A and C in the PC. Additional objectives include OS analyses between all treatment arms, safety, tumor responses and immune analyses. Results: 303 patients were enrolled: 213 in the PC and 90 in an exploratory 2 nd -line cohort (SC). Common AEs associated with CRS-207 treatment included transient fevers, chills, and nausea. High dropout rates were observed in Arm C prior to treatment (40% in PC, 63% in SC). Clinical trial information: NCT02004262 . Subset and immune analyses, as well as OS data from SC, will be presented at the meeting. Conclusions: The combination of CY/GVAX + CRS-207 did not show a survival benefit over chemotherapy in patients with previously-treated mPDA, although survival of patients receiving CRS-207 alone appeared similar to chemotherapy. The regimens were well tolerated with no new significant safety findings. The high dropout rate in the chemotherapy arm demonstrates a potential challenge for conventional controls in immunotherapy trials. [Table: see text]
The potential of peripheral blood HERV-K expression as a biomarker for diagnosis with prostate cancer in older men.
Authors: Sharon A. Glynn, Tiffany Wallace, Ronan Downey, Caleb Seufert, Aaron Schetter, Francis J. Giles, Frank Sullivan, Tiffany Dorsey, Radoslav Goldman, Peisha Yan, Feng Wang-Johanning, Stefan Ambs
Journal: Journal of Clinical Oncology (2014)

5049 Background: Aberrant expression of human endogenous retrovirus-k (HERV-K) has been observed in prostate cancer (PCa). HERV-K is unique as it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker. Methods: We evaluated HERV-K gag mRNA expression in PBMCs of African-American (AA) and European-American (EA) men via qRT-PCR (294 PCa cases and 135 male controls). We examined HERV-K env protein expression in PCa by immunohistochemistry. Fisher's exact test and logistic regression were used to analyze continuous and dichotomized data and calculate odds ratios (ORs). Multivariable models adjusted for age at diagnosis and race/ethnicity. Mann-Whitney test was used to compare HERV-K Ct-based expression values between groups. Results: HERV-K gag expression in PBMCs was significantly higher in PCa cases than controls (Table). Men with gag in the highest quartile had > 12-fold increased odds [OR = 12.87 (95% CI 6.3-26.25)] of PCa than those in the lowest quartile. Additionally, HERV-K may perform better in older than younger men (sensitivity of PSA testing decreases with age). HERV-K envelope protein was up-regulated in PCa, with the most abundant expression observed in AA patients (61% versus 40%, P < 0.01). Conclusions: Combining non-invasive HERV-K testing with PSA testing may improve the efficacy of PCa detection specifically among older men. Association between HERV-K gag mRNA levels in PBMC and a PCa diagnosis. Univariate analysis† Multivariable analysis* OR 95% CI P value n OR 95% CI P value n Logistic regression as a continuous variable (per Ct value) Gag mRNA 1.33 1.24-1.43 <0.0001 429 1.36 1.26-1.47 <0.0001 427 Logistic regression evaluating dose response effect** 1st Quartile 1 48 1 48 2nd Quartile 1.38 0.61-3.11 0.433 57 1.58 0.69-3.62 0.280 57 3rd Quartile 4.14 1.98-8.67 <0.0001 98 5.90 2.69-13.0 <0.0001 96 4th Quartile 12.87 6.30-26.3 <0.0001 226 17.3 8.07-37.0 <0.0001 226 Ptrend <0.0001 Ptrend <0.0001 †294 cases and 135 controls. *Adjusted for age at diagnosis and ethnicity. ***HERV-K gag levels were divided into quartiles based on control population.
Phase II clinical studies of UTD1, an epothilone analog, in metastatic breast cancer.
Authors: Binghe Xu, Pin Zhang, Zhongsheng Tong, Fuguo Tian, Yongsheng Wang, Jun Lan Yang, Lijun Di, Weilian Li, Wei Liu, Rongguo Qiu, Li Tang
Journal: Journal of Clinical Oncology (2014)

1040 Background: UTD1, a genetically engineered epothilone analog, is a microtubule stabilizing agent that showed promising activities in phase I trials. In this report, two open-label, multicenter phase II studies of UTD1 alone or UTD1 plus capecitabine (CAP) were carried out to evaluate its efficacy and safety in metastatic breast cancer (MBC) patients (pts). Methods: In both studies, MBC patient who was pretreated with taxanes, anthracyclines and/or CAP received UTD1 at a dose of 40mg/m2/d intravenously on day 1 to day 5 or at 30mg/m2/d (d1-d5) in combination with CAP (2000mg/m2/d, orally) on d1-d14, every 21 days until disease progression or unacceptable toxicity occurred for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) and the secondary endpoints were toxicity and progression-free survival (PFS) for the combination. Results: 25 pts received a total of 128 cycles in the combination with a median of 6 cycles (range 1-6 cycles) per patient. Among 24 pts who were evaluable for efficacy, responses included one complete response (CR), 11 partial responses (PR), 9 stable diseases (SD), and a median PFS of 7.5 months. In the UTD1 monotherapy, 34 pts received a median of 4 cycles of UTD1 and 30 pts were evaluable for efficacy. One patient had a confirmed CR, 7 had PR and 13 had SD. Peripheral neuropathy (PN) was the major adverse event associated with UTD1 toxicity in both studies, but was manageable. 40% of pts in the combination had grade 3 PN or/and foot syndrome compared to 11% in the monotherapy. One patient was removed from the monotherapy after the first cycle because of grade 3 neurotoxicity, which was reversed after 3 weeks. There were no drug-related deaths in the two studies. Other grade 3 toxicities included neutropenia (12% vs 3%, combination vs monotherapy), diarrhea (4% vs 3%), myalgia/arthralgia (8% vs 0%), dizziness (4% vs 0 %). Conclusions: UTD1 was well-tolerated in both studies with the primary toxicity being PN, and demonstrated notable antitumor activities in MBC pts. 27% of ORR was seen for the monotherapy or 50% of ORR and a median PFS of 7.5 months for the combination. A multicenter, phase III study of UTD1 plus CAP vs CAP alone in MBC is underway. Clinical trial information: TRC-13004205.
Analysis of the expression of Wnt signaling ligands in metastatic renal cell carcinomas tissue samples.
Authors: Urbano Anido, Vanessa Medina Villaamil, Guadalupe Aparicio Gallego, Maria Quindós Varela, Sergio Vazquez-Estevez, Luis Leon Mateos, Francisco J. Afonso Afonso, Manuel Ramos Vazquez, Jose Luis Firvida Perez, Lucía Santomé, Ovidio Fernández Calvo, Martin Lázaro Quintela, Isabel Santamarina Cainzos, Luis M. Antón Aparicio
Journal: Journal of Clinical Oncology (2012)

e15077 Background: Renal cell carcinomas (RCC) constitute a morphologically and genetically heterogeneous tumor.Wnt proteins are a large family of secreted glycoproteins that activate intracellular signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity.Wnt signalling may be playing a central role during RCC development. Methods: To characterize Wnt signalling activity in RCC, we gathered 48 tumor samples from patients diagnosed with metastatic RCC between years 2006 and 2011. Expression levels of Wnt family members (Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt7a, and Wnt9a) were examined by real-time PCR and immunohistochemistry in tumor and normal tissue from removed kidneys. Results: Wnt1 and Wnt5a were up-regulated in clear cell RCC being their relative expression 2.4.10 3 (Wnt1) and 4.10 2 (Wnt5a) times higher in renal tumor tissue than in normal tissue. One-way ANOVA test showed Wnt3a and Wnt4 as the best protein markers to distinguish clear cell RCC (F=3.95, p=0.010 and F=3.05, p=0.029, respectively). Wnt1 and Wnt7a were over-expressed in those cases which had undergone nefrectomy (Mann-Whitney U test p=0.065 and p=0.056 respectively). Finally, Wnt2 protein level was associated with those patients with high risk prognosis (Kruskal-Wallis test p=0.001). Conclusions: Our results indicate that Wnt3a and Wnt4 are potentially useful immunohistochemical markers for the differential diagnosis between clear cell RCC and other subtypes of RCC and also suggest a role for Wnt2 as a high risk prognosis marker.
Correlation of phase 2 trials (Ph2t) results with outcomes of phase 3 trials (Ph3t) of investigational agents (IA) in locally advanced and metastatic pancreas cancer (LAMPC).
Authors: Monica Tang, Julia Chen, David Goldstein, Matthew Links, Sally Lord, Ian Marschner, John Simes, Chee Khoon Lee
Journal: Journal of Clinical Oncology (2017)

227 Background: There has been minimal improvement in treatment outcomes in LAMPC. We examined results of Ph2t and Ph3t to better understand potential reasons in order to improve future trial design. Methods: We conducted a systematic review of published Ph2t and Ph3t (1978-2015) of first-line treatment for LAMPC. Data for baseline characteristics and best objective response rate (ORR) were compared. Where possible, we compared outcomes for IA tested in Ph2t with corresponding Ph3t. Results: We identified 149 Ph2t with 180 treatment arms comprising 7499 participants. Ph2t were predominantly single-arm (83%) or multi-arms with different IA doses or combinations (5%). Only 12% were randomized studies with concurrent control. The median sample size was 42 (range 8-133). The pooled ORR was 13.8% (95% CI 13.0%-14.6%) but there was substantial heterogeneity (range 0-60%, P heterogeneity &lt; .001; I 2 = 75.9%). Although 56% of Ph2t concluded that IA should be considered for Ph3t, only 11% actually proceeded to Ph3t testing. Factors associated with Ph3t testing included absence of randomized design with concurrent control (12.2% vs 5.6%), higher proportion of performance status 0 patients (24.4% vs 21.7%), higher proportion of locally advanced disease only (23.4% vs 15.4%), and higher median ORR (22.0% vs 15.4%). Of 26% Ph2t that investigated novel biological IA, 92% had a potential predictive biomarker but only 1 trial was enriched for the biomarker. Only 8% of Ph2t with novel biological IA proceeded to Ph3t. ORR of IA tested in Ph2t correlated moderate poorly with ORR (r2 = 0.21) and 6 month progression-free survival rate (r2 = 0.26) in corresponding Ph3t. Only 3 IA in Ph3t demonstrated clinically meaningful improvements. Conclusions: Despite multiple Ph2t conducted over 4 decades, only 11% progressed to Ph3t, with 3 IA ultimately improving clinical outcomes. Ph2t results do not inform Phase 3 testing of IA. Potential reasons include patient heterogeneity, overly optimistic interpretation of Ph2t results, lack of concurrent control in Ph2t and ineffective agents. These issues should be addressed in order to improve success of future Ph3t in LAMPC.
Novel heteroclitic XBP1 peptides evoking antigen-specific cytotoxic T lymphocytes targeting various solid tumors.
Authors: Jooeun Bae, Ruben Carrasco, John Daley, Glen Dranoff, Kenneth Carl Anderson, Nikhil C. Munshi
Journal: Journal of Clinical Oncology (2013)

3067 Background: Activation of the unfolded protein response (UPR) allows for tumor cells to survive prolonged endoplasmic reticulum stress and hypoxic conditions. XBP1 is an upstream element and a critical transcriptional activator of the UPR, and its up-regulation in a variety of human solid tumor cancers makes it as a promising immunotherapeutic target. The purpose of these studies was to evaluate immunogenic HLA-A2 XBP1-specific peptides for their ability to elicit cytotoxic T lymphocytes (CTL) against a variety of solid tumor cell lines. Methods: Upon the validation of XBP1 peptides for their strong HLA-A2 bindings and stabilities, peptide-specific CTL were generated ex vivo by repeated stimulation of CD3 + T lymphocytes obtained from HLA-A2 + normal donors with XBP1 peptides-pulsed antigen-presenting cells, either dendritic cells or T2 cells. Results: A cocktail of heteroclitic XBP1 US 184-192 (YISPWILAV) and heteroclitic XBP1 SP 367-375 (YLFPQLISV) peptides with significantly improved HLA-A2 affinity and stability from their native counterparts were used to evoke XBP1 antigen-specific CTL. The CTL were predominantly CD3 + CD8 + T cells (&gt;80%) containing a high percentage of Effector Memory (EM; CCR7 - CD45RO + ) cells, which were distinctively evoked by repeated stimulation with the XBP1 peptides. In addition, the XBP1-CTL displayed a high level of cellular activation (CD69 + /CD3 + CD8 + ). The XBP1-CTL demonstrated effective anti-tumor responses including cell proliferation and IFN-g production, as well as degranulation (cytotoxic activity) against HLA-A2 + breast cancer (MB231, MCF7), colon cancer (LS180, SW480) and pancreatic cancer (8902, Panc1, PL45) cell lines, which over-express both unspliced and spliced XBP1 antigens. Importantly, the specific anti-tumor activities were detected primarily in the EM CTL subset. Conclusions: These results suggest the immunotherapeutic potential of a cocktail of heteroclitic XBP1 US 184-192 and XBP1 SP 367-375 peptides to elicit effective anti-tumor responses against various solid tumors, and provide the framework for clinical development of vaccine trials to improve patient outcome.
Biofunctionalized Plants as Diverse Biomaterials for Human Cell Culture
Authors: Gianluca Fontana, Joshua Gershlak, Michal Adamski, Jae‐Sung Lee, Shion Matsumoto, Hau D. Le, Bernard Binder, John Wirth, Glenn Gaudette, William L. Murphy
Journal: Advanced Healthcare Materials (2017)

The commercial success of tissue engineering products requires efficacy, cost effectiveness, and the possibility of scaleup. Advances in tissue engineering require increased sophistication in the design of biomaterials, often challenging the current manufacturing techniques. Interestingly, several of the properties that are desirable for biomaterial design are embodied in the structure and function of plants. This study demonstrates that decellularized plant tissues can be used as adaptable scaffolds for culture of human cells. With simple biofunctionalization technique, it is possible to enable adhesion of human cells on a diverse set of plant tissues. The elevated hydrophilicity and excellent water transport abilities of plant tissues allow cell expansion over prolonged periods of culture. Moreover, cells are able to conform to the microstructure of the plant frameworks, resulting in cell alignment and pattern registration. In conclusion, the current study shows that it is feasible to use plant tissues as an alternative feedstock of scaffolds for mammalian cells.