tbuckley/cabot-search huggingface dataset:
Intraductal papillary neoplasm of the bile duct (IPNB): A biliary equivalent to IPMN of the pancreas?
Authors: F. G. Rocha, H. Lee, N. Katabi, R. P. DeMatteo, Y. Fong, M. I. D'Angelica, P. J. Allen, D. S. Klimstra, W. R. Jarnagin
Journal: Journal of Clinical Oncology (2011)

201 Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of cholangiocarcinoma characterized by intraductal growth, mucin production and a better outcome compared to the more common nodular-sclerosing type. IPNB may be analogous to IPMN of the pancreas and may be a precursor of invasive cholangiocarcinoma, but its pathogenesis and natural history are ill-defined. This study examines the incidence, clinicopathologic features and outcome of IPNB in a single center. Methods: A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic or distal) was reviewed and those with papillary features identified. Histopathologic morphology and immunohistochemical staining for cytokeratin and mucin proteins were utilized to classify IPNB into subtypes. Survival data were analyzed and correlated with clinicopathological parameters. Results: Between 1993 and 2008, 40 IPNBs were identified in hilar (24/144), intrahepatic (4/86) and distal (12/113) bile duct cancer specimens (11.7%). Histopathologic examination revealed 27 pancreatobiliary, 4 gastric, 3 intestinal, and 6 oncocytic subtypes; cytokeratin and mucin staining was similar to that of IPMNs of the pancreas. Invasive carcinoma was seen in 29/40 (72%) IPNBs. Overall median survival was 59 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included depth of invasion (39 months for &gt; 5mm, 128 months for &lt; 5mm, and 144 months for none, p &lt;0.05), R1 vs R0 resection (36 months vs 82 months, p &lt;0.05), MUC1 expression (53 months for positive vs 144 months for negative, p &lt;0.006), and CEA expression (42 months for positive vs 128 for negative, p&lt;0.02). Expression of MUC2, MUC5A, MUC6, CDX2, mesothelin, p53, Ki67, HepPar1, and B72.3 were not predictive of outcome. Conclusions: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all cases, occur throughout the biliary tract and share histologic and clinical features with IPMNs of the pancreas. These lesions may represent an alternative carcinogenesis pathway. Given their significant malignant potential, they should be treated aggressively with margin-negative resection. No significant financial relationships to disclose.
Circulating tumor cell (CTC) counts and CTC telomerase activity (TA) as prognotic markers of overall survival (OS) in SWOG S0421: Docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Amir Goldkorn, Nicholas J. Vogelzang, Louis M. Fink, Benjamin Ely, David I. Quinn, Catherine M. Tangen, Yu-Chong Tai, Przemyslaw Twardowski, Peter J. Van Veldhuizen, Neeraj Agarwal, Michael Anthony Carducci, J. P. Monk, Mark Garzotto, Philip C. Mack, Primo Lara, Celestia S. Higano, Maha Hussain, Richard J. Cote, Ian Murchie Thompson
Journal: Journal of Clinical Oncology (2012)

1 Background: CTCs are promising biomarkers in mCRPC, and telomerase activity (TA) is a recognized cancer marker. In this phase III trial we analyzed CTCs using 2 methods: CellSearch for fixed cell enumeration, and a novel Parylene-C slot filter for live CTC capture and TA measurement. Methods: Blood samples (7.5 ml) were drawn at baseline (d1) and pre-cycle 2 (d21) of Rx and shipped overnight for central processing. For CellSearch enumeration, Cox regression was used to evaluate the association between OS, baseline CTC counts, and CTC dynamics (d1 to d21). For TA, filter-trapped cells were lysed and assayed for TA using qPCR-based telomeric repeat amplification. Cox regression evaluated the association between OS and TA overall and within subgroups characterized by good vs. poor (&lt;5 vs. &gt;=5) prognosis baseline CTC counts. For all measurements, receiver operator characteristic (ROC) analysis and characteristics and regression trees (CART) were used to explore further prognostic cutpoints. Results: Samples were obtained from 263 men. Median d1 CTC count was 5, and there was a significant difference in OS for d1 CTC &lt; vs. &gt;=5, hazard ratio (HR) 2.92 (p&lt;0.001) after adjustment for other factors. D1 CTC and OS had ROC AUC of 0.781. In men with low d1 CTC (&lt; 5), an increase in CTC was associated with shorter OS, HR 4.04 (p=0.004); in men with high d1 CTC (&gt;=5), a &gt;=2-fold decrease in CTC was associated with longer OS, HR 0.45 (p=0.012); adjusting for risk factors. For TA, men with baseline CTC &gt;=5 (41% of cohort) who had high CTC TA had HR 1.14 (p&lt;0.005) for OS after adjustment for other factors including CTC counts. CART identified additional risk subgroups based on CTC counts and TA. Conclusions: In this phase III trial, d1 CTC and d1 to d21 CTC dynamics were prognostic of OS after risk factor adjustment, comprising the largest docetaxel-based prospective cohort to date which validates a 5 CTC prognostic threshold and identifies new potentially useful enumeration subgroups. In men with CTCs &gt;=5, TA from cells live-captured on a new slot filter constitutes the first CTC-derived biomarker prognostic of OS in a prospective clinical trial.
Preliminary results of a phase I trial with dose escalated lenalidomide (L) in separate cohorts of relapsed acute leukemia (AL) or chronic lymphocytic leukemia (CLL): evidence of activity in acute myeloid leukemia (AML) and toxicity in CLL at starting dose
Authors: W. G. Blum, L. A. Andritsos, A. J. Johnson, R. B. Klisovic, C. Kefauver, S. M. Devine, G. Marcucci, J. C. Byrd
Journal: Journal of Clinical Oncology (2008)

7075 Background: L is active in myelodysplastic syndromes and myeloma and may also have activity in AL or CLL. Methods: A phase I dose escalation study of L in separate cohorts of relapsed AL or relapsed CLL, respectively, is ongoing. L was given initially at 25mg/day orally on days 1–21 of repeated 28 day cycles in both cohorts. Results: In AL, 12 patients (pts) have enrolled to date (11-AML) with a median age of 62 years (range, 22–79). 4 pts were treated at dose level 1 (25mg/day) and 8 at level 2 (35mg/day). One DLT was seen at level 2: an AML pt, age 79, died suddenly of uncertain cause (no pulmonary embolism), and the level was expanded. 3 pts had early progression and were replaced (pts were not evaluable for toxicity). Complete remission (CR) occurred in two pts. At level 1, a 74 year old with AML and normal karyotype in 2nd relapse, with widespread leukemia cutis but no blood/marrow involvement, had remarkable resolution of disease after 2 cycles and is in CR after 4 cycles. At level 2, a 69 year old with AML and trisomy 13 had CR (by IWG criteria, including cytogenetic CR) after 2 months. In the CLL cohort, 4 pts (ages 43–60 with 2–9 prior therapies) have enrolled. 3 pts were given the initial starting dose of 25mg/day. Each had early or late DLT including serious tumor flare in 2 cases, one with airway obstruction due to massive tonsillar adenopathy requiring emergent tonsillectomy. The tonsil had increased expression of Ki67, CD3, CD4, CD8, and granzyme B positive cells after L, relative to a pretreatment node. Due to excess toxicity with the 25mg initial dose, a 2.5mg/day dosing schedule with gradual intra-patient escalation was initiated. 1 pt has enrolled at this dose to date. Pharmacodynamic (PD) studies in CLL demonstrate L-induced B-cell activation (upregulation of CD40 and CD86) that may correlate with development of tumor flare. Conclusions: L induced CR in 2 cases of relapsed non-del 5q AML. Dose escalation continues in AL. In CLL, higher doses had unacceptable toxicity; low dose followed by gradual intra-patient dose escalation is being pursued. PD studies suggest B-cell activation may contribute to development of tumor flare in CLL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene
Metastatic colorectal cancer (MCC) and irinotecan (IRI), 5-flourouracil (5FU), leukovorin (LV) three day chemotherapy
Authors: V. Entezari, S. Z. Latifzadeh, S. Akhavanfard
Journal: Journal of Clinical Oncology (2005)

3729 Background: 5FU based regiments have become standard first line option for chemotherapy in MCC. IRI, is a topoisomerase I inhibitor and when is added to 5FU shows significant improvement in response rate and progression free survival of pts. Combination of IRI and Myoclinic regiment (bolus 5FU) has very high toxicity. For improving pts compliance and lowering toxicity profile this study aims to evaluate administration of IRI and Three day bolus IV infusion of 5FU in pts with MCC. Method: twenty four pts were enrolled in a prospective study from 1999 to 2004. Eligibility criteria were: ECOG performance status I-II, pathologically proven MCC and adequate hematologic, hepatic and renal function. Pts received IRI: 175 mg/m2 IV d 1, 5FU: 425 mg/m2 bolus IV infusion d 1–3 and LV: 20 mg/m2 IV d 1–3. The regiments were repeated every 3 weeks. Toxicity was evaluated by National Cancer Institute - Common Toxicity Criteria (NCI-CTC). The primary endpoint was time to progression (TTP) and the main secondary endpoint was overall survival (OS). Results: a total 135 cycles were given and 21 pts were available for response analysis; median age was 54 years (40 - 82 years), Male/Female sex ratio was 16/8 and site of tumor was rectum (50%) and colon (50%). The liver was the most common site of metastasis (33.3%) and 16.7% of pts had more than one site of metastasis. fifteen pts (62.5%) was chemotherapy-nive. There were 2 (9.5%) pts with compete response (CR), 12 (57%) pts with partial response (PR) and 3 (14%) stable and 4 (19%) progressive disease. Overall responses rate (CR+PR) was 67%. Fourteen disease progressions occurred and the median TTP was 4.2 moths and median OS was 11.8 months. The most common grade III-IV toxicities per cycle were: diarrhea, neutropenia and vomiting. No episodes of neuro-sensory and hepatic grade IV toxicity were reported. Conclusion: this regiment can be more convenient for patients who are not able to carry indwelling catheters and receiving chemotherapy in the outpatient setting. Also this regiment has favorable response rate and toxicity profile comparing with other popular regiments like FOLFIRI. No significant financial relationships to disclose.
Cardio-oncology interventions in outpatients referred for autologous bone marrow transplantation.
Authors: Edith Pituskin, Nanette Cox-Kennett, Harald Becher, Irwindeep Sandhu, Chris Venner, Ian Paterson
Journal: Journal of Clinical Oncology (2016)

137 Background: Cancer patients (PTS) referred for autologous bone marrow transplantation (autoBMT) are frequently pre-treated with established cardiotoxins and as a result may not have adequate cardiac function to meet eligibility criteria for autoBMT. Furthermore, mobilizing and consolidation chemotherapy result in additional serial exposures with acute and long-term negative cardiac sequelae. Accordingly, these PTS represent a population with a major unmet need for appropriate cardiovascular screening and interventions. Aim: to evaluate the need and effectiveness of prospective multidisciplinary cardio-oncology assessment and intervention in an unselected outpatient population referred for autoBMT. Methods: From January 1, 2013 – December 31, 2013, PTS referred for autoBMT were systematically screened for comorbid conditions, cardiovascular risk factors and eligibility for transplant. Physical exam, laboratory (ECG, complete profile) and transthoracic echocardiogram with contrast were performed. Those with EF &lt; 50%, increased IVsd/LVpWd, ECG abnormalities +/- significant cardiac history underwent proBNP and high sensitivity troponin testing. PTS with abnormal findings or decreased left ventricular (LV) function were referred to the Edmonton Cardio-Oncology REsearch (ENCORE) program. Results: 73 unique PTS were screened by the Edmonton autoBMT program. Of these, 16 (20%) were reviewed by ENCORE. Reasons for referral included: decreased LV function (n = 6, 38%); increased IVsd (n = 5, 31%); arrhythmia (n = 4, 25%); angina (n = 1, 5%). Pharmacotherapy was initiated for 6 PTS; additional modality or serial cardiac imaging for 12 PTS; urgent stent for 1 PT. 100% proceeded to autoBMT without adverse cardiovascular outcomes or mortality. Conclusions: With systematic screening, a high proportion of PTS referred for autoBMT required cardio-oncology assessment and interventions, with 100% proceeding safely as a result. ENCORE represents a novel approach in the provision of cardio-oncology expertise for autoBMT PTS acutely during the mobilizing and transplantation period. Future examination of our prospective dataset will elucidate the longer term effects of our interventions.
Using exon-capture, deep sequencing of high-grade bladder urothelial carcinoma to identify recurrent genetic alterations and potential therapeutic targets.
Authors: Philip H. Kim, John P. Sfakianos, Sasinya N. Scott, Gopa Iyer, Eugene K. Cha, Hikmat Al-Ahmadie, Arony J. Sun, Ilana Rebecca Garcia-Grossman, Richard Martin Bambury, Guido Dalbagni, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, David B. Solit, Bernard H. Bochner
Journal: Journal of Clinical Oncology (2014)

308 Background: Urothelial carcinoma (UC) is highly lethal malignancy with limited therapeutic options in the advanced setting. Using a targeted, deep sequencing approach, we analyzed high grade bladder tumors to determine the prevalence of known cancer genes and to identify potential targets for therapy. Methods: High-grade bladder UC frozen tumor and matched germline blood was obtained from 109 patients (pts) undergoing transurethral resection or cystectomy. Tumor and normal DNA were analyzed using IMPACT (Integrated Molecular Profiling of Actionable Cancer Targets), a next generation, exon-capture targeted deep sequencing assay designed to identify point mutations, indels, and copy number alterations in the coding regions of 300 cancer-associated genes. Results: Median age was 68 and 82 pts (75%) were male. Mean target coverage for all sequenced exons was 579X. The most commonly mutated gene was TP53 (63 pts, 58%). Alterations in genes regulating cell cycle were also prevalent, including mutations in Rb (25 pts, 23%), and copy number gains of CCND1 (19 pts, 17%) and CCNE1 (8 patients, 7%). Mutations in several chromatin remodeling genes were also highly prevalent, including KDM6A (46 pts, 42%), MLL2 (34 pts, 31%), and ARID1A (31 pts, 28%). Alterations within recognized cancer-related signaling pathways were common. PI3K pathway alterations were prevalent, with PIK3CA mutations found in 25 pts (23%), 23 of which were recurrent missense mutations. Six pts (6%) had mutations in PTEN. Mutations in TSC1 were also found in six pts (6%). Alterations in select MAPK pathway genes were common, including FGFR3 (21 pts, 19%) and ERBB2(15 pts, 14%). Conclusions: High-grade bladder UC is a genetically heterogenous disease. However, over half of the tumors analyzed in this study harbor alterations in genes that have been targeted for therapeutic benefit in other cancers. Results from our targeted exon-sequencing analysis therefore provide a compelling case for clinical trials using novel agents in UC. Moreover, this deep sequencing assay may be used clinically to prospectively identify pts for trials enriched for patients with specific alterations.
Who dies in the ICU? A qualitative analysis of cancer deaths.
Authors: Caitlin C. Donohue, Belen Fraile, Yichen Zhang, Sherri Oliver Stuver, Carole Kathleen Dalby, Joseph O. Jacobson
Journal: Journal of Clinical Oncology (2014)

118 Background: Providing safe and nurturing end-of-life (EOL) care to cancer patients is a challenge in any setting, but particularly so in the intensive care unit (ICU). In a unique collaboration between a comprehensive cancer center and a payer, we sought to identify cancer patients who died in the ICU and conducted a chart review-based qualitative analysis to better understand their location of death. Methods: We completed an exploratory, qualitative analysis based on a cohort of 264 active Dana-Farber Cancer Institute (DFCI) patients who died during 2012 and had claims data from Blue Cross Blue Shield of Massachusetts. Of the 160 patients admitted to the hospital in the last 30 days of life, 28 (17.5%) expired in an ICU. For the 22 patients who died in the ICU of a DFCI-associated hospital, vignettes were created from a chart abstraction. Using an inductive qualitative analysis approach, we explored each vignette using rounds of open, axial, and selective coding and identified common themes that described the patients’ ICU death incidents. Results: For the 22 cases, the most salient themes are reflected in the Table below. Conclusions: Using a qualitative research approach, we identified relevant factors to help understand why cancer patients die in the ICU. Most families requested aggressive therapy and, even though goals of care may have been modified, patients remained in the ICU. In addition, a substantial proportion of patients were transferred from a community hospital to an academic, tertiary hospital presumably to receive more aggressive treatment. In the future, the relationships among the themes identified from this research should be tested by a quantitative approach. [Table: see text]
Precision cancer therapy through nanoparticle delivery of siRNA against KRAS.
Authors: Matthew S. Strand, Hua Pan, Julie G. Grossman, Peter S. Goedegebuure, Timothy Fleming, Samuel A. Wickline, Ryan C. Fields
Journal: Journal of Clinical Oncology (2016)

260 Background: Small interfering RNA (siRNA) has potential for highly specific gene manipulation, making it attractive for delivering precision therapy to cancer patients. However, efforts to employ siRNA therapeutically have been limited by its short half-life in circulation, low target tissue specificity, and cellular entrapment within endosomes. We utilized serum-stable, cell-penetrating, and endosomolytic peptide-based nanoparticles (NPs) to overcome these obstacles and deliver siRNA against KRAS to KRAS-mutant human and mouse pancreas and colorectal cancers. Methods: Human and mouse pancreas and colorectal cancer cell lines were tested for NP uptake in vitro utilizing fluorescent siRNAs. Uptake was assessed via fluorescent microscopy and flow cytometry (FC). Mice bearing tumors from these cells were injected IV with the same NP, and uptake was assessed with an in vivo imaging system (IVIS), and FC. Cell lines were treated with KRAS-siRNA NP and KRAS knockdown was assessed by real-time PCR. Results: Mouse and human pancreas and colorectal cancer cell lines took up NP in vitro, with signal detected within &gt; 93% of cells at 24 hours. Tumors from these cells grown in mice were strongly fluorescent after IV injection of fluorescent NP within 2 hours, and until at least 30 hours. FC of a tumor treated with fluorescent NP showed that 86% of tumor cells expressed fluorescent signal 24 hours post-injection. IVIS revealed signal in mouse liver and kidneys, but when assessed by FC, only 17.8% and 13.5% of cells from these tissues were fluorescent, respectively. The brain, heart, lungs, spleen, and pancreas of mice receiving injections were negative. Cancer cell lines exposed to KRAS-siRNA NP for 48 hours express KRAS at levels that are 4.5 to 15.1% of untreated cells. Conclusions: Human and mouse pancreas and colorectal cancers efficiently and specifically take up NP in vitro and in vivo. Selected limitations of siRNA are overcome with this NP delivery system, and NP-packaged siRNA effectively inhibits KRAS. This platform represents a highly specific approach to targeting tumor genes of interest, which may ultimately enable selective knockdown of putative drivers of tumor progression.
Cell-free microRNA expression profiles in malignant effusion associated with patient survival in non-small cell lung cancer.
Authors: Tingting Wang, Baorui Liu, Yayi Hou
Journal: Journal of Clinical Oncology (2012)

13 Background: MicroRNAs (miRNAs) expression is altered in cancer cells, and miRNAs could serve as diagnostic and prognostic biomarker for cancer patients. This study was designed to analyze circulating miRNAs expression in the malignant pleural effusion (MPE) and their association with patient survival in non-small cell lung cancer (NSCLC). Methods: Pleural effusion from 184 patients with NSCLC and MPE were collected. MiRNA microarray and bioinformatics interpretation were used to evaluate miRNA expression profiles in 10 NSCLC patients with different survival prognosis. Associations were validated in 184 patients (randomly classified into training and validation set with equal number in each group) using quantitative RT-PCR. Risk scores were formulated based on the expression signature of miRNAs. Clinical data, such as patient survival, were collected for correlation analysis. Results: Thirty-three miRNAs were found to be altered more than two-fold by microarray in malignant effusions between longer-survival and shorter-survival groups, and levels of five miRNAs (miRNA-93, miRNA-100, miRNA-134, miRNA-151, and miRNA-345) were significantly associated with overall survival. High expression of miR-100 and low expression of miRNA-93, miRNA-134, miRNA-151, and miRNA-345 were associated with poor survival in both the training and validation cohort. Patients with high risk scores had overall poor survival compared to the patients with low risk scores. Risk score was an independent predictor of patient survival. Conclusions: Expression patterns of miRNAs are systematically altered in MPE of patient with NSCLC. The five miRNA signature from the effusion may serve as a predictor for the overall survival of patients with lung cancers.
IKZF1 Regulates BRD4 Retention and Recruitement at Enhancer in Myeloma Cells: Role of BRD4 in IMiDs Resistance
Authors: Paola Neri, Ines Tagoug, Ranjan Maity, Jacquelyn Babich, Lindsay Lockwood, Jonathan J Keats, Larry H Boise, Leif Bergsagel, Nizar J. Bahlis
Journal: Blood (2016)