tbuckley/cabot-search huggingface dataset:
Nazartinib (EGF816) in patients with treatment-naïve <i>EGFR</i>-mutant non-small cell lung cancer (NSCLC): Updated phase II results.
Authors: Daniel Shao-Weng Tan, Natasha B. Leighl, James Chih-Hsin Yang, Gregory J. Riely, Lecia V. Sequist, Ryo Toyozawa, Juergen Wolf, Enriqueta Felip, Sang-We Kim, Santiago Ponce Aix, Egbert F. Smit, Toyoaki Hida, Christian Grohé, Samson Ghebremariam, Leslie O’Sullivan-Djentuh, Riccardo Belli, Monica Giovannini, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2020)

9574 Background: Prior data from a phase I/II study showed durable responses, including efficacy in brain lesions, and a tolerable safety profile with nazartinib in treatment (tx)-naïve patients (pts) with EGFR-mutant (mut), locally advanced (adv)/metastatic NSCLC. Here we report updated phase II results, including overall survival (OS). Methods: Tx-naïve adult pts with activating EGFR-mut (L858R or ex19del), stage IIIB/IV adv NSCLC with neurologically stable and controlled brain metastasis (BM) received oral nazartinib 150 mg once daily (continuous schedule). Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1; secondary endpoints: disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), OS, and safety. Results: At data cut-off (Nov 1, 2019), 45 pts were enrolled (median [range] age: 64 [28–83] years; 26 pts [58%] ECOG PS 1; 18 pts [40%] had baseline BM). EGFR mutations: 56% ex19del, 40% L858R, 4% other. 26/45 pts (58%) discontinued tx, with the primary reason being progressive disease in 19 pts (42%); 2 pts (4%) discontinued tx due to AEs. Median (range) follow-up for OS: 25 (0–33) months (mo); and for PFS: 17 (0–33) mo. ORR by BIRC: 69%; median PFS by BIRC: 18 mo; median OS was NE and at 33 mo, 56% of pts were alive (Table). BIRC results by baseline BM are shown in the Table. Median (range) duration of exposure: 24 (0–34) mo. Most frequent AEs (≥20% all grade, all causality): diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough and stomatitis (27% each), decreased appetite and pruritus (24% each), and dermatitis acneiform (22%). Most frequent grade 3/4 AEs (≥10%, all causality): maculopapular rash (5 pts [11%]; all grade 3) and increased lipase (5 pts [11%]; 1 pt with grade 4; no clinical pancreatitis AE was observed). Conclusions: After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3 rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Clinical trial information: NCT02108964 . [Table: see text]
The spatial localization of CD163+ tumor-associated macrophages predicts prognosis and response to therapy in inflammatory breast cancer.
Authors: Christophe Van Berckelaer, Charlotte Rypens, Steven Van Laere, Koen Marien, Pieter-Jan Van Dam, Peter B. Vermeulen, Cecile Colpaert, Luc Yves Dirix, Mark Kockx, Peter Van Dam
Journal: Journal of Clinical Oncology (2020)

3086 Background: The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are under investigation. A specific immune response seems to be an important driver, but the functional role of infiltrating immune cells in IBC remains unclear. Tumor-associated macrophages (TAMs) are associated with worse outcome, while CD8+ cytotoxic T cells demonstrate anti-tumor properties in breast cancer. In this study, we assessed spatial associations between CD163+ TAMs, CD8+ cells and cancer cells in IBC, using deep-learning and ecological statistics. Methods: We collected clinicopathological variables, evaluated PDL1-positivity (SP142, Ventana) and scored TILs according to the TIL working group guidelines on H&amp;E slides for 144 IBC patients. Immunostainings for CD8 and CD163 (Hematoxylin-DAB) were done according to validated protocols. All slides were digitized, underwent virtual multiplexing and were evaluated in Visiopharm to quantify the number of DAB+ immune cells. Each immune cell was located using XY coordinates and spatial interactions were examined using a Morisita Horn Index (MHI). Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8-stained slide. This algorithm was trained in 18 images with more than 150.000 iterations (Deeplabv3+). Results: Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 30.6% (n= 30/98) of the patients with initially localized disease. Besides PDL1-postivity ( P= .03), infiltration with CD8+ T cells ( P= .02) and TAMs ( P= .01) also predicted pCR. However, a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, the colocalization of CD163+ and CD8+ cells (MHI &gt;0.83) was associated with pCR (P= .01) and remained significant in a multivariate model (OR: 3.18; 95% CI: 1.04 – 10.6; P= .05) including TIL score, PDL1-positivity and hormone receptor (HR) status. Furthermore, a shorter disease-free survival (DFS) was associated with HR- status, no pCR and the colocalization of TAMs near tumor cells (HR: 3.3; 95% CI: 1.6 – 7.1; P= .002) in a multivariate model. The density of TAMs was not associated with outcome. Conclusions: The impact of TAMs on clinical outcome appears to depend on the spatial arrangement. The number of TAMs solely was not associated with outcome, but patients with more TAMs in proximity of the tumor cells had a worse DFS. Surprisingly, the clustering of TAMs near CD8+ cells was associated with pCR independent of the number of TAMs or TILs.
Relationship of chronic neurogenic pain and fibrinolysis in the blood of patients with melanoma.
Authors: Ludmila Ya. Rozenko, Elena M. Frantsiyants, Valeria A. Bandovkina, Yulia A. Pogorelova, Natalia D. Cheryarina, Marina A. Gusareva, Oleg I. Kit
Journal: Journal of Clinical Oncology (2020)

e22085 Background: The plasminogen regulation system is critical in triggering proteolysis to cleave the extracellular matrix and basement membrane. The “uPA-uPAR” system is involved in extravascular fibrinolysis and is responsible for the formation of plasmin associated with invasion and metastasis. The purpose of the study was to analyze levels of factors of the plasminogen regulation system in the blood of patients with cutaneous melanoma (M) and chronic neurogenic pain (CNP). Methods: Blood levels of PAP, uPA, uPAR and PAI-1 were measured by ELISA in patients with Т 3-4 N x M 0 melanoma: 21 women with CNP (pelvic pain - 7, osteochondrosis – 14), mean age 67.2±2.7 years; 17 men with CNP (osteochondrosis), mean age 65.6±3.1 years. The control group included patients with melanoma similar in age, gender and disease stages without CNP. Results: Blood levels of PAP in women with M+CNP were twice higher than in patients with M without CNP, the levels in men with M+CNP did not change; uPA content increased in both women and men with M without CNP by 1.4 and 1.5 times, uPA activity was elevated only in women by 2.4 times, in men it was reduced by 2 times; uPAR was increased by 1.5 times in women and men compared to the values in both female and male patients with M without CNP. PAI-1 content in women and men with M+CNP was similar to control values, and its activity was increased in women by 1.5 times and decreased in men by 2.5 times. Conclusions: The study gives significant additional information on the effect of CNP on relationships in the plasminogen activation system in a combination of cutaneous melanoma and CNB showing marked gender differences. The results should be taken into account in the special treatment of patients with melanoma.
Association of oxygen uptake efficiency in exercise test with exercise capacity in patients of obstructive sleep apnea hypopnea syndrome
Authors: Jiawei Ren, Yihui Zhang, Jinming Liu, Jian Guo, Changwei Wu
Journal: BMJ (2015)

Objective
To explore the characteristics of oxygen uptake efficiency (OUES) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and analyze the relationship between OUE and severity of disease.


Methods
Pulmonary function test, polysomnogram and cardiopulmonary exercise testing were performed in 35 patients with OSAHS and 25 age-matched healthy volunteers. Their successive breathing respiratory exchange parameters were collected and analyzed. And t and χ2 tests were used for 2 sample comparison. Correlation analysis was performed by Pearson correlation test.


Results
Significant differences in peak VO2 and peak VO2%pred existed between OSAHS and normal control groups [(18±4) vs.(28±6) L/min, P<0.01; (68±14) vs.(84±16) %, P<0.01]. Compared with normal control group [(2.3±0.5) L·min-1·lg-1; (36±4) ml/L; (36±4) ml/L], OUES, OUEP and OUE@AT of OSAHS group [(1.8±0.4) L·min-1·lg-1; (31±5) ml/L; (30±5) ml/L] were significantly lower (t=3.78-4.49, all P<0.01). And OUES, OUEP and OUE@AT in OSAHS patients were correlated (r=0.53-0.67, all P<0.01) positively with exercise tolerance (peak VO2%pred) while negatively with apnea hypopnea index (AHI) (r=-0.67--0.54, all P<0.01).


Conclusion
The oxygen uptake efficiency of patients with OSAHS is significantly reduced compared to that of normal subjects. And it is correlated negatively with severity of disease.


Key words: 
Sleep apnea, obstruction; Exercise testing; Ventilatory efficiency
A clinical observation of single doxepin or trimebutine mealate and combination of them in the treatment of irritable bowel syndrome
Authors: Jing-dong Wang
Journal: BMJ (2008)

193 patients with irritable bowel syndrome (IBS) were divided into 3 groups stochastically:73 cases were treated with both trimebutine malate and doxepin. 56 cases were only treated with doxepin, and this group was given doxepin to take orally. The other 64 cases were only treated with trimebutine malate. This group were given trimebutine malate to take orally. Doxepin was given 12.5-25.0 mg tid po, and trimebutine malate was given 200 mg tid po. This is for a course of 4-week-therapy. The rates of the total response of the 3 groups were 95.9%, 83.9% and 81.3% respaefively. The effect of the combination of the 2 drugs is much higher than the other two (P<0.01), and especially it has the highest effect on diarrhea type IBS. The rates of the improvement of nervos and mental symptoms were 87.0%, 79.0% and 71.6% respectively. The effect of combination use is the highest. It suggests that both the single use and combination use of doxepin and trimebutine malate has the effect on the treatment of IBS, but the combination use can improve the effect obviously.

Key words: 
Rritable bowel syndrome;  Doxepin;  Trimebutine
Phase II trial of induction chemotherapy plus chemoradiotherapy with aspirin or placebo in high-risk rectal cancer (ICAR).
Authors: Juliana Souza, Rodrigo Otavio Araujo, Marcus Valadão, Victor Marcondes Lopes Santos, Jamille Gonzaga, Monica Luciana Agostinho Padoan, Monique Alvares Barbosa, Claudia Torres, Raquel Guimarães, Juliana Carvalho, Roberto de Almeida Gil, Isabele Small, Maria Aparecida Ferreira, João Pedro Araujo Simões Correa, Ivanir Martins Oliveira, Eduardo Linhares Rielo Mello, Andreia Cristina De Melo, Luiz H. Araujo
Journal: Journal of Clinical Oncology (2020)

e16131 Background: Induction chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in locally-advanced, high-risk rectal cancer. Additionally, aspirin has shown potential to lower recurrence rate in colorectal cancer, and improve outcomes alongside CRT in rectal cancer, with higher rate of tumor downstaging. Methods: Randomized, double-blind phase 2 trial to evaluate induction treatment with XELOX, followed by capecitabine-based chemoradiotherapy with aspirin or placebo in a high risk population selected by MRI. The aim of this study was to evaluate MRI response after total neoadjuvant treatment with aspirin or placebo. Results: Of the 25 pts who started treatment between January 2018 and March 2019, 4 pts did not complete (1 pt grade 5 diarrhea; 1pt treatment adherence). Median age was 55yo (32.9 - 73.6), 8 pts (32%) were women, and 80% had 3 or more high-risk criteria. 20 pts (80%) showed symptom improvement in the first cycle of IC. Of the 21 patients who finished treatment until interim analysis, 11 pts received aspirin (2 pts had MRI complete response (CR), 3 pts had minor/no response, and 3 pts had progression disease (PD)). 10 pts received placebo (4 MRI CR, 3 pts had minor/no response, and no PD). Conclusions: Aspirin added to chemoradiotherapy was safe but did not improve response to total neoadjuvant treatment. The study was closed due absence of benefit. Clinical trial information: NCT03170115 .
Monitoring of inflammatory response to cancer immunotherapies.
Authors: Qimin Quan, John Geanacopoulos, Joshua Ritchey, Mark Clenow, Joe Wilkinson, John Boyce
Journal: Journal of Clinical Oncology (2020)

e15199 Background: Inflammation observed in response to some monoclonal antibody drugs and adaptive T-Cell therapies has become a major issue in cancer immunotherapy. Prognostic monitoring of the inflammatory response requires simultaneous measurement of multiple cytokines at widely divergent concentrations. At present, no analytical method, known to us, can provide large dynamic range (&gt; 6 logs), high sensitivity (&lt; 1pg/ml) and high multiplex in a single test. Methods: The NanoMosaic platform is a cytokine quantification technology powered by silicon nanoneedle biosensors that are densely integrated on a plate and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a label-free biosensor, functionalized with capture antibodies. Each analyte specific sensing area consists a total of ~23k nanoneedles divided into a digital region (~20k nanoneedles) and an analog region (~3k nanoneedles), combined to cover the entire range of inflammatory biomarkers from 0.1pg/ml to 1ug/ml. Results: We demonstrated that the digital nanoneedles achieve the single molecule sensitivity. Therefore, at ultra-low concentrations when antigens that are captured by the nanoneedles follow Poisson statistics, the number of antigens can be quantitated by counting the presence or absence of color changes of individual nanoneedles in a binary fashion. As the protein concentrations increase, the binding events increase accordingly and achieve saturation when all nanoneedles capture more than one protein. Above the digital saturation concentration, an adjacent section of analog nanoneedles perform quantitative analysis based on the level of color change, thus providing a wider dynamic range up to 1ug/ml. Each single analyte area, including both digital and analog sensors, is less than 500um. Therefore, high level multiplex can be achieved by duplicating the detection sensor in a microarray format without loss of sensitivity and dynamic range. Conclusions: The CMOS-compatible NanoMosaic technology provides the cost-effectiveness, sensitivity, dynamic range and multiplexing capacity required to fully integrate patient immune response into therapeutic development and decision making.
Abstract 237: Using the Thoracic Impedance to Predict Measures From Invasive Arterial Blood Pressure in Out-Of-Hospital Cardiac Arrest
Authors: Andoni Elola, Elisabete Aramendi, Unai Irusta, Per-Olav Berve, Fredrik K Arnwald, Lars Wik, Fred W Chapman
Journal: Circulation (2019)

Background: During cardiopulmonary resuscitation (CPR), pulse detection can be challenging. Invasive blood pressure measurements (IBP) can help monitoring patient hemodynamics, but arterial catheter placement is difficult. Transthoracic impedance (TI) measured between the defibrillator pads can detect circulation activity. We hypothesized that TI changes can predict the corresponding IBP, and potentially be used to non-invasively detect pulse during CPR. Materials and methods: We included 28 out of hospital cardiac arrest patients receiving CPR by the Oslo Emergency Service who had concurrent recordings of IBP (radial artery, BD, 20G, US) and TI (via defibrillator pads, LP15, Stryker, US). 5-second segments with stable and CPR artefact free signals were extracted (Figure). The circulation component of the TI signal (Figure, red line) was extracted using a Kalman smoother. Ten waveform features were computed per segment and fed into a random forest regressor to predict systolic and diastolic arterial pressures (SAP, DAP), their difference (DifAP) and area of the IBP signal (ArAP). Pearson correlation coefficients between the regression model and the IBP metrics were computed. Data were divided by patient into training/test sets to fit and evaluate the model, respectively, and the process was repeated 500 times. Results: 235 minutes (2261 segments) were extracted with median (Q1-Q3) values of 71.3(39.2-88.1) mmHg for SAP, 44.2(30.0-50.0) mmHg for DAP, 25.6(7.1-38.8) mmHg for DifAP and 63.4(17.0-85.9) mmHg*sec for ArAP. The correlation coefficients between TI-predicted and IBP-measured SAP, DAP, DifAP and ArAP were 0.62 (0.49-0.72), 0.36 (0.22-0.49), 0.69 (0.57-0.76) and 0.64 (0.50-0.73), respectively. Conclusions: Different hemodynamic phases can be observed in both TI and IBP (Figure). TI-based predictions showed good correlation with IBP measures. This could lead to new non-invasive methods to monitor different phases of circulation based on the TI.
Immunohistochemical characterization of anaplastic large cell lymphoma using tissue microarray.
Authors: Poorvi Kirit Desai, Ling Zhang, Qianxing Mo, Lubomir Sokol
Journal: Journal of Clinical Oncology (2020)

8048 Background: Anaplastic Large Cell Lymphoma (ALCL) is a subtype of mature T-cell lymphoma comprised of systemic (ALK+ or ALK-) and primary cutaneous (PCALCL) forms. ALK+, usually associated with NPM1-ALK gene, has a favorable prognosis. PCALCL is usually indolent. Despite worse prognosis for ALK-, pts with DUSP22 rearrangement have favorable outcomes similar to ALK+ while those with p63 aberration have poor outcomes. We hypothesize that other genetic alterations in ALCL could aid in diagnosis and prognosis. We compared protein expression levels of selected signaling molecules (JAK1, STAT3, DUSP22, ERBB4/HER4, PRDM1/BLIMP1 and SOCS3) among the subtypes and correlated to outcomes. Methods: Of 50 pts with ALCL at Moffitt (MCC) from 2000-2019, 27 tissue samples (6 ALK+, 10 ALK-, 8 PCALCL, 3 controls) met eligibility criteria. Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded lymph node biopsies. Up to 3 replicate cores were taken from each block. Immunohistochemistry was performed with antibodies to the selected proteins. Stained TMA slides were scanned using the Aperio™ ScanScope XT2 to determine % positive biomarker stain within each core per established algorithm. Statistics: ANOVA was used to compared protein expression levels, with pairwise tests when significant. T-test compared PCALCL to systemic ALCL. Boxplots were created for differences in protein expression levels and time to event outcomes (OS and RFS) using Log rank test and Cox proportional hazards models. Kaplan-Meier curves were used for clinical time-to-event outcomes and quartiles of the protein expression levels. Results: The 3 subgroups had a significant difference in SOCS3 expression with mean and std respectively: 42.4% (0.153), 17.4% (0.089), and 21.0% (0.155), p = 0.008. Among all pairs, ALK+ and PCALCL groups were statistically different (P = 0.011). Patients with high BLIMP1 (≥28.5%) across 3 ALCL subgroups were associated with better median OS (not reached) in comparison to pts with lower expression (27.3 mos) (Log rank test p = 0.014, HR = 0.17, 95% CI 0.034-0.829). The same was seen for median RFS (81.1 vs. 12.5 mos). (Log rank test p = 0.009, HR 0.23, 95% CI 0.069-0.755). Conclusions: High BLIMP1 suggests favorable prognosis in ALCL and could potentially be a positive prognostic marker. High SOCS3 appears more prevalent in PCALCL than systemic and could aid in differential. Larger samples should be used to validate results. Secondary markers like Bcl-2 can be considered in the future to correlate expression levels to targeted treatments like venetoclax.
一家庭两成员共患肾综合征出血热的诊治
Authors: 黄绍萍, 卢水华, 王介非, 谢德胜
Journal: BMJ (2009)

近十多年来,肾综合征出血热(hemorrhagic fever with renal syndrome,HFRS)发病率明显减少,不少低年资医师,对此病不熟悉.为减少误诊、提高对本病的早期诊断水平,介绍2例不典型HFRS患者的诊治及文献复习。
The study of the treatment efficacy in metastatic castration-resistant prostate cancer of low dose abiraterone with food.
Authors: Kanta Makphanchareonkit, Thitiya Sirisinha Dejthevaporn, Dittapol Muntham, Phichai Chansriwong
Journal: Journal of Clinical Oncology (2020)

e17571 Background: Abiraterone acetate and prednisolone (AAP) + ADT has been approved for treatment metastatic castration-resistant prostate cancer (CRPC) in the standard dose 1,000 mg with fasting state. Data in Ramathibodi hospital showed patients who had treated with standard dose of Abiraterone acetate (AA); had PSA response 47.83%. Previous studies showed using low dose AA of 250 mg with food had the non-inferiority results in efficacy. AA was not be reimbursed in Thailand, so the ability to use a highly effective drug at a quarter of the dose, could help in patient accessibility to cancer treatments. We sought to test the hypothesis that low-dose AA with food would have the comparable activity in Thai CRPC patients in both of the pre-Docetaxel and post Docetaxel treatment groups, and exploring the quality of life (QOL) of these patients. Methods: An observational cohort enrolled newly diagnosed metastasis CRPC at Ramathibodi hospital from 1 st Jan 2019 to 31 st Dec 2019. Patients were assigned to AA (250mg) with actual daily life meal. We collected the data of serum PSA and the adverse events every 4 weeks for 4 months. The QOL data was collected with the EuroQoL (EQ-5D) questionnaire which were done at baseline and every 4 weeks. The primary end point was PSA response that defined as PSA decreased ≥ 50% from PSA level at baseline. The secondary endpoint were the depth of PSA change, QOL and adverse events by using Fisher's exact test and T-test. Results: 21 patients were enrolled. At 12 weeks, there were 11 patients (52.38%) achieved 50% PSA response and 6 patients (28.57%) achieved 90% PSA response. The adverse events occurred 23.8%, and mostly were mild grade. The adverse events were comparable with the historical data in standard dose of AA. Low dose AA has significantly shown the improvement in quality of life from baseline (p &lt; 0.001), and especially the significant improvement in pre-Docetaxel subgroup. Conclusions: Low-dose AA with food has good efficacy in PSA response, adverse events and QOL. Moreover, low dose AA shows more efficacy especially in pre-Docetaxel mCRPC patients. Low dose AA may be helping in reducing cost of cancer care, enabling in delivering affordable cancer care and increasing value of treatment.