tbuckley/cabot-search huggingface dataset:
Targeting pulmonary metastases of renal cell carcinoma by inhalation of Interleukin-2 (IL-2)
Authors: O. Merimsky, E. Gez, R. Weitzen, T. Peretz, R. Rubinov, M. Ben-Shahar, H. Hayat, R. Katsenelson, V. Mermershtein, D. Loven
Journal: Journal of Clinical Oncology (2004)

4662 Background: Pulmonary metastases of renal cell carcinoma (RCC) are associated with poor prognosis especially when the disease is rapidly progressing. The lung is a common site for metastases and respiratory failure is a common cause of death in patients with RCC. Inhalation therapy with IL-2 is thus an appealing method for palliation. This multi-center study summarizes the national experience with IL-2 inhalation in patients with lung metastases of RCC. Methods: All the patients had to have radiologically documented lung metastases, had to be able to comply with inhalation technique, and were not candidates for other treatment options. Treatment included 3 daily inhalations of 18 MU IL-2 by using a Salvia Lifetec Jetair inhalator. Treatment had to be continued until progression or complete response or life threatening toxicity or patient's refusal. Response was evaluated according to RECIST. Results: Forty patients (median 66.5 years), with histological or cytological diagnosis of RCC were enrolled. Nephrectomy was performed in a total of 32 patients. Previous treatments for metastatic disease included various combinations of systemic chemo-immunotherapy in 12 patients. Twenty-eight patients were systemic-treatment-naïve.The observed true response rate was 2.5% and disease stabilization rate was 55%. The disease-control rate (partial response plus disease stabilization rate) reached 57.5%. Time to progression ranged from 0.3 (in case of rapidly progressing disease) to more than 43 months, with a median of 8.7 months. The side effects included cough in 8 patients, weakness in 9, dyspnea in 3, fever in 2, sleepiness in 1, asthenia in 1, decreased appetite in 1, and abdominal pain in 1. Conclusions: Inhalation of IL-2 for treating pulmonary metastases of RCC is feasible, tolerable, and efficacious in controlling a progressive disease for considerable periods of time. Definition of response of biological therapy by RECIST system should be re-assessed and modified: stable disease should be regarded as a favorable and an important response. No significant financial relationships to disclose.
Exclusive enteral nutrition in active pediatric Crohn disease: Effects on intestinal microbiota and immune regulation
Authors: Tobias Schwerd, Klara Frivolt, Thomas Clavel, Ilias Lagkouvardos, Gabor Katona, Doris Mayr, Holm H. Uhlig, Dirk Haller, Sibylle Koletzko, Philip Bufler
Journal: Journal of Allergy and Clinical Immunology (2016)
Cognition and quality of life after chemotherapy plus radiotherapy (RT) vs. RT for pure and mixed anaplastic oligodendrogliomas: Radiation therapy oncology group trial 9402
Authors: M. Wang, G. Cairncross, E. Shaw, R. Jenkins, B. Scheithauer, D. Brachman, J. Buckner, L. Souhami, N. Laperriere, M. Mehta, W. Curran
Journal: Journal of Clinical Oncology (2009)

e20519 Background: Radiation Therapy Oncology Group 9402 compared PCV chemotherapy plus radiation therapy (PCV+RT) versus RT alone for anaplastic oligodendroglioma. Here we report 1) longitudinal changes in cognition and quality of life, 2) effects of patient factors and treatments on cognition, quality of life and survival, and 3) prognostic implications of cognition and quality of life. Methods: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL) by repeat assessments. Scores were analyzed for survivors and within five years of death. Shared parameter models evaluated MMSE/B-QOL with survival. Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those dying within 5 years, MMSE scores were stable initially, while B-QOL scores decreased; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (P=0.0413 for MMSE; P=0.0016 for B-QOL) and were superior with age &lt; 50 years (P&lt;0.001 for MMSE; P=0.0554 for B-QOL) and KPS 80–100 (P&lt;0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV+RT (HR=0.66, 95% CI=0.49–0.9, P=0.0084; HR=0.74, 95% CI=0.54–1.01, P=0.0592) in models with MMSE and B-QOL. There were no differences in MMSE and B-QOL scores between arms (P=0.4752 and P=0.2767, respectively); higher scores predicted longer survival. Conclusions: MMSE and B-QOL scores held steady in both arms for survivors. For those who died, B-QOL scores declined slowly until the last year of life, then rapidly. Younger, fitter patients had better MMSE and B-QOL scores and longer survival. No significant financial relationships to disclose.
Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma
Authors: P. A. Lind, B. Isaksson, M. Almström, A. Johnsson, N. Albiin, P. Byström, J. Permert
Journal: Journal of Clinical Oncology (2007)

15073 Background: The optimal care for patients with irresectable, non-metastatic pancreatic carcinoma (PAC) is debated. We treated 17 consecutive cases with preop radiochemotherapy (RCT) as a means for downstaging their tumors and compared outcome with 35 patients undergoing direct surgery for primarily resectable PAC during the same time period. Methods: The patients had biopsy proven, irresectable, non-metastatic PAC which engaged &gt;50% of the circumference of a patent mesenteric/portal vein for a distance &gt;2 cm and/or &lt;50% of the circumference of a regional artery for &lt;2 cm. The preop therapy included 2 courses of Xelox (oxaliplatin 130mg/m2 d1; capecitabine 1000mg/m2 X 2 d1–14 q 3 w) followed by 3-D conformal radiotherapy (50.4 Gy; 1.8 Gy fractions) with reduced Xelox (d1–5 q 1 w X 6). Results: 6 cases of RCT-related CTC Grade 3–4 non-hematologic side-effects were diagnosed. Sixteen patients completed the RCT and were rescanned with CT/reevaluated for surgery 4 weeks post-RCT. Five cases were diagnosed with new metastases to the liver. Eleven patients were accepted for surgery and 8 underwent a curative R0-resection. The median overall survival for the latter group was 29 mos, which compared favorably with our control group of patients undergoing direct surgery for primarily resectable PAC (median OS: 16 mos (P=0.02). RO- rate: 75%). Periop morbidity was similar in the two cohorts but the duration of surgery was longer (576 vs 477 min; P&lt;0.05) and the op blood loss was greater (3288 vs 1460 ml; P&lt;0.05) in the RCT-cohort. The 30-day mortality was zero in both cohorts. Conclusions: Preop RCT in fit patients with locally advanced PAC resulted in a high rate of curative resections and promising median survival in our treatment series. This trimodality approach merits further exploration in new studies, which are currently underway at our Department. No significant financial relationships to disclose.
Elucidation of the physicochemical properties and potency of siRNA-loaded small-sized lipid nanoparticles for siRNA delivery
Authors: Yusuke Sato, Yusuke Note, Masatoshi Maeki, Noritada Kaji, Yoshinobu Baba, Manabu Tokeshi, Hideyoshi Harashima
Journal: Journal of Controlled Release (2016)
Gene expression profiles in formalin-fixed, paraffin-embedded (FFPE) core biopsies predict docetaxel chemosensitivity
Authors: J. C. Chang, A. Makris, S. G. Hilsenbeck, J. R. Hackett, J. Jeong, M. Liu, J. Baker, K. Sexton, C. K. Osborne, S. Shak
Journal: Journal of Clinical Oncology (2006)

538 Background: Docetaxel has one of the highest response rates as a single agent in breast cancer, but de novo resistance is frequent. Previously, we had identified a 92-gene expression pattern that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis (Paik, NEJM 2004) but better response to chemotherapy (Gianni, JCO 2005). We investigated whether tumor gene expression of these 21 genes and other candidate genes can predict response to docetaxel. Methods: Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m 2 q3 weeks). Baseline and post-treatment measurements of the primary breast cancers were recorded. Three 10-micron FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Results: Of the 97 patients, 81 (84%) had sufficient invasive breast cancer, 80 (82%) had sufficient RNA for assay of 192 genes, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) by RECIST were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). The concordance of IHC and RT-PCR results was &gt;80% for ER, PgR, and HER2. By univariate logistic regression, a significant correlation (p&lt;0.05) between gene expression and CR was observed for 14 genes. Notably, CYBA-1 involved in mitochondrial metabolism, identified by gene expression profiling, significantly predicted CR (p=0.006). CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group. Multivariate analysis indicated that panels of genes better predictors of docetaxel response. Of note, CR was more likely with high RS and less likely with a low RS (p=0.008). Conclusion: We have established molecular profiles for breast cancers either responding or not responding to neoadjuvant docetaxel. This technology is a potential predictive test for docetaxel sensitivity by using small amounts of FFPE material, and may reduce unnecessary treatment, toxicity, and cost for breast cancer patients. [Table: see text]
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification
Authors: Dan L. Li, Zhao V. Wang, Guanqiao Ding, Wei Tan, Xiang Luo, Alfredo Criollo, Min Xie, Nan Jiang, Herman May, Viktoriia Kyrychenko, Jay W. Schneider, Thomas G. Gillette, Joseph A. Hill
Journal: Circulation (2016)

Background— The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Methods and Results— Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1 . Beclin 1 +/− mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. Conclusions— Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates
Authors: Christopher W. Peterson, Jianbin Wang, Krystin K. Norman, Zachary K. Norgaard, Olivier Humbert, Collette K. Tse, Jenny J. Yan, Richard G. Trimble, David A. Shivak, Edward J. Rebar, Philip D. Gregory, Michael C. Holmes, Hans-Peter Kiem
Journal: Blood (2016)
New Clinical Trial Designs Hasten Approvals for Targeted Therapies
Authors: Charlie Schmidt
Journal: JNCI Journal of the National Cancer Institute (2016)

Last November, the U.S. Food and Drug Administration granted accelerated approval to a new targeted therapy for non-small-cell lung cancer (NSCLC) called AZD9291.The drug had a remarkable 61% response rate among patients harboring the epidermal growth factor receptor T790→M mutation, which confers resistance to frontline treatment.Also, the approval was based on singlearm phase II data instead of results from a randomized clinical trial.In this experience, many experts see the best hope for the future of cancer drug development: one based on streamlined evaluations of targeted treatments given to patients who are most likely to experience clinical benefits."We're no longer interested in big randomized studies that produce statistically significant results that aren't clinically meaningful," said Gary Middleton, M.D., a professor of medical oncology at the UK's University of Birmingham."We're looking for big gains from targeted drugs in single-arm studies that look for high levels of activity."
Well differentiated thyroid carcinoma: Ten years' experience of one single institution
Authors: M. Steiner, M. Sheinfeld, E. Baron, R. Rubinov, A. Rabkin, M. Leviov
Journal: Journal of Clinical Oncology (2004)

5592 Background: During 1988–1997, 261 patients with well differentiated thyroid carcinoma were referred to our departments for further evaluation, treatment and follow up. Their files were retrospectively reviewed for treatment results analysis. After initial operation most patients had radioiodine ablation and suppressive thyroxine therapy and then were followed on a regular basis with serum Tg levels and WBS when indicated. Methods: 81% of patients were female and 19% male, their median age was 50 years (15–83), 40% were younger and 60% older than 45 years of age. 81% had papillary and 19% follicular carcinoma. 79% of younger patients had stage I disease (15% node positive) and 21% had stage II. 30 % of older patients had stage I disease, 43% had stage II, 18 % stage III (12% node positive) and 6% presented with metastatic disease. 91% of patients had total or near total thyroidectomy with lymph node resection if indicated. 72% had radioiodine ablative therapy, 30–100 mc according to post operative iodine uptake. Results: Median follow up was 119 months (51–187). 23 patients who achieved NED status at end of therapy recurred, median time to recurrence was 28 months (6–108) . The most common site of recurrence was cervical nodes (52%) followed by thyroid bed (26%) and distant metastases (22%). In 61% of patients the recurrent disease was diagnosed by clinical signs or symptoms and in 39% by regular Tg or WBS monitoring. 86% of patients are alive without evidence of disease, 4% are alive with disease (81–151 months from diagnosis, median 118), 5% died of disease (within 6–91 months from diagnosis, median 52 ) and 5% died of unrelated causes. 3% of papillary carcinoma patients and 16% of follicular carcinoma died of disease during the study period. Conclusions: We conclude that the presentation, stage distribution, histology subgroups and survival of well differentiated thyroid carcinoma patients in our institution is similar to other reported series. Regular follow up is warranted as recurrence may be late and it is usually detected at routine follow up visits. No significant financial relationships to disclose.
EPIG-16MOST DIFFERENTIAL DNA METHYLATION CHANGES OCCUR AT CANDIDATE ENHANCER ELEMENTS FOR RECURRENT LOWER GRADE GLIOMA AND GLIOBLASTOMA
Authors: Camila Souza, Tathiane Malta, Thais Sabedot, Lindsay Stetson, Daniela Tirapelli, Luciano Neder, Carlos Carlotti, Jean ZenKlusen, Sofie Salama, Laila Poisson, Daniel Brat, Jill Barnholtz-Sloan, Houtan Noushmehr
Journal: Neuro-Oncology (2015)

Clinical behavior of lower grade glioma (LGG) and glioblastoma (GBM) is characterized by recurrence and progression, yet with highly variable patterns and intervals. Our current study aims to establish a DNA methylation profile associated with the recurrence of LGG (n = 28) and GBM (n = 24) by comparing primary and recurrent matched samples. Illumina Methylation 450k data were used from The Cancer Genome Atlas (TCGA) project. Genome-wide DNA methylation remained almost unchanged at CpG islands and shores. Unsupervised DNA methylation consensus clustering of 2,000 CpG with highest standard deviation (sd > 0.25) demonstrated that recurrent LGG and GBM clustered next to their primary counterparts. Strikingly, 78.6% of recurrent LGG showed depletion of DNA methylation at recurrence and 50% of recurrent GBM showed enrichment of DNA methylation at recurrence. Enrichment analysis of CpG sites with most DNA methylation changes between primary and recurrent samples revealed that 14.3% of LGG and 33.3% of GBM samples showed enrichment of opensea located probes (fold > 1.3). A random permutation of 10,000 probes and confidence intervals (99%) demonstrated that these results do not occur by chance. More than 50% of CpG sites enriched at openseas map to candidate TSS distal and hypomethylated enhancers, and are related to adhesion, apoptotic, developmental, immune system, and metabolic processes. Compared to 10 paired non-glioma tumor (lung, colon, liver, sarcoma), the signature of glioma relapse appears distinctive. Our results provide evidence that DNA methylation may represent a stable signature of glioma recurrence and that the crosstalk between DNA hypomethylation at openseas and chromosomal instability is involved in glioma recurrence. We plan to integrate our findings with whole-genome & RNA sequencing and perform DNA motif analyses to identify networks disrupted and associated with such pronounced epigenetic signature.
A phase I trial of intratumoral (i.t.) administration of reovirus in patients with histologically confirmed recurrent malignant gliomas (MGs)
Authors: P. A. Forsyth, G. Roldan, D. George, C. Wallace, D. G. Morris, J. Cairncross, M. Vallee Matthews, M. Coffey, B. Thompson, M. Hamilton
Journal: Journal of Clinical Oncology (2006)

1563 Background: Reovirus is an oncolytic virus which replicates preferentially in transformed cells possessing activated Ras signaling pathways. Promising activity was found in in vivo models of MGs and in a phase I trial in patients (pts.) with cutaneous metastases from systemic cancer. We performed this dose-escalation trial of i.t. administration of reovirus to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in pts. with recurrent MG. Response, survival and time to progression (TTP) were secondary aims. Methods: Pts. were ≥ 18 yrs old, had a KPS ≥ 60, received prior radiotherapy ± chemotherapy, a histologically proven recurrence of MG and recurred ≤ 3 times. Reovirus was administered i.t. stereotactically at one of three dose levels (1 × 10 7 , 1 × 10 8 or 1 × 10 9 TCID50) in a volume of 0.9 mls. Results: Twelve pts. were treated at 3 dose levels; seven were men, the median (mdn) KPS was 80, mdn age was 53.5 yrs, 10 had glioblastoma multiforme, one anaplastic astrocytoma and another anaplastic oligoastrocytoma. There were the 1 st , 2 nd or 3 rd recurrences in 6, 5 and 1 pts., respectively. During i.t. viral administration all pts. were treated with prophylactic anticonvulsants and 6 (50%) were receiving corticosteroids. The 1 st , 2 nd and 3 rd cohorts contained 3, 6 and 3 pts., respectively. There were no grade 3 or 4 adverse events definitely or probably related to the administration of reovirus. A transient increase in GGT was possibly related to reovirus administration and a patient experienced grade 3 motor weakness that could be related to post-injection edema. Viral shedding and systemic immune responses were examined but results are pending. There were no CR, or PR; a pt. had SD, 10 PD and one was not evaluable. The mdn survival was 20 weeks (range, 6–171), 6 pts. survived &gt; 6 months and 3 are alive 6, 7 and 40 months from the reovirus injection. The mdn TTP was 4.3 weeks (range: 3.4–39). Conclusions: A MTD was not reached. The intratumoral administration or reovirus was well tolerated in patients with recurrent MGs. Phase 2 studies in MGs are planned. [Table: see text]
A phase II study of capecitabine, irinotecan, and bevacizumab (XELIRI-A) in patients (pts) with previously untreated metastatic colorectal cancer (mCRC)
Authors: E. X. Chen, S. Welch, M. Krzyzanowska, H. MacKay, J. Knox, R. Feld, J. Petronis, C. Blatter, L. Wang, M. J. Moore
Journal: Journal of Clinical Oncology (2009)

e15019 Background: Capecitabine (XEL), irinotecan (IRI) and bevacizumab (A) are all active agents in the treatment of mCRC. However, combining these agents has proven to be problematic due to overlapping toxicities. Optimal dosing strategies for this combination remain unclear. This study prospectively evaluated toxicity and efficacy of the XELIRI-A combination with dose modification. Methods: This was a single-institution, open-label phase II clinical trial. Eligible pts include those with previously untreated metastatic CRC, adequate organ function and ECOG performance status 0–2. IRI (200 mg / m 2 ) and A (7.5 mg / kg) were given on day 1, and XEL (1000 mg / m 2 p.o. BID) was given on days 1–14 of every 21-day cycle. The dose of XEL was reduced to 750 mg / m 2 BID for pts age ≥ 65. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, time to progression, overall survival and toxicity. Results: 50 pts (ECOG PS 0:1 = 27:23; male:female= 34:16) were enrolled over 19 months. Median age was 58 (range: 35–72). 7 pts had prior adjuvant chemotherapy. A total of 360 cycles were administered, with a median of 6 (range: 1–16). To date, 20 confirmed PR, 3 unconfirmed PR, and 20 SD by RECIST criteria were observed (ORR= 40%, disease control rate 86%). The median PFS was 11.1 months (95% CI: 9.2 months - not reached), and the 1-year progression-free rate was 49%. 7 pts have gone on to have metastatectomy. The most frequently reported related grade 3 or 4 adverse events were neutropenia (6), hand-foot syndrome (6), and diarrhea (5). One death was seen on study, and 1 pt had treatment-emergent grade 3 hypertension. Conclusions: XELIRI-A at doses studied appears to be well- tolerated. Results are favorable compared to those from previous studies. XELIRI-A at reduced doses is safe and effective as first-line treatment for mCRC. [Table: see text]
Recommendations for kidney disease guideline updating: a report by the KDIGO Methods Committee
Authors: Katrin Uhlig, Jeffrey S. Berns, Serena Carville, Wiley Chan, Michael Cheung, Gordon H. Guyatt, Allyson Hart, Sandra Zelman Lewis, Marcello Tonelli, Angela C. Webster, Timothy J. Wilt, Bertram L. Kasiske
Journal: Kidney International (2016)