tbuckley/cabot-search huggingface dataset:
Five-year results of a non-randomised study evaluating spiral computed tomography (sCT) for early detection of lung cancer (LC)
Authors: S. Novello, M. Giajlevra, P. Lausi, M. Brizzi, G. Selvaggi, D. Sardo, P. Borasio, L. Dogliotti, C. Fava, G. V. Scagliotti
Journal: Journal of Clinical Oncology (2006)

7210 Background: In high-risk subjects low-dose sCT showed a 4-fold increase in the detection rate of neoplastic nodules in comparison with chest-X-ray. However, among studies there is a considerable discrepancy in the % of lung nodules, overall lung cancer and stage I detection rate as well as of the additional diagnostic work up. Subjects &amp; Methods: From April to December 2001, 520 asymptomatic volunteers aged ≥ 55 years with a history of cigarette smoking ≥ 20 packs-year and of no previous cancer received annually chest sCT for 5 consecutive years. Results: At baseline 73% were male, median age was 59 years and 91% current smokers. At baseline sCT 127 subjects (24.5%) had nodules &lt;5 mm while nodules ≥5 mm were detected in 114 (22%); the size of lung nodules ranged from 5 to 9.9 mm in 81.5% of the cases. The % of nodules worth of additional investigation varied over time (2 yr: 6%; 3 yr: 5%; 4 yr: 11%). Five (1%) cases of LC were detected during the 1st year (3 stage I) and in two additional resections an atypical adenomatous hyperplasia was found. Three new cases of thoracic cancers were detected in the 2nd, 3rd and 4th year of the study. Drop-out rate in the first year was 5% (2 yr 4,5%, 3 yr 2.3% and 4 yr 3%). One interval case was detected during the 3 rd year. Subjects who quitted smoking in the 1 st year were 13% and the % decreased over years (6% at the end of 3rd yr and 3% at 4th and 5th yr) and among quitters failure rate was 1–2%/year. In 3% of cases quitting was related to an acute cardiovascular or respiratory event. Fifty % of subjects showed some radiological signs of emphysema. Conclusions: Evidence from ongoing randomised trials is needed to support the routine use of sCT for early detection of LC. A program of smoking cessation is strongly recommended for further studies. Currently a conservative attitude should be encouraged. No significant financial relationships to disclose.
Extracellular DNA NET-Works With Dire Consequences for Health
Authors: Nicoletta Sorvillo, Deya Cherpokova, Kimberly Martinod, Denisa D. Wagner
Journal: Circulation Research (2019)

Neutrophils play a central role in innate immune defense. Advances in neutrophil biology have brought to light the capacity of neutrophils to release their decondensed chromatin and form large extracellular DNA networks called neutrophil extracellular traps (NETs). NETs are produced in response to many infectious and noninfectious stimuli and, together with fibrin, block the invasion of pathogens. However, their formation in inflamed blood vessels produces a scaffold that supports thrombosis, generates neo-antigens favoring autoimmunity, and aggravates damage in ischemia/reperfusion injury. NET formation can also be induced by cancer and promotes tumor progression. Formation of NETs within organs can be immediately detrimental, such as in lung alveoli, where they affect respiration, or they can be harmful over longer periods of time. For example, NETs initiate excessive deposition of collagen, resulting in fibrosis, thus likely contributing to heart failure. Here, we summarize the latest knowledge on NET generation and discuss how excessive NET formation mediates propagation of thrombosis and inflammation and, thereby, contributes to various diseases. There are many ways in which NET formation could be averted or NETs neutralized to prevent their detrimental consequences, and we will provide an overview of these possibilities.
Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study
Authors: Michael Wang, Simon Rule, Pier Luigi Zinzani, Andre Goy, Rene-Olivier Casasnovas, Stephen D. Smith, Gandhi Damaj, Jeanette K. Doorduijn, Thierry Lamy, Franck Morschhauser, Carlos Panizo, Bijal Shah, Andrew Davies, Richard Eek, Jehan Dupuis, Eric Jacobsen, Arnon P. Kater, Steven Le Gouill, Lucie Oberic, Tadeusz Robak, Todd Covey, Richa Dua, Ahmed Hamdy, Xin Huang, Raquel Izumi, Priti Patel, J. Greg Slatter, Wojciech Jurczak
Journal: Blood (2017)
Health-related quality of life after IMRT or IMRT+ HDR brachytherapy for intermediate or high-risk prostate cancer: Five-year results of a prospective trial.
Authors: Benjamin Guix, Teresa Maria Lacorte, Jose Maria Bartrina, Jose Ignacio Tello, Ines Guix, Guillermo Galdon, Marc Espino, Teresa Guix
Journal: Journal of Clinical Oncology (2013)

e16071 Background: To report long term Health Related Quality of Life (HRQoL) in a prospective series of 629 patients with intermediate or high-risk clinically localized prostate cancer treated with either IMRT or IMRT + HDR. Methods: Between December 1999 and December 2010, 629 patients (pts) with PSA›10, Gleason score›6 and/or T2b-T3 N0 M0 prostate cancer entered the study. Pts were prospectively assigned to one of the two treatment groups: 76 Gy HD-3D-IMRT to the prostate in 38 fractions (group 1; 315 patients) or 46 Gy LD-3D-CRT+ 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2, 316 patients), limiting the maximum rectal dose to 85% of the prescribed dose. Both groups were well balanced taking into account patient’s as well as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels as well as HRQOL was done. Results: All pts completed treatment. None pts included in group 1 or 2 had grade 3 or more rectal toxicity. With a mean follow-up of 96 m, the 8-year free-from-failure survival was 90.7% and 98.3% (p&lt;0.02) in group 1 and 2 respectively; free-from-metastases survival 96.9% and 97.9% (p&lt;0,08)for group 1 and 2; and cause-specific survival 97.4% and 98.3% (p&lt;0.09). HRQoL was evaluated before treatment, at 3 months interval during the first year follow up and in a yearly basis until 10-year. I-PSS and EORTC’s QLQ-C30 with PR-25 were used. I-PSS scores at 1, 3 and 6 months and at 1, 2, 3, 5 and 8 years follow-up were 6.39, 5.00, 2.52, 2.21, 2.35, 3.65 and 1.43 for group 1 pts and 1.50, 1.10, 1.01, 1.05, 0.89, 0.66, 0.67 for group 2 pts. Global HRQoL scores at 1, 3 and 6 months and at 1, 2, 3 and 5 years follow up were 5.56, 5.75, 5.33, 6.00, 5.40, 5.58 and 5.11 for group 1 pts and 5.60, 6.40, 5.78, 5.89, 5.83, 6.37, 6.00 for group 2 pts, being found to be statistically significant at 3 and 5 years follow up (p&lt;0,001 and p&lt;0,024). Conclusions: High-dose 3D-IMRT + HDR brachytherapy was found to be a method of escalating the dose to the prostate that not only increased the chances of cure for patients if not increased their long-term Health Related Quality of Life.
Differential Responsiveness of Monocyte and Macrophage Subsets to Interferon
Authors: Shuhong Han, Haoyang Zhuang, Pui Y. Lee, Mingjia Li, Lijun Yang, Peter A. Nigrovic, Westley H. Reeves
Journal: Arthritis & Rheumatology (2019)

Objective Peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature. Methods Proinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN‐α/β/ω receptor (IFNAR‐1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFNα, and pSTAT1was measured. Results Transcriptional profiling of peritoneal macrophages from mice with pristane‐induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages ( P &lt; 0.0001 and P &lt; 0.05, respectively, by Student's t ‐test). Nonclassic monocyte/macrophages were also relatively insensitive to IFNα‐driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression ( P &lt; 0.0001 by Student's t ‐test) and IFNα‐stimulated gene expression ( P &lt; 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages. Conclusion This study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFNα signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.
Capture of EpCAM-negative and vimentin-positive circulating cancer cells (CCCs) from blood of metastatic breast cancer patients using ApoStream.
Authors: Christopher Neal, Sujita Sukumaran, Vishal Gupta, Insiya Jafferji, Dave Hasegawa, Vladislava O. Melnikova, Darren W. Davis
Journal: Journal of Clinical Oncology (2012)

e21029 Background: Up-regulation of epithelial mesenchymal transition (EMT) and the reduction of epithelial marker expression is associated with invasion, cancer progression, resistance to conventional therapies and poor prognosis. ApoStream, a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, was used to enable antibody-independent capture of circulating cancer cells (CCCs,also referred to as circulating tumor cells, CTC) for subsequent phenotyping of EMT markers. Methods: A side-by-side comparison of CellSearch and ApoStream was performed on 10 metastatic breast cancer patients. A multiplexed immunofluorescent assay and laser scanning cytometry analyses were used to unambiguously identify CK + /CD45 – /DAPI + CCCs and quantify their EpCAM and vimentin expression. Results: ApoStream recovered CK + /CD45 – /DAPI + CCCs from each breast cancer patient sample tested (mean=255 CCCs per 7.5 ml blood, see Table). ApoStream consistently recovered significantly higher number of CCCs compared to CellSearch (p=0.024). ApoStream recovered both EpCAM + and EpCAM – CCCs in 50% and 90% of patients, respectively. Vimentin + CCCs were isolated from 90% of patients. Conclusions: ApoStream’s higher capture efficiency demonstrated the majority of CCCs from breast cancer patients were EpCAM negative and vimentin-positive. ApoStream technology can be used to monitor CCCs undergoing EMT. [Table: see text]
Treatment patterns and site of metastasis in patients with metastatic colorectal cancer (mCRC).
Authors: Sheikh Usman Iqbal, Stephen F Thompson, Sarah Naoshy, Daniel B Ng, Michael Wooten, Steven A Sherman, Elisabetta Malangone, Lee Stern, Magdaliz Gorritz-Kindu
Journal: Journal of Clinical Oncology (2012)

e14030 Background: The real-world impact of metastatic (met) site on Tx choice in mCRC is unknown. Therapeutic associations across metastases can identify gaps in care and inform clinical decision support systems. This study assessed Tx patterns in mCRC pts by met site. Methods: 4656 stage III/IV pts ≥18 yrs at mCRC diagnosis receiving anticancer agents were followed in a retrospective observational study using electronic medical records from the largest oncology database (SDI) from 1/1/04-7/31/11. 1st- (1L), 2nd- (2L), and 3rd-line (3L) therapies were identified for top 4 met sites. Logistic regression adjusting for met site overlap determined Tx use by met site and therapy line. Results: Pts were mostly male (54.1%) and on average 61.6 yrs. The top 4 met sites were liver (34.2%), lung (15.9%), lymph (15.8%), and bone (7.5%). Leading regimens are presented in the table below. Bevacizumab (B) use varied by met site and therapy line. Against other/unknown met sites, 1L B was more common in liver (OR=2.06 [1.75-2.42]) and bone (OR=1.46 [1.16-1.84]), less common in lymph (OR=0.60 [0.50-0.73]), and statistically equal in lung (OR=1.01 [0.85-1.20]). In 2L, B was more likely to be given for liver (OR=1.77 [1.48-2.11]) and lung (OR=1.45 [1.21-1.74]) vs no significant difference for bone (OR=1.17 [0.92-1.50]) and lymph (OR=0.87 [0.71-1.07]) sites. B use in 3L mirrored 2L. Conclusions: Besides 1L in pts with lymph metastases, top regimens across met sites for 1L, 2L, and 3L were FX + B, FR + B, and IRI + C, respectively; however, significant differences in B Tx patterns were evident. Further research should examine the impact of differential B use on outcomes. [Table: see text]
The value of RCAS1 as a potential biomarker in non-small cell lung cancers.
Authors: Nikolaos Tsoukalas, Ioannis Kostakis, Spiros Siakavellas, Maria Tolia, Aristoula Papakostidi, Andreas Karameris, Alexandros Tzovaras, Ioannis Sfiniadakis, Evangelos Tsiambas, Alexandros Ardavanis, Evangelos Manolis, Christos Kittas, Stamatios Theocharis
Journal: Journal of Clinical Oncology (2012)

e21098 Background: RCAS1 (Receptor-binding Cancer Antigen expressed on SiSo cells) is a membrane protein that is expressed in different types of cancer. It halts the cell cycle and/or induces the apoptosis of the immune system cells within the tumour microenvironment. Hence, it is possible that this molecule is involved in the mechanism of the tumour cells’ escape from the immune system surveillance (immunoescape). Methods: Patients with primary non small cell lung cancer, initially eligible for surgical treatment, were included. The tissue samples (paraffin cubes) were processed using the Tissue Micro-arrays Method. Immunohistochemical study was done with specific monoclonal antibodies for RCAS1 and Ki-67. The image analysis was feasible due to a special program (image analysis software). In addition, a database was created that included the clinical and pathological characteristics of the patients. After the surgery patients received chemotherapy and/or radiotherapy according to the guidelines. Associations between variables were analyzed with non-parametric tests (Mann-Whitney and Kruskal-Wallis test) and the survival analysis with the Cox proportional hazards model. Two tailed p values ≤ 0.05 were considered to be statistically significant. Results: In total, 112 patients were examined (93 men and 19 women), mean age 63,6 years old. Almost 53% of the cases were adenocarcinoma, 33% squamous cell, 9% large cell, and 5% other types. Statistical significance was identified correlating RCAS1 over-expression to lower overall survival (p=0.032), to grade III (p=0.006) and in a positive correlation between RCAS1 and Ki-67 (p&lt;0.001). Moreover, there is a trend of RCAS1 over-expression in advanced or metastatic stages and in tumours with lymphovascular invasion. In contrast, protein expression was not strongly associated to tumour size, to histological type, to patient age or to gender. Conclusions: The most important conclusions of this study are the negative correlation between RCAS1 and overall survival, the over-expression of RCAS1 in grade III tumors and the positive correlation between RCAS1 and Ki-67 which means that when Ki-67 increases RCAS1 is higher. Consequently, this molecule RCAS1 probably could be considered as a marker of the tumor’s aggressiveness.
Phase I/II trial of crolibulin and cisplatin in solid tumors with a focus on anaplastic thyroid cancer: Phase I results.
Authors: Ann Wild Gramza, Sanjeeve Balasubramaniam, Antonio Tito Fojo, Jean Ward, Samuel A. Wells
Journal: Journal of Clinical Oncology (2013)

6074 Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors, with a median survival of 3-5 months. Chemotherapy has not impacted local control or survival. Crolibulin (CRO) is a microtubule destabilizing agent that disrupts vascular endothelial cells, and in turn, blood flow to the tumor. Preclinical studies showed synergism with cisplatin (CIS). The phase I portion of this phase I/II study, designed to assess the safety and tolerance of CRO and CIS in patients with solid tumors, has completed accrual. Methods: Patients with advanced solid tumors, ECOG ≤ 1, and adequate organ function were treated on a dose escalation schema with CIS (75-100 mg/m 2 ) IV day 1 and CRO (13-20 mg/m 2 ) IV days 1, 2, 3 (21-day cycles). CIS and CRO were continued until unacceptable toxicity or progressive disease (PD), with an option to continue CRO alone if toxicity was CIS-related. Results: Between Jan 2011 and Jan 2013, 21 patients were enrolled and assigned CIS/CRO (mg/m 2 ) at 75/13 (6), 75/20 (3), and 100/20 (12). Diagnoses were as follows: ATC (16), urothelial carcinoma (2), prostate carcinoma (2) and mesothelioma (1). Patients received a median of 2 cycles of CIS/CRO (range: 1-6). Presently, four remain on CIS/CRO and one on CRO alone. The most common grade (G) 3 toxicities were: lymphopenia (33%), hyponatremia (29%), anemia (19%), hypertension during infusion (14%), and hypophosphatemia (9%). There were two G4 toxicities: elevated lipase and thrombocytopenia; and one G5 toxicity of laryngeal hemorrhage related to tumor erosion. There were two dose-limiting toxicities: G3 pancreatitis at dose level (DL) 1 and laryngeal hemorrhage at DL3. Eight ATC patients were treated at DL3. Of these, one (13%) had RECIST 1.1 complete response (CR) and one (13%) had stable disease (SD). Three (38%) had PD, and three are not yet evaluable. The CR has been on study for &gt; 12 months and remains on CRO alone. Conclusions: CIS plus CRO deserves further evaluation as a regimen for ATC. The MTD of CIS/CRO is 100 mg/m 2 IV day 1 and 20mg/m 2 IV days 1, 2, 3 every 21 days. This combination is well tolerated, with toxicity primarily related to CIS. The phase II portion of this trial will compare CIS/CRO versus CIS in ATC patients. Clinical trial information: NCT01240590.
The ABCD-10 Risk Prediction Model for In-Hospital Mortality Among Patients With Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis—Reply
Authors: Megan H. Noe, Rebecca A. Hubbard, Robert G. Micheletti
Journal: JAMA Dermatology (2019)

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Endothelial Cell Development and Its Application to Regenerative Medicine
Authors: Jingyao Qiu, Karen K. Hirschi
Journal: Circulation Research (2019)

The formation and remodeling of a functional circulatory system is critical for sustaining prenatal and postnatal life. During embryogenesis, newly differentiated endothelial cells require further specification to create the unique features of distinct vessel subtypes needed to support tissue morphogenesis. In this review, we explore signaling pathways and transcriptional regulators that modulate endothelial cell differentiation and specification, as well as applications of these processes to stem cell biology and regenerative medicine. We also summarize recent technical advances, including the growing utilization of single-cell sequencing to study vascular heterogeneity and development.
Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients.
Authors: Eric Jonasch, Paul Gettys Corn, Lance C. Pagliaro, Primo Lara, Xuemei Wang, Kim-Anh Do, Racheal Garza, Shelly Bird, Joseph J. Drabick, Valerie Marcott, David Quinn, Austin Doyle, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2013)

4517 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poorer prognosis in pts with advanced RCC. We hypothesized that optimal blockade of AKT in pts refractory to anti-VEGF therapy eliminates key drivers of tumor growth and proangiogenic signaling, and will prolong progression-free survival (PFS). We tested whether MK-2206, a selective allosteric inhibitor of AKT, will yield superior PFS to everolimus in anti-VEGF therapy refractory RCC pts. Methods: Eligible pts with metastatic RCC who progressed on an anti-VEGF agent were randomized (2:1 ratio) to receive MK2206 or everolimus. Up to two prior therapies allowed. Primary endpoint was PFS. The study had 80% power to detect a 67% increase in PFS with MK2206 over everolimus (8.2 vs. 4.9 mo) with a 1-sided log-rank at alpha= 0.10. One interim futility analysis was planned. Secondary endpoints: safety, overall survival, &amp; response rate. Tumor tissue was collected in correlative analyses. Results: A total of 43 patients were accrued; 42 were evaluable for efficacy. Demographics: Male, 77%;White, 81%; median age 62 (range 41-83). MK2206 was held in 3 pts due to grade 3 rash; 1 came off study for rash. No everolimus pt discontinued study drug due to AEs. 30 events had occurred at first futility analysis. The 1-sided log-rank p-value for rejecting null hypothesis was 0.979, exceeding p-value boundary of 0.6413 for stopping trial. Median PFS for MK2206 was 3.65 mo (95%CI 1.77-5.52) and 7.43 mo for everolimus (95%CI 1.84-13.27). Two out of 29 MK2206 pts demonstrated dramatic response with greater than 50% disease regression and PFS of 8 months and 6 months (ongoing). Conclusions: Monotherapy with MK2206 was not superior to everolimus in this randomized, phase II study. However, dramatic response to MK2206 was seen in a subset of patients. Planned translational studies to allow genotype-phenotype correlations may help explain this observation. Clinical trial information: NCT01239342.