tbuckley/cabot-search huggingface dataset:
Phase IB study on combined intradermal (ID) and intravenous (IV) administration of autologous mRNA electroporated dendritic cells (DC) as a single-agent cellular immunotherapy or combined with ipilimumab.
Authors: Bart Neyns, Sofie Wilgenhof, An M. T. Van Nuffel, Daphné Benteyn, Jurgen Corthals, Carlo Heirman, Cindy Aerts, Ivan Van Riet, Aude Bonehill, Kris Thielemans
Journal: Journal of Clinical Oncology (2012)

2507 Background: Autologous monocyte-derived DC electroporated with synthetic mRNA encoding CD40 ligand, a constitutively active TLR4, and CD70 (TriMix-DC) have superior T-cell stimulatory capacity. In a pilot clinical trial, ID administration of TriMixDC-MEL (a mixture of TriMix-DC co-electroporated with mRNA encoding a fusion of DC.LAMP and 1 of 4 melanoma associated antigens) was immunogenic but resulted in limited anti-tumor activity in patients (pts) with advanced melanoma. Ipilimumab (IPI) is a CTLA-4 blocking mAb with established activity in pts with advanced melanoma. Methods: TriMixDC-MEL by the IV and ID-route was investigated as a single-agent or in combination with IPI (10 mg/kg q3wks x4, allowing for maintenance with IPI-alone q12wks in pts PFS at &gt;24 wks). Ratio of ID/IV administered DC: Cohort-1: 20.10 6 /4.10 6 DC [2pts], -2: 12.10 6 /12.10 6 DC [3pts], -3: 4.10 6 /20.10 6 [6pts], and -4: 0/24.10 6 DC [4pts]; DC were administered 4x q2w, and a 5 th administration on w16. in cohort-5, DC (4.10 6 -ID/20.10 6 -IV) were first administered alone and 2w thereafter in combination with IPI for a total of 4 administrations [6pts]. Results: Local skin reactions (gr1-2) were observed in all pts receiving DC ID, flu-like symptoms (&lt; gr2) were observed in 12/21 pts, post IV-infusion chills (gr2) in 7/21 pts. Cytokines release (including a &gt;2-fold rise in the serum levels of IL-1RA, IL-6, IL-8, IL-17, G-CSF, IFN-g, MIP-1a, MIP-1b, TNF-a) was documented during chills. Best objective tumor response: 2x PR + 2x CR (by RECIST) out of 15 pts (27%) treated with DC-only (ongoing after 10+, 14+, 19+, and 20+ mths) and 3 PR out of 6 pts (all stage IV-M1c) treated with DC+IPI (ongoing after 5+, 5+, 6+ mths). Conclusions: ID/IV-administration of TriMixDC-MEL as a single-agent cellular immunotherapy or combined with IPI is associated with distinct but manageable side-effects and has clinical activity against pretreated advanced melanoma. Activity compares favorably with TriMixDC-MEL by ID-administration-only. Combined ID/IV administration of TriMixDC-MEL with IPI is currently under further evaluation in a phase II trial.
Effect of tumor subtype on overall survival in brain metastatic breast cancer patients treated with cranial irradiation.
Authors: Vipin Das Villgran, Aju Mathew, Margaret Quinn Rosenzweig, Shira Abberbock, Rohan Dilipbhai Naik, Mini Jacob, Rachel Catherine Jankowitz, Shannon Puhalla, Barry C. Lembersky, Adam Brufsky
Journal: Journal of Clinical Oncology (2014)

74 Background: Brain metastatic breast cancer (BMBC) is often treated with whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) or both. Breast cancer tumor subtypes defined by hormone receptor (HR) and HER2 status have an important prognostic role in metastatic disease. It is unclear if tumor subtypes have a prognostic role in patients receiving WBRT or SRS. We aimed to investigate the association between breast cancer subtype and overall survival (OS) among BMBC patients treated with WBRT and SRS. Methods: In a single-institution cohort study, BMBC patients treated with WBRT/SRS during 1997-2013 were identified. Clinico-pathological characteristics and survival information were prospectively collected. Tumor subtype category were defined as HR+/HER2-, HER2+/HR+, HER2+/HR- and triple negative (TN). WBRT category patients received that modality and SRS category patients, only SRS for treatment of brain metastases. OS is defined as time from diagnosis of brain metastasis to death or last follow-up. We conducted univariate analyses using the Kaplan-Meier method and log-rank tests and multivariate analysis using Cox proportional hazards models. Results: Among 193 BMBC patients who received WBRT or SRS, 62 received just SRS, and among them, 45% was HR+/HER2-. The distribution of subtypes was similar in WBRT patients. The median OS in SRS group was 15 months (95% CI 11-18) compared to WBRT with 10 months (95% CI 7-14) (p=0.03). Among patients receiving WBRT, median OS in HER2+/HR- tumor was 30 months (95% CI 13-37), HER2+/HR+ tumor - 14 months (95% CI 5-24), HER2-/HR+ tumor - 8 months (95% CI 4-11) and TN - 5 months (95% CI 3-9) (P=0.0003). There was no significant difference in OS between the breast cancer subtypes among SRS patients: median OS among patients with HER2+/HR- tumor was 11 months (95% CI 5–27), HER2+/HR+ tumor - 25 months (95% CI 7-32), HER2-/HR+ tumor - 18 months (95% CI 14-32), and TN - 12 months (95% CI 3-24) (p=0.07). Conclusions: Among patients with BMBC,tumor subtype is a prognostic factor for survival in those who received WBRT. Tumor subtype provided no prognostic information for those who were treated with only SRS.
Vorinostat provides prolonged safety and clinical benefit to patients with advanced cutaneous t-cell lymphoma (CTCL)
Authors: E. A. Olsen, M. Duvic, D. Breneman, T. R. Pacheco, S. Parker, E. C. Vonderheid, J. L. Ricker, S. Rizvi, K. Boileau, L. J. Geskin
Journal: Journal of Clinical Oncology (2008)

14588 Background: Vorinostat, a histone deacetylase inhibitor, was approved in 2006 by the FDA for the treatment of the cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or following 2 prior systemic therapies. Methods: Patients with stage ≥IIB CTCL who had received ≥two prior therapies and recovered from all prior treatment-related toxicities were eligible for an open-label, Phase IIb trial of oral vorinostat 400 mg daily. Patients took study medication until intolerable toxicity or progressive disease (PD). The primary endpoint was objective response rate as measured by the severity weighted assessment tool. Time to response, duration of response, safety and tolerability were also evaluated. This post hoc subset analysis reports results from patients who received vorinostat therapy for ≥2 years as of 11/1/07. Results: Six of 74 patients in the original study had received vorinostat therapy for ≥2 years as of 11/1/07, including five responders (one complete response, four partial responders) and one with stable disease. The median age was 65 years (range, 57–74), the median number of prior therapies was 2.5 (range, 1–5), and the median time from CTCL diagnosis to enrollment was 1.8 years (range, 0.7–5.9). Diarrhea (100%), nausea (83%), fatigue (67%), and alopecia (50%) were the most common drug-related adverse events (AEs) as determined by study investigator. The only serious AE was pulmonary embolism, which resolved in 7 days and patient is continuing therapy as of Day 955. Grade ≥3 AEs were anorexia (n=1), increased creatinine phosphokinase (CPK, n=1), rash (n=1), and thrombocytopenia (n=1). One patient experienced both increased CPK (Day 490) and rash (Day 645), and remained on therapy until Day 948. One patient discontinued due to PD, one discontinued due to PD, rash and increased CPK, and four are continuing on therapy as of 11/1/07. Updated data on these patients will be presented. Conclusions: Vorinostat has demonstrated prolonged safety and clinical benefit in these patients with advanced CTCL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Merck
Doxorubicin induced apoptosis in oocytes—Mechanism and possible executers
Authors: I. Ben-Aharon, H. Bar-Yosef, S. Rizel, A. Sulkes, S. M. Stemmer, R. Shalgi
Journal: Journal of Clinical Oncology (2008)

9611 Background: Premature ovarian failure and infertility are well-known side-effects observed in young girls and reproductive-age women treated for cancer. Long-term consequences of chemotherapy observed on non-target tissues, such as ovaries are substantial. Oocytes are among the cells most sensitive to collateral damage from chemotherapy, raising concern and potential health risks for women surviving diseases such as breast cancer, Hodgkin’s disease and leukemia. Our study aims at exploring the lethal effect doxorubicin exerts on oocytes. Methods: Retrieved ovulated or ovarian mouse oocytes, served as our biological model. Oocytes were exposed to doxorubicin and studied at several time-intervals. Using state of the art confocal microscopy, we performed fluorescent immunohistochemistry to follow doxorubicin localization within the oocytes as well as possible cellular targets at various post-treatment intervals. To evaluate doxorubicin induced apoptosis, we also used specific activity assays to trace potential effectors such as caspases and calpain. Results: Doxorubicin appears to be localized simultaneously at two cellular compartments - the nucleus (being the known original target site, as expected), where it induces acute obliteration of the DNA, and the mitochondria. We demonstrated activation of the mitochondria by doxorubicin as reflected by changes in its membrane potential. The effect on the mitochondria appears to be direct and is not inhibited by caspase2-inhibitor, an effector that mediates signals of the nuclear pathway. Exploring the apoptotic cascade within the oocyte, we showed that doxorubicin induces caspase-12 activation, probably via calpain activation. Conclusions: Our results imply that doxorubicin elicits a unique apoptotic signal transduction pathway within the oocyte via direct co-localization within the mitochondria and its activation. Possible cellular effectors appeared to be caspase12 and calpain, as formerly described in cardiomyocytes. Revealing the cellular mechanisms by which doxorubicin executes oocyte destruction might shed light on chemotherapy- induced infertility and could serve in discovering biological keys needed for protecting the germ cells against chemotherapy-induced damage. No significant financial relationships to disclose.
9. Hodgkin's Disease
Authors: S Proctor, B Angus, K Wood, T Mainou-Fowler, C Hoffmann, R Siebert, C Schrader, M Weniger, S Gesk, R Parwaresch, M Tiemann, K Ernestus, M Vierbuchen, T Barth, Z Kral, J Mayer, L Kren, P Fabian, L Smardova, D Antic, D Tomin, V Cemerikic, B Mihaljevic, D Boskovic, K Keresztes, Z Miltenyi, B Bessenyei, Z Beck, Z Szollosi, Z Nemes, E Olah, A Illes, J Tajer, E Lampka, W Osiadacz, E Kraszewska, B Brzeska, J Walewski, J Meder
Journal: Annals of Oncology (2005)
Surgical cytoreduction in patients with colorectal peritoneal carcinomatosis treated with contemporary chemotherapy.
Authors: V. G. Gava, D. L. Reidy, P. Paty, L. Saltz, K. Y. Chung, M. R. Weiser, L. K. Temple, N. H. Segal, L. F. Moreira, G. Nash
Journal: Journal of Clinical Oncology (2010)

3546 Background: In the setting of contemporary chemotherapy (CH) regimens there are limited data evaluating cytoreductive surgery (CRS) and outcomes of patients with colorectal adenocarcinoma (CRC) and isolated peritoneal surface disease (PSD). Methods: A retrospective review of a single-cancer center experience in the management of CRC and PSD was performed. Cases with PSD diagnosed between 1998 and 2007 were identified from an institutional database and medical records were reviewed. Patients with appendiceal carcinoma, concurrent metastasis to other sites (e.g., liver, retroperitoneum), or second malignancies were excluded. The role of CRS to microscopic disease only (CC0), used selectively, was analyzed with overall survival (OS) as the primary endpoint. Results: Of 8,052 patients with CRC, 686 (8.5%) were found to have PSD and 214 (2.7%) had isolated PSD. Of these 151 received FOLFOX or FOLFIRI with or without a biologic agent for metastatic CRC. Of these, 35 (23.2%) had a CC0 resection. Of the remaining 116 (76.8%) patients, surgical procedures were used selectively for palliation. The median follow up at the institution was 21.2 months. 93.8% of treatment was delivered at the cancer center. There was no difference between the CC0 and non-CC0 patients with respect to gender, age, comorbidities, performance status, previous exposure to CH, histology, stage at presentation, and burden of PSD. Ascites was less frequent in the CC0 group (11.4% vs. 33.3% p = 0.02). During the follow up period 76.2% of patients were admitted to an inpatient service and 38.4% had a bowel obstruction (BO). CC0 patients had delayed presentation with BO (median time to BO 53.1 vs. 31.5 months, p = 0.02). CC0 was associated with longer OS (median 31.6 vs. 20.3 months, p = 0.003). Index PSD CEA, index PSD albumin, stage IV presentation, burden of PSD, achievement of CC0, and having received biological agents in any combination were independently associated with OS. Conclusions: CRC with isolated PSD is rare and major morbidity related to it is high. Among patients treated with contemporary CH, patients in whom CC0 resection was achieved had a median OS of 31.6 months compared to 20.3 months in whom CC0 resection was not achieved. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alchemia, Biothera, Delcath, ImClone Systems, Merck, Novartis, Roche Pfizer Amgen, Biothera, Bristol-Myers Squibb, Curetech, Genentech, ImClone Systems, Lilly, Merck, Pfizer, Roche, Tercica
Long-term survival in small-cell carcinoma of the lung: a population experience.
Authors: S Davis, P W Wright, S F Schulman, D Scholes, D Thorning, S Hammar
Journal: Journal of Clinical Oncology (1985)

Small-cell lung carcinoma (SCLC) is a rapidly progressive and fatal disease. Historically, surgical resection or radiotherapy of the primary tumor has done little to prolong survival, although the use of combination chemotherapy is more effective. Reported here is the survival experience of 1,538 incident cases of SCLC identified through the Surveillance, Epidemiology and End Results Program in western Washington State from 1974 to 1982. The survival experience of this population series is similar to that reported from specialized referral centers. For 71 of 78 persons surviving at least 24 months, the original diagnostic slides were independently reviewed, 47 cases being confirmed as SCLC. No differences were found in actuarial survival estimates between those confirmed and those not confirmed as SCLC. Multivariate survival analysis was conducted to estimate the effects on survival of stage, therapy, age, sex, primary site, and histologic type. All factors except primary site and histologic type significantly influence initial survival rates. However, the only factor related to post--two-year (ie, long-term) survival, once stage is accounted for, is whether surgery was received as a first course of therapy. Those not receiving surgery were at four times the risk of death as those who did. These results indicate that long-term survival can be achieved in patients with SCLC treated in the community, and that the chance of surviving an additional two years for such patients is approximately 40%.
Abstract 341: The Wearable Cardioverter Defibrillator Protects Older Patients from Sudden Cardiac Death
Authors: Chingping Wan, Steven J Szymkiewicz
Journal: Circulation (2014)

Purpose: Patients ≥65 years old are at higher risk for cardiac mortality, including sudden cardiac death (SCD), since age plays a role in the development and progression of cardiovascular diseases....
Abstract 4894: Targeted sequencing of myeloid cancers using single-molecule enrichment in picodroplets
Authors: Michael L. Samuels, Steve K. Kotsopoulos, Frances Long, Holly Gettler, Omo Clement, Jeff Olson
Journal: Cancer Research (2015)

Abstract A new method for enrichment of targeted genomic regions for next generation sequencing (NGS) is the use of single-molecule formatted PCR amplification, with the sample's target DNA partitioned into uniform picoliter volume droplets such that there are either zero or one target molecule in each droplet. All the droplets contain all of the primers and PCR reagents, ensuring that every target molecule from the sample is amplified, minimizing the amount of input required. Endpoint PCR using this single molecule format results in highly uniform yields that facilitate efficient use of the sequencing platform. In addition, the primers contain ‘Illumina tails’ that enable easy sample indexing and a workflow for loading directly onto a MiSeq without additional library preparation. Here we detail the use of this method with the ThunderBolts Myeloid Cancer Panel, which targets ∼550 commonly mutated regions in 49 genes implicated in the causation, prognosis, and recurrence of myeloid disorders. The panel targets include an expert-curated set of 16 full genes and 33 mutational hotspot regions, including challenging targets such as CEBPA and NOTCH1. We present results showing sample inputs as low as 10 nanograms (no pre-amplification used) provide sequencing metrics with 100% coverage at &amp;gt;100x depth (&amp;gt;95% at &amp;gt;500x depth) with a normalized mean read depth of 2500x and high uniformity (&amp;gt;90% of amplicons within 0.2x of the mean), enabling detection of low minor allele frequencies (&amp;lt;5%). The workflow is easy and rapid, with &amp;lt;2 hours hands-on time and sample-to-results in &amp;lt;48 hours. In addition, we demonstrate similar performance metrics when adding additional primer pairs (ThunderBolts PLUS), ensuring continued flexibility for researchers to use the core panel plus additional key targets as they are identified and validated. In summary, the ThunderBolts Myeloid Cancer Panel shows excellent sequencing coverage, high read depth and uniformity, and detection of low frequency mutations implicated in myeloid cancers. Starting from low input DNA samples, the workflow is easy and fast, enabling low cost targeted Illumina NGS sequencing with an expert curated panel that provides flexibility for expansion. Citation Format: Michael L. Samuels, Steve K. Kotsopoulos, Frances Long, Holly Gettler, Omo Clement, Jeff Olson. Targeted sequencing of myeloid cancers using single-molecule enrichment in picodroplets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4894. doi:10.1158/1538-7445.AM2015-4894
Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.
Authors: Gautam Borthakur, Jorge E. Cortes, Susan Mary O'Brien, Tapan M. Kadia, Zeev Estrov, Stefan Faderl, Farhad Ravandi, Varsha Gandhi, William Plunkett, Joyce Bass, Mark Brandt, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m 2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m 2 and cytarabine 2 gm/m 2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x10 6 /L (range, 1.3-97.2); 12 patients (24%) were &gt;60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.
Granulocyte-Macrophage Colony-Stimulating Factor Treatment Before Doxorubicin and Cyclophosphamide Chemotherapy Priming in Women With Early-Stage Breast Cancer
Authors: Nathan L. Kobrinsky, Diane E. Sjolander, Mary S. Cheang, Ralph Levitt, Preston D. Steen
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 ± 2.5 days v 14.8 ± 1.5 days, respectively; P = .0001) and platelet nadir (mean ± SD, 10.1 ± 1.9 days v 11.1 ± 2.2 days, P &lt; .05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean ± SD, 490 ± 310/μL v 550 ± 350/μL, respectively; P = .2); however, on day 16 the mean neutrophil count was higher (mean ± SD, 1030 ± 580/μL v 690 ± 370/μL, P = .004), and the proportion of patients with a neutrophil count less than 500/μL was lower after priming than before (six of 35 or 17.1% v 12 of 34 or 35.3%, respectively; P = .04). The platelet nadir was higher (mean ± SD, 166,000 ± 51,000/μL after priming v 151,000 ± 45,000/μL before priming, P = .007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/μL, was shorter (1.5 ± 2.1 days v 2.8 ± 2.9 days, P = .0025) after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (&lt; 500/μL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.