tbuckley/cabot-search huggingface dataset:
Induction 3D-chemoradiation (CRT) yields a high rate of pathologic complete response in stage IIB(Pancoast)/III NSCLC operable patients (pts) without increasing perioperative mortality after (bi-)lobectomy: A review of 107 cases treated in a community- based center
Authors: N. Pourel, W. Hilgers, N. Santelmo, N. Naffaa, F. Reboul
Journal: Journal of Clinical Oncology (2007)

7704 Background: Optimal preoperative treatment for stage IIB/III NSCLC remains a subject of controversy. According to the results of INT0139 trial (Albain KS et al in Proc ASCO 2005, abstr #7014), induction CRT appears to be superior to chemotherapy alone (CT) in terms of pathologic complete response (or microscopic residual foci, pCR), but increases postoperative (postop) mortality after pneumonectomy. Methods: Pts were selected through a multidisciplinary committee according to functional and resecability criteria. Induction treatment comprised 45 Gy/25 fractions/5 weeks. RT delivered to the primary tumor and pathologic hilar and/or mediastinal nodes (CTV) with an extra-margin of 1 to 1.5 cm (PTV). A 3D 5-field technique was used for all patients with 8–25 MV photons. Concurrent CT regimen was Cisplatinum 20 mg/m 2 and Etoposide 50 mg/m 2 (PE), d1–5, d29–33. Surgery was performed 4 to 6 weeks after CRT completion in deemed resectable pts. Inoperable pts were referred for a 20 Gy boost ± 1 extra-cycle of PE. Results: From 1996 to 2005, 107 NSCLC pts received CRT (stage IIB-Pancoast 18, IIIA 58 and IIIB 31). One hundred pts received the whole 45 Gy+PEx2; 72 pts had a thoracotomy (pneumonectomy 21, lobectomy 45, bi-lobectomy 5, exploratory only 1). During the 3-month postop time, 5 pts (6.9%) died, 4 after pneumonectomy (R 3, L 1, 19%), 1 after lobectomy (2.2%); 34 pts had 1–3 significant complication(s) (mainly, arrhythmia 10, pneumonia 8 (lethal 1), prolonged air leak 7, fistula 4, empyema 4 (lethal 2), pulmonary embolism 3 (lethal 2)).A pCR was observed in 39.5% of 71 resected pts; mediastinal nodes were sterilized in 60.9% of 46 cN2 pts. Analysis of survival and predictive factors is ongoing. Conclusions: Surgery is feasible after induction chemo-RT, particularly (bi-)lobectomy, in stage IIB/III NSCLC pts but pneumonectomy carries an inacceptable risk of postop death (particularly, right pneumonectomy). CRT yields an encouraging pCR rate of 39.5%. No significant financial relationships to disclose.
EULAR gout treatment guidelines by Richette <i>et al</i>.: uric acid and neurocognition
Authors: Jasvinder A Singh, N Lawrence Edwards
Journal: Annals of the Rheumatic Diseases (2017)

We appreciate the efforts of the authors of the recent ‘2016 updated EULAR evidence-based recommendations for the management of gout’ and congratulate them on the publication.1 We would like to draw attention to recommendation #6: ‘For patients on urate-lowering therapy (ULT), serum urate (SUA) level should be monitored and maintained to <6 mg/dL (360 µmol/L). A lower SUA target (<5 mg/dL; 300 µmol/L) to facilitate faster dissolution of crystals is recommended for patients with severe gout (tophi, chronic arthropathy, frequent attacks) until total crystal dissolution and resolution of gout. SUA level <3 mg/dL is not recommended in the long term’. We agree with the first half of the recommendation that proposes the treat-to-target recommendations similar to that in the American College of Rheumatology 2012 gout treatment guidelines of reducing serum urate to <6.0 mg/dL in all patients with gout …
Understanding and preferences for receiving prognostic information: A comparison of the views of Australian and Canadian patients with metastatic cancer
Authors: S. Dimitry, P. M. Ellis, P. N. Butow, R. G. Hagerty, M. H. Tattersall
Journal: Journal of Clinical Oncology (2006)

6014 Background: Previous research suggests that the majority of cancer patients desire full disclosure of their prognosis and treatment options. The current study compares the views of Australian (A) and Canadian (C) patients with metastatic cancer towards disclosure of prognostic information. Methods: Cross sectional studies were undertaken with A and C patients with newly diagnosed metastatic cancer to assess their preferences for and understanding of prognostic information. The primary outcome was patients’ preferences for the mode of delivery of prognostic information. Remaining analyses were primarily descriptive. Results: Survey response rate was A: 58% (n = 126) and C: 57% (n = 117). Patient mean age was 62.8yrs (A), 63.2yrs (C). 56% (A) and 39% (C) of patients were male. There were some differences in type of cancer: breast (25%A, 30%C), colorectal (18%A, 44%C), lung (10%A, 26%C) and other cancers (47%A). The main outcomes of the A and C surveys were very similar. The majority of all patients surveyed wanted to know prognostic information. Most patients preferred both words and numbers (46%A, 52%C), or words only (28%A, 31%C) for presenting prognostic information. Respondents were more likely to like words (66%A, 47%C), percentages (65%A, 45%C), or fractions (60%A, 47%C) for presenting prognostic information, than diagrams (37%A, 33%C), pie charts (42%A, 32%C) or graphs (33%A, 29%C). The majority of patients want to receive information on treatment goals and options when first given a metastatic diagnosis (84%A, 86%C). Fewer patients want to receive information on life expectancy at this time (59%A, 56%C) and only the minority want to discuss information about dying at this time (34%A, 36%C). Respondents indicated the specialist should just tell the patient (83%A, 74%C) rather than check first if the patient wants to know (15%A, 22%C). Conclusions: A and C patients have similar and strong preferences for receiving prognostic and treatment option information. However, more research is needed on the timing of delivery of this information. No significant financial relationships to disclose.
Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).
Authors: Jeanne Tie, Isaac Kinde, Hui-Li Wong, Joseph James McKendrick, Peter Gibbs, Madhu Sudan Singh, Christos Stelios Karapetis, Jayesh Desai, Ben Tran, Justin Kelvin Roebert, Kenneth W. Kinzler, Bert Vogelstein
Journal: Journal of Clinical Oncology (2013)

11015 Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with &lt; 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.
Macrophage density in early surveillance biopsies predicts future renal transplant function
Authors: Jan Hinrich Bräsen, Abedalrazag Khalifa, Jessica Schmitz, Wei Dai, Gunilla Einecke, Anke Schwarz, Michael Hallensleben, Bernhard M.W. Schmidt, Hans H. Kreipe, Hermann Haller, Sibylle von Vietinghoff
Journal: Kidney International (2017)
Utility of endoscopic ultrasound-guided biopsy for genomic analysis of pancreatic exocrine malignancies.
Authors: Brent K Larson, Nan Deng, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2017)

423 Background: Endoscopic ultrasound-guided fine needle biopsy (EUS FNB) and aspiration (FNA) are the gold standard for diagnosis of pancreatic malignancies. Oncologists increasingly use tumor genomic analysis to assist with management decisions for these malignancies. While the diagnostic use of FNB/A is known, adequacy of FNB/A tissue for next-generation sequencing (NGS) has not been evaluated. This study examined adequacy of FNB/A and other biopsy types for features that might predict inadequacy for NGS using an Illumina HiSeq platform. Methods: 76 consecutive biopsies (54 EUS FNBs, 8 radiology-guided biopsies, 7 EUS FNAs, 5 endoscopic forceps biopsies, and 2 biopsies of unknown type) of pancreatic exocrine malignancies (74 pancreatic ductal adenocarcinomas, 1 acinar cell carcinoma and 1 ampullary adenocarcinoma) submitted for NGS were assessed for adequacy. Adequacy was compared to other tumor/biopsy features. Subgroup analysis was performed on FNB/As. Analysis was performed via Spearman correlation. Results: 22/76 (29%) samples were inadequate, including 16/54 (30%) FNBs and 4/7 FNAs (57%). 17 were inadequate due to low tumor cellularity, 4 due to tissue size, and 1 due to both. Recorded needle gauges were 18 (n = 2), 19 (n = 2), 22 (n = 42), and 25 (n = 3). Larger needles were associated with adequacy in all samples (p = 0.0047) and in FNB samples (p = 0.05). Samples from metastases were more associated with adequacy than those from the pancreas (p = 0.0357). Radiology-guided biopsies were more likely to be adequate than EUS-guided FNB/As, though this trend did not reach significance (p = 0.0558). Tumor size (range: 1.3-8.7 cm), needle manufacturer (n = 3), number of passes (range: 1-5), biopsy size (range: 0.008-0.336 cm 3 ), endoscopist (n = 4), and tumor location in the pancreas (head/uncinate/body/tail) were not associated with adequacy. Conclusions: These results suggest that metastatic lesions accessible by radiology-guided core biopsy may be preferable to EUS FNB/A for obtaining tissue for NGS. EUS-guided FNB were more likely to be successful using a larger gauge needle.
Characteristics of intrahepatic cholangiocarcinoma according to tumor location.
Authors: Mitsuo Shimada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Shuichi Iwahashi, Yu Saito, Masato Yoshikawa, Hiroki Teraoku, Jun Higashijima
Journal: Journal of Clinical Oncology (2017)

406 Background: Recently, the perihilar cholangiocarcinoma was defined as a tumor existing perihilar region between the right side of the umbilical portion of the left portal vein and the left side of the origin of the right posterior portal vein, in the General Rules for Clinical and Pathological Studies on Cancer of the Biliary Tract (The 6 th edition). The study was aimed to investigate characteristics of intrahepatic cholangiocarcinoma (IHCC) according to tumor location. Methods: Study 1: Sixty-two IHCC patients who underwent hepatic resection were divided into the following 3 groups; peripheral type (n=41), perihilar type (n=10) and unclassified type (peripheral type with perihilar invasion: n=11). Clinicopathological data including CA19-9 and immnohistochemical staining of Ki67 and hypoxia inducible factor-1 (HIF-1) were compared. Study 2: The effect of 2 cycles of adjuvant gemcitabine combined with 5-FU and cisplatin (GFP) (Morine and Shimada. Hepatogastroenterology 2009) was retrospectively investigated, in advanced IHCC with one of 3 prognostic factors of LN metastasis, intrahepatic metastasis and R2 resection. Results: Study 1: There was no difference in background variables except for more frequent hilar biliary invasion in perihilar and unclassified types, and the largest tumor size in unclassified-type. The 5-year survival rate in the peripheral, perihilar and unclassified-types were 44%, 20% and 0%, respectively. In addition, CA19-9 level, Ki67 labelling index and positive rate of HIF-1 expression in the unclassified type were higher than those in other 2 types. Multivariate analysis revealed the unclassified type as an independent prognostic factor. Study 2: In 29 patients (47%) having one of the 3 prognostic factors, 9 patients including 4 unclassified-type IHCCs received the adjuvant GFP. The prognosis in GFP group tended to be better than that in non-GFP group (3-year survival rate: 38% vs. 6%, p = 0.07). Two patients with unclassified-type IHCC in non-GFP group died within 1 year after surgery. Conclusions: The unclassified-type IHCC indicated the most aggressive tumor biology, and the adjuvant GFP may be a useful strategy for such a highly malignant tumor with poor prognostic factors.
Canadian ALK (CALK): A multicenter, prospective study of concurrent ALK immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in NSCLC.
Authors: Jean Deschenes, Jean-Claude Cutz, Gilbert Bigras, Kenneth J. Craddock, Emina Torlakovic, Iyare Izevbaye, Rania Gaspo, Ming-Sound Tsao
Journal: Journal of Clinical Oncology (2014)

8070 Background: : FISH has been considered the “gold standard” for identification of ALK rearranged (ALK+) NSCLC, but its cost-effectiveness as a screening method for ALK+ lung cancer is debated. Recent reports suggest that ALK IHC may be an alternative screening/diagnostic method. However, most studies evaluating IHC performance were retrospective or from a single-institution. ALK IHC screening and FISH confirmation have been validated across Canadian centers in a prior CALK study. This follow-up study was initiated to prospectively assess the accuracy of IHC compared to FISH in cases requiring ALK status determination. Methods: 3 centres conducted parallel IHC (5A4 antibody) and FISH (Abbott kit) testing of 411 consecutive clinical cases using previously validated and optimized protocols. 4 um unstained sections were used as well as published criteria for FISH scoring. The centres scored cases showing diffuse cytoplasmic staining of tumor cells clearly greater than background as ALK IHC + (2+, 3+,as well as diffuse 1+ in previously published ALK scoring systems), cases showing only focal faint staining above background (focal 1+) were scored as IHC equivocal, and cases with no tumor staining above background as IHC(-) . In almost all cases, background staining was completely absent. Results: Among the 411 cases, 373 (90.8%) were informative by both methods and 38 (9.2%) failed FISH testing. Of the dual informative cases, 18 (4.8%) were both IHC + and FISH +, 326 (87.4%) tested IHC (-) and FISH (-), 29 (7.8%) tested as IHC equivocal and FISH (-). 2/411 cases were initially discordant (i.e. IHC (-) and FISH borderline+). After rescoring by 2 blinded experienced readers, FISH was negative. When considering equivocal cases as positive, IHC sensitivity and specificity were 100% and 91.8 %, respectively. From the informative cases, FISH (-) / IHC (-) had 3.2% ± 3.2% abnormal FISH signal counts vs. 48.6% ± 18.7% for FISH+/IHC+ and 4.1% ± 3.7% in IHC equivocal cases. Conclusions: Results of this prospective study support IHC as a reliable method to screen for ALK-rearranged lung cancers. They also suggest that a clearly positive IHC result may be used to determine ALK status.
QClamp Liquid Biopsy Technology (QLBT) rapid sensitive detection of somatic mutations in tumor-derived DNA from whole blood.
Authors: Michael Joseph Powell
Journal: Journal of Clinical Oncology (2014)

e22130 Background: In the field of targeted cancer therapy precise knowledge of the genetics of a specific patients tumor is essential for therapeutic decisions. Distant tumor metastases often harbor unique genomic characteristics not detectable in the corresponding primary tumor of the same patient. Thus, the mere analysis of the resected primary tumor alone (current standard practice in oncology) may not reveal sufficient information for treatment decisions. This dilemma can be solved by a new diagnostic concept: liquid biopsy, that is, analysis of therapeutic targets and drug resistance–conferring gene mutations on circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA) released into the peripheral blood from metastatic deposits. QClamp liquid biopsy technology (QLBT) enables CTCs and ctDNA to be effective biomarkers in future oncology trials assessing new drugs or drug combinations. Methods: QClamp is a qPCR method for the direct precise analysis of cancer gene mutations in DNA from formalin-fixed paraffine embedded (FFPE), fresh or frozen tumor biopsy samples or whole blood samples. QClamp utilizes a novel PCR Direct sample preparation method called 'QZol' which only takes 20 min. prior to direct use of an aliquot of the QZol lysate in a real-time PCR reaction. The use of a xeno-nucleic acid (XNA) clamp probe specific for the target wild-type gene sequence allows the genration of only mutation specific amplicons which are detected by the fluorecent interchelating dye SYBR Green. Results: Mutations in the JAK2 gene (V617F) in blood samples from patients suffering from myeloproliferative cancer were detected by QClamp and showed 100% concordance with sequencing data obtained from analysis of the DNA purified from the patients blood samples by a commercial DNA purification kit. Conclusions: QClamp Liquid Biopsy Technology (QLBT) is a direct, rapid, precise and sensitive method for analysis of a cancer patients tumor genetic characteristics form a wide range of clinical samples including FFPE, fresh and/or frozen tumor biopsy samples or from whole blood samples to aid in targeted cancer therapy decisions.
536. Multiple Molecular Alterations in Phosphodegrons 1-3 within AAV2 Capsid Demonstrates Higher Hepatic Gene Transfer Efficiency
Journal: Molecular Therapy (2013)

The success of AAV2 mediated hepatic gene transfer in human trials for diseases such as hemophilia has been hampered by a combination of low transduction efficiency and a robust immune response directed against these vectors. We have previously shown that AAV2 is targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal degradation machinery and modification of the serine(S)/threonine(T) kinase and lysine(K) targets on AAV capsid is beneficial. Thus targeted single mutations of S/T>A(S489A, S498A, T251A) and K>R (K532R) improved the efficiency of gene transfer in vivo as compared to wild type (WT)-AAV2 vectors (∼6-14 fold). In the present study, we evaluated if combined alteration of the phosphodegrons (PD), which are the phosphorylation sites recognized as degradation signals by ubiquitin ligases, improves further the gene transfer efficiency. Thus, we generated four multiple mutant vectors (PD: 1+3, S489A+K532R, PD: 1+3, S489A+K532R together with T251 residue which did not lie in any of the phosphodegrons but had shown increased transduction efficiency compared to the WT-AAV2 vector (∼6 fold) and was also conserved in 9 out of 10 AAV serotypes (AAV 1 to 10), PD: 1+3, S489A+K532R+S498A and a fourth combination of PD: 3, K532R+T251. We then evaluated them in vitro and in vivo and compared their gene transfer efficiency with either the WT-AAV2 or the best single mutant S489A-AAV2 vector. The novel multiple mutations on the AAV2 capsid did not affect the overall vector packaging efficiency. All the multiple AAV2 mutants showed superior transduction efficiency in HeLa cells in vitro when compared to either the WT (62-72% Vs 21%) or the single mutant S489A (62-72% Vs 50%) AAV2 vectors as demonstrated by FACS analysis (Fig. 1A). On hepatic gene transfer with 5x10^10 vgs per animal in C57BL/6 mice, all the multiple mutants showed increased transgene expression compared to either the WT-AAV2 (∼15-23 fold) or the S489A single mutant vector (∼2-3 fold) (Fig.1B and C). These novel multiple mutant AAV2 vectors also showed higher vector copy number in murine hepatocytes 4 weeks post transduction, as compared to the WT-AAV2 (∼5-6 Vs 1.4 vector copies/diploid genome) and further higher when compared to the single mutant S489A(∼5-6 fold Vs 3.8 fold) (Fig.1D). Further ongoing studies will demonstrate the therapeutic benefit of one or more of the multiple mutants vectors in preclinical models of hemophilia.
Outcomes of definitive radiotherapy (dRT) and chemo-radiotherapy (dCRT) for loco-regionally confined (LRC) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ).
Authors: Vidhya Karivedu, Michael J. McNamara, Lisa A. Rybicki, Haider Al taii, Davendra Sohal, Cristina P. Rodriguez, Gregory M.M. Videtic, Kevin L. Stephans, Denise I. Ives, Joanna Bodmann, David J. Adelstein
Journal: Journal of Clinical Oncology (2017)

114 Background: Surgery is the cornerstone of curative intent therapy for patients with ACA of the E/GEJ. Many patients (pts) with LRC disease are medically unsuitable for resection, and thus alternative treatment strategies are required. Definitive CRT is a standard of care for esophageal squamous cell carcinoma, but less is known regarding the outcomes for ACA of the E/GEJ. Methods: Through the Cleveland Clinic tumor registry, and under an IRB approved protocol, pts with LRC (clinical stage I-III, AJCC 7 th ) ACA of the E/GEJ treated with either dRT or dCRT between 7/04 and 12/14 were identified. Overall survival (OS) from the date of diagnosis was the primary endpoint. In univariate analysis, Cox proportional hazard analysis was used to identify risk factors for mortality. On multivariable analysis, stepwise Cox proportional hazard analysis with variable entry criterion p≤0.10 and variable retention criteria p≤0.05 was used to identify risk factors for mortality. Results: From 7/04 to 12/14, 155 pts received definitive non-operative treatment (103 dCRT, 52 dRT). Clinical stage I disease was present in 20 (13.2%); stage II in 40 (26.5%) and stage III in 91 (60.3%) of the pts. Pts who received dCRT were younger (67 v 74 years, p&lt;0.001) and had more advanced clinical stage (p=0.026). Loco-regional recurrence / persistence was the predominant form of treatment failure occurring in 60% of pts (dCRT 54.3%, dRT 71.2%, p=0.044). With a median follow-up of 34.9 months (range 2.0-107.1), the median OS was 17.3 months (15.6m dCRT, 19.8m dRT, p=0.40) and the projected 5 year OS was 11.5% (16.1% dCRT, 4.0% dRT, p = 0.030). On univariable and multivariable analysis, a worse ECOG performance status, increasing clinical T descriptor, and increasing clinical N descriptor were prognostic for a worse OS. After adjusting for these variables, dRT was associated with a worse OS [dRT/dCRT HR 1.79 (1.20-2.68) p=0.005]. Conclusions: Definitive RT/CRT for LRC ACA of the E/GEJ is associated with poor OS. Long-term survival is nonetheless possible in a small number of pts and appears more likely after dCRT.