tbuckley/cabot-search huggingface dataset:
A Phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate resistant prostate cancer (mCRPC) receiving XL184.
Authors: Alexa Campanile, Milica Medved, Aytekin Oto, Theodore Karrison, Daniel H. Shevrin, Greg S. Karczmar, Walter Michael Stadler, Russell Zelig Szmulewitz
Journal: Journal of Clinical Oncology (2015)

e16112 Background: XL184 (cabozantinib) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. Trials of XL184 have shown significant improvements in bone pain and bone scintigraphy in patients (pts) mCRPC. We hypothesized that functional magnetic resonance imaging (fMRI) could elucidate the biological processes behind these changes by demonstrating an early decrease in vascular permeability (Ktrans) and subsequent decrease cell density (apparent diffusion coefficient-ADC) within bone metastases. Methods: mCRPC pts were treated with XL184 at 60 mg daily. The primary endpoint was change in Ktrans after two weeks of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and to correlate these with bone scan, PSA, RECIST, and changes in patient-reported pain. 20 patients were to be enrolled to demonstrate a 20% reduction in Ktrans with 80% power and a two-sided alpha of 0.05. All patients underwent baseline fMRI and bone scan, with repeat imaging at day 15 and every 12 weeks. Results: Seventeen pts were treated across two sites. Median age 68 yrs (range = 51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events (AE’s), and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 weeks, Ktrans decreased an average 35%, 0.074 to 0.048 min-1 (SD = 0.016, p < 0.0001). There was no change in Ktrans between week 2 and end of study. There was a subjective decrease in radiotracer uptake on bone scan uptake in 71% of pts. Analyses of secondary endpoints are ongoing. Conclusions: Ktrans decreased significantly after 2 weeks of treatment, consistent with antiangiogenic properties of XL184. Compared to week 2, Ktrans at disease progression is unchanged, which could signify that adaptive vascular change is not the primary mechanism of resistance to the drug. Further bone metastasis biomarker investigation for therapies such as XL184 could refine drug development for theses agents in mCRPC. Clinical trial information: NCT01599793.
DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells—Implications for age-related macular degeneration (AMD)
Authors: Juha M.T. Hyttinen, Janusz Błasiak, Minna Niittykoski, Kati Kinnunen, Anu Kauppinen, Antero Salminen, Kai Kaarniranta
Journal: Ageing Research Reviews (2017)
Correlation between inflammatory markers in blood and expression of costimulatory molecules on tumor-infiltrating CD8+ lymphocytes in renal cell carcinoma.
Authors: Haydn T. Kissick, Kyu Seo Kim, Yun Min Chang, Viraj A. Master
Journal: Journal of Clinical Oncology (2017)

508 Background: Loss of co-stimulatory molecules by CD8 T-cells is associated with reduced proliferative and cytotoxic function in chronic viral infections, aging, and cancer. Several lines of evidence suggest that a more functional immune system is associated with better patient outcomes, and improved response to immunotherapy in a range of different cancers. For this reason, understanding the features of a patient that predict the loss of T-cell function is important. In this study we characterized how co-stimulatory molecules are expressed by T-cells in the tumors of RCC patients. Additionally, we characterized how distant sites of metastasis differ from the primary tumor, and finally, we evaluated levels of blood inflammatory markers (BIMs) to predict how co-stimulatory on CD8+ TILs change. Methods: Patients that underwent resection of primary and/or metastatic RCC at Emory University Hospital were prospectively enrolled in the study. Levels of pre-op BIMs were retrieved from medical records. A portion of resected tumor tissue was analyzed by flow cytometry to measure percentage of CD8+ cells expression of the co-stimulatory molecules, ICOS, CD27, CD40L, CD226, CD28, and CD2. A composite co-stimulatory score (co-stim score) was calculated by taking a weighted average of the number of co-stimulatory receptors expressed per cell. BIMs were correlated with CD28 expression and co-stim score. Expression of co-stimulatory receptors was compared between patient-matched primary tumor and metastatic tumor pairs. Results: We found that by CD8 T-cells in tumors often lost co-stimulatory molecules. Furthermore, albumin and Hgb both had a strong positive correlation with CD28 expression and overall co-stim score, while WBC, Plt, neutrophil-lymphocyte ratio (NLR), ESR, and CRP was negatively correlated. Expression of co-stimulatory receptors did not differ significantly between primary tumor and metastatic tumor pairs suggesting that a systemic effect controlled TIL phenotype rather than site specific factors. Conclusions: Our data show that BIMs have the potential to predict the immunologic phenotypes of cytotoxic TILs in RCC noninvasively.
Transcriptional profiling of Tu212 cell line treated with EGCG and resveratrol to identify actionable targets for adjuvant therapy.
Authors: Dong Moon Shin, Bhakti Dwivedi, Ruhul A R M Amin, Abedul Md Haque, Nabil F. Saba, Michael R. Rossi, Zhuo Georgia Chen, Jeanne Kowalski
Journal: Journal of Clinical Oncology (2014)

e17057 Background: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) is an incurable disease with poor outcome. The use of natural compounds may avoid or delay the recurrence of this disease. We have demonstrated a synergistic/additive anti-tumor effect of two natural compounds, Epigallo-catechin-gallate (EGCG) and Resveratrol in SCCHN. We hypothesize that the synergistic anti-tumor effects of EGCG and resveratrol combination may be regulated by actionable targets identified by differential expression, coding mutations and fusion transcripts. Methods: We performed transcriptional profiling using RNAseq data on a head and neck cell line, Tu212, treated with EGCG, Resveratrol, and the combination. Differential expression of genes was analyzed using BWA alignment and Cufflinks. PANTHER was utilized for the analysis of enriched GO processes and KEGG pathways in the set of differentially expressed genes. The expressed coding variants were identified in the tumor cells using SAMtools and VarScan. Results: The combination of EGCG and Resveratrol induced expression of pro-apoptotic genes: BIM, BAD and TP53, and down-regulated expression of anti-apoptotic BCL2 relative to a control gene, SMG5, known to be stably expressed across 186 different tissues. Amongst the most significantly differentially expressed genes were the ATF3, HEY1, FGF22, GDF15, which are known to affect apoptosis, Notch, FGF, and TGF-β signaling pathways. Expression of the genes, ATF3 and FGF22 showed additive effects of the combination compared to the individual agents. Our RNAseq data was able to validate the confirmed TP53 mutation (P151S) in the Tu212 cell line. Conclusions: These results confirm our previous findings of pathway involvement that distinctly characterizes the combination of EGCG and Resveratrol, and further, that this combination could prove beneficial as a non-toxic adjuvant therapy. We will confirm these gene expression profiles in other SCCHN cell lines with qPCR and Western blot. Additional analyses to examine fusion transcripts, coding mutations, and splice variants as events driving SCCHN that could potentially affect response to therapy are underway.
Comprehensive genomic profiling identifies clinically relevant genomic alterations in relapsed and metastatic penile squamous cell carcinoma.
Authors: Norma Alonzo Palma, Siraj Mahamed Ali, Eric M. Sanford, Julia Andrea Elvin, Mark Bailey, Garrett Michael Frampton, Roman Yelensky, Jie He, Doron Lipson, Edward Dow, Deborah Morosini, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller
Journal: Journal of Clinical Oncology (2015)

e15628 Background: Penile squamous cell carcinoma (PSCC) is difficult to manage due to the physiological and psychological implications of local treatment with surgery and radiation but minimal evidence is available to guide systemic therapy. We performed comprehensive genomic profiling (CGP) on 20 patients with relapsed/metastatic PSCC in the course of clinical care to identify clinically relevant genomic alterations (CRGA). Methods: DNA was extracted from 40 microns of FFPE sections of advanced PSCC cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 692X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 20 male patients with a mean age of 60 years (range 46-87). Three cases (15%) were grade III and 17 (85%) were grade IV. CGP revealed 109 GA (5.45 per tumor), 44 of which were CRGA (2.2 per tumor). TP53 was mutated in 13 (65%) of cases and was the most common GA. At least one CRGA was detected in 19 (95%) cases and the most common CRGA were CDKN2A (40%), NOTCH1 (25%), PIK3CA (25%), and CCND1 (20%). HPV-16 was detected in 2 cases, HPV-6 in 1 case and HPV18 was not detected in any cases. Of the three HPV+ cases, only the HPV6+ case harbored TP53 alterations. Conclusions: The low frequency of HPV 16/18 positivity was unexpected in this PSCC series given the high frequency of HPV 16/18 positivity in cervical squamous cell carcinoma (66%) and anal squamous cell carcinoma (87%) as identified by CGP on the same platform. The low frequency of HPV positivity precluded definitively identifying mutual exclusivity of HPV positivity and TP53 alterations as observed in oral pharyngeal squamous cell carcinoma however, these data suggest that penile SCC may be evolving via HPV non-16/non-18 infection and these cases may harbor TP53 alterations. CGP identified CRGA that may lead to routes of benefit from targeted therapy for these patients.
Regional differences in the treatment approaches for relapsed multiple myeloma: An IMF study.
Authors: Brian G. Durie, Philippe Moreau, Pieter Sonneveld, Gareth J Morgan, Juan José Lahuerta, Meral Beksac, Evangelos Terpos, Roman Hajek, Vânia Tietsche de Moraes Hungria, Angelo Maiolino, WeeJoo Chng, Jae Hoon Lee, Hou Jian, Paul Gerard Guy Richardson, Wenming Chen, Stefan Knop, Antje Hoerring, Xavier Leleu, Jesùs F. San-Miguel, Shaji Kumar
Journal: Journal of Clinical Oncology (2012)

8095 Background: Multiple myeloma (MM) remains incurable and invariably relapses after initial therapy. There is no uniform approach to management of relapsed MM and is dictated by type of initial therapy and the response seen, and availability of new drugs. The outcomes associated with current approaches have not been systematically examined. Methods: We enrolled 383 patients (pts) with myeloma who had a documented relapse between Jan 2007 and June 2010, including 220 from Europe, 106 from Asia, and 31 from South America and 26 from North America. Time Zero (T 0 ) was defined as date of treatment after first relapse. Results: Across the study, 61% were male and 49% were over 65 years at T 0 . ISS stage distribution at diagnosis included 26, 40 and 33% of patients in stages 1, 2 and 3, respectively. Among regimens used at first relapse; bortezomib (Btz) containing regimens were most common (54%), followed by lenalidomide (Len, 25%) and cyclophosphamide (21%). The overall response rate (&gt;=PR) to first therapy after relapse was 58% including 14% with a CR. There was a progressive decrease in the response rates with successive regimen; 45%, 30% and 15% for regimens 2, 3 and 4 respectively. Len use was considerably lower in the Asian cohort, while Btz use was comparable across the regions. The median PFS from T 0 was 13 mos and OS was 35 mos, for the entire cohort. The PFS to first salvage regimen was similar across the regions, while OS was shorter for the Asian and South American cohorts. In a univariate analysis, ISS stage 3, presence of cytogenetic abnormalities, history of plasma cell leukemia or extramedullary disease (EMD), bone marrow PC% &gt; 33% and presence of renal insufficiency were all associated with a shorter PFS as well as shorter OS (P&lt;=0.01). In a multivariate model, ISS stage 3 and presence of EMD were most associated with short OS. Conclusions: Median PFS for current second line regimens, typically containing Btz or Len appear to be 1 yr with an OS from first relapse of about 3 yrs. The OS from first relapse is nearly double that seen in a cohort of patients in first relapse prior to introduction of new drugs. Clear-cut regional differences can be seen in terms of patterns of drug use and likely reflect drug availability and healthcare costs.
Gemcitabine based chemotherapy in recurrent or advanced pediatric solid tumors: A phase II study
Authors: A. Olaya Vargas, A. Castellanos Toledo, R. Rivera Luna, R. Cardenas Cardos, A. Rivera Ramirez, R. Gonzalez Perez, G. Escamilla Asiain
Journal: Journal of Clinical Oncology (2004)

8574 Background: Although rare, cancer is the leading cause of death in children younger than 15 years around the world. Advances have been made in treating these patients over the last three decades by apropiate therapy. This dramatic improvement in outcome has led to the estimation that in the year 2000, one in every 1,000 young adults between the ages 20 and 29 years would have been a survivor of childhood cancer; and this due to the chemotherapy. Methods: There were 11 children: 7 male and 4 female. The inclusion period was since january 2003 until the last patient entried in september 2003. Patients had recurrent or refractory solid tumor; TREATMENT: Gemcitabine alone 800 mg/m2 days 1 and 8 or in combination with cisplatin at 80 mg/m2 day 1. Results: The median age was 7.7 years (2–17) The histopathology was 2 pts with Ewing sarcoma, 2 pts germ cell tumors, 1 pt Wilms tumor, 2 pt rhabdomiosarcoma, 1 pt rethnoblastoma, 1 pt ostheosacoma and 1 pt hepatoblastoma. All patients were previous treated with chemotherapy: 5 pts received VAC (vincristine, adryamicin and cyclophospamide); 3 received ICE (Ifosfamide, cyclophospamide and epirubicin); and 3 pts received: VeIP, VAI and ethoposide- carboplatin. Nine pts received gemcitabine alone and 2 pts received gemcitabine plus cisplatin. There were 1 Partial Response (PR), 3 patients with Stable disease (SD) and 3 with progresión disease (PD).0verall Survival (OS) by Kaplan Meier curves was 66.7% at 6 mo. The current status is: 5 patients alive with tumoral activity and 2 dead patients with tumoral activity. There were 24 courses of chemotherapy. Anemia G3,4 was presented in 2 pt (8.3%); Leucopenia G3,4: 2 pt (8.7%); Neutropenia G3,4: 2 pt (8.3%); thrombocytopenia G3,4 in 3 pt (12.5%). Conclusión: Gemcitabine alone or in combination with cisplatin demostrated some efficacy in patients heavly previous treated with good tolerance, it could be an option for rescue treatment. No significant financial relationships to disclose.
Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database.
Authors: Jonathan R. Strosberg, Sarah Bobiak, Carrie C. Zornosa, Michael A. Choti, Emily K. Bergsland, Al Bowen Benson, Mark Bloomston, Matthew Kulke, Manisha H. Shah, James C. Yao
Journal: Journal of Clinical Oncology (2013)

4142 Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n=40), colorectal (n=4), and unknown (n=34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n=5, 33%), 30mg every 2 weeks (n=4, 27%), and 60 mg every 4 weeks (n=4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.
Efficacy and tolerability of intrathecal liposomal cytarabine for central nervous system embryonal tumors
Authors: S. Partap, P. A. Murphy, H. Vogel, P. D. Barnes, M. S. Edwards, P. G. Fisher
Journal: Journal of Clinical Oncology (2009)

2064 Background: Liposomal cytarabine (DepoCyt) is a sustained-release intrathecal (IT) preparation of cytarabine, formulated by encapsulating the drug in spherical aqueous chambers within a lipid matrix. While proven effective in lymphomatous meningitis, this drug has shown some activity in medulloblastoma (MB) with spinal metastases in limited pediatric phase I study. Methods: We reviewed all patients at our institution treated with liposomal cytarabine for primary central nervous system (CNS) embryonal tumors-MB, primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Results: A cohort of 17 patients were treated with liposomal cytarabine at diagnosis of CNS embryonal tumor (2 PNET, 3 ATRT) or relapse (12 MB [7 average-risk, 5 high-risk]); nine had leptomeningeal metastases. Drug was dosed at 2 mg/kg up to 50, every 2 weeks to monthly, along with dexamethasone. Concurrent systemic chemotherapy was given in 16 patients. Median age at first dose was 10.8 years (range 0.9 to 27.9 years). A total of 102 doses were administered (lumbar IT 76, Ommaya intraventricular 36) with a mean of six treatments (range 1–16). Only three administrations were associated with adverse effects of arachnoiditis or headache; no dose reductions were required. Median overall survival from relapse was 11.8 months. All six evaluable patients with malignant cerebrospinal fluid (CSF) cytology and treated with at least two doses cleared their spinal fluid (mean 3 doses, range 1–5). No patient developed malignant CSF cytology while receiving liposomal cytarabine. Ten patients developed progressive disease and died, with only one later recurrence in the spinal fluid. Seven patients remain alive (4 initial and 3 relapse) with five in continuous complete remission (2 ATRT) for a median 13.7 months from first liposomal cytarabine. Conclusions: Liposomal cytarabine was well tolerated and easily administered. All patients with neoplastic meningitis cleared malignant cells from their spinal fluid after treatment with IT liposomal cytarabine and systemic chemotherapy. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of liposomal cytarabine in newly diagnosed or recurrent CNS embryonal tumors. [Table: see text]
How to reflect tumor response after preoperative chemoradiotherapy in rectal cancer? A proposal for application of tumor regression grade as an alternative to current TNM staging system.
Authors: Im-kyung Kim, Jeonghyun Kang, Seung-Kook Sohn, Kang Young Lee
Journal: Journal of Clinical Oncology (2014)

e14564 Background: In current tumor, node, and metastasis (TNM) staging system for rectal cancer, pathologic tumor response after preoperative chemoradiotherapy is not reflected without practical influence on further treatment strategy. This study was designed to assess prognostic value of tumor regression grade and applicability as an alternative to current staging system. Methods: From 2000 to 2011, the patients with preoperative chemoradiotherapy followed by total mesorectal excision were identified and their medical records were reviewed. Among them, the patients able to be assessed by Mandard tumor regression grade were selected and classified into three groups: Grade 1(TRG1, complete response without residual tumor), Grade 2(TRG2, presence of residual tumor cells scattered through fiborosis), and Grade 3(TRG3 to TRG5, from increased residual tumor cells to no regression). Overall recurrence rates and five-year disease-free survival (DFS) were compared according to tumor regression grade by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression model. Results: In all, 492 patients were classified into three groups: Grade 1(n=96, 19.5%), Grade 2 (n=122, 24.8%) and Grade 3 (n=274, 55.7%). Tumor regression grade was associated with overall recurrence rates (Grade 1 vs 2 vs 3 = 1.4% vs 4.9% vs 16.1%, p<0.001) and five-year DFS (91.4% vs 77.6% vs 67.1%, p<0.001). By subgroup analysis according to nodal status, five-year DFS was 90.0% vs 80.5% vs 78.7% (p=0.085) in node-negative group and 100% vs 61.1% vs 49.7% (p=0.208) in node-positive group without statistical significance. Conclusions: Tumor regression grade can be suggested to guide further treatment strategy as an alternative to current staging system in patients with rectal cancer after preoperative chemoradiotherapy.