tbuckley/cabot-search huggingface dataset:
Safety and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) plus subsequent taxane therapy.
Authors: Celestia S. Higano, Lauren C Harshman, Sabina Dizdarevic, John Logue, Timothy Richardson, Saby George, Danny Song, Igle J. de Jong, Jeffrey Tomaszewski, Fred Saad, Kurt Miller, Jeffrey Meltzer, Per Sandstrom, Bertrand F. Tombal, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2020)

5542 Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ≥6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles. Clinical trial information: NCT02141438 . [Table: see text]
Gender and time estimation as novel potent indicators of emotional concerns in cancer patients.
Authors: Asen Yanchev, Martina Ivanova, Ivan Donev, Eleonora Dimitrova, Nikolay Vladimirov Conev
Journal: Journal of Clinical Oncology (2020)

e24195 Background: Psychological stress is frequent after a cancer diagnosis. Thus screening is crucial for detecting it. The emotion thermometers (ETs) are validated screening tools and have five dimensions (distress, anxiety, depression, anger, and need‐for‐help). Methods: Time estimation was assessed in 374 chemonaïve patients with solid tumors by evaluating each subject’s prospective estimation of how quickly one minute passed compared to the actual time. ETs were used at the beginning of treatment to evaluate level of psychological stress of each patient. A multivariate analyses of covariance was run for the ETs as dependent variables with the addition of the following covariates: age and time estimation and gender as a fixed factor. Results: There were significant negative correlations between values of ETs and time estimation except anger. Women exhibited significantly faster time estimation than men. Using Pillai’s Trace, we found that there was a significant effect of gender and fast time estimation on reported values of ETs (V = 0.06, F (5,366) = 4.96, p &lt; .001; V = 0.05, F (5,366) = 3.84, p = .002, respectively). The covariate, time estimation, was significantly related to reported values of all ETs. There was also a significant effect of relationship on the gender and reported values of all ETs, except for depression and need-for-help after controlling for the effect of age and time estimation. Planned contrasts revealed that female are significantly more distressed, anxious and less angry when compared to males. Conclusions: Gender and time estimation are novel potent indicators of emotional concerns in cancer patients prior to starting chemotherapy.
Inflammatory bowel disease and risk of small bowel cancer: a binational population-based cohort study from Denmark and Sweden
Authors: Jordan E Axelrad, Ola Olén, Michael C Sachs, Rune Erichsen, Lars Pedersen, Jonas Halfvarson, Johan Askling, Anders Ekbom, Henrik Toft Sørensen, Jonas F Ludvigsson
Journal: Gut (2020)

Objective Crohn’s disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies have been small. We aimed to examine the risk of incident SBC and death from SBC in patients with inflammatory bowel disease (IBD). Design In a binational, population-based cohort study from Sweden and Denmark of patients with IBD during 1969–2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC and death from SBC. Cox regression was used to estimate adjusted hazard ratios (aHRs). Results We identified 161 896 individuals with IBD (CD: 47 370; UC: 97 515; unclassified IBD: 17 011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100 000 person-years; UC: 5.88/100 000 person-years), compared with 640 cases in reference individuals (2.81/100 000 person-years and 3.32/100 000 person-years, respectively). This corresponded to one extra case of SBC in 385 patients with CD and one extra case in 500 patients with UC, followed up for 10 years. The aHR for incident SBC was 9.09 (95% CI 7.34 to 11.3) in CD and 1.85 (95% CI 1.43 to 2.39) in UC. Excluding the first year after an IBD diagnosis, the aHRs for incident SBC decreased to 4.96 in CD and 1.69 in UC. Among patients with CD, HRs were independently highest for recently diagnosed, childhood-onset, ileal and stricturing CD. The relative hazard of SBC-related death was increased in both patients with CD (aHR 6.59, 95% CI 4.74 to 9.15) and patients with UC (aHR 1.57; 95% CI 1.07 to 2.32). Conclusion SBC and death from SBC were more common in patients with IBD, particularly among patients with CD, although absolute risks were low.
Abscopal effect induced intratumoral injection of chemotherapy drugs with hapten and tumor microstructure changes with protein expression of distal untreated tumors in mice.
Authors: Baofa Yu, Feng Gao, Peng Jing, Jian Liu, Jian Zhang, Bian Li, Huanzhen Yang, Yan Han, Yanfei Wu, Qiang Fu
Journal: Journal of Clinical Oncology (2020)

e15518 Background: To observe the abscopal effect by intratumoral injection of chemo drugs with hapten on tumor, and analyze the difference in expression of bilateral tumor proteins and the inhibition of tumor growth on the opposite side. Methods: Balb/c mice 45, H22 ascites were inoculated in left forelimb armpit. When longest diameter of about 4-5mm randomized (day 0); the next day, intratumoral injection different combination drugs, the three days later in the right armpit mice were inoculated inoculated 0.2ml (105/ml) H22 cells, the seven days later of secondary administration, while observing the contralateral sides, especially tumor growth. 15 days after first treatment each group were sacrificed 6 mice, tumor tissue on both sides for immunohistochemistry, quantitative RNA PCR quantitative determination. Results: It showed an upward trend in body weight in mice, 15 days after administration of DNP sustained release drug group and PYM control group of mice were significantly lower than the body weight of the negative control group, the difference between groups (P&lt;0.05); three groups of mice after administration of tumor volume on the left. On the 15th day after the administration, the left and right tumors in DNP group were significantly smaller than those in PYM group and negative control group, and the difference was statistically significant (P &lt; 0.05); the left tumors in PYM group were significantly smaller than those in negative control group, and the difference was statistically significant (P &lt; 0.05). After administration PYM control group’s Col1a1, CD4, Il12aA, TGF, Ela, NFKB, Cox2, CD11c, CD8, TNFa expression was significantly lower than the negative control group and DNP sustained-release drug group; DNP sustained-release drug group’s Col1a1, CD4,Il12aA, TGF, Elastin, NFKB, CD11c, CD8 expression was significantly lower than the negative control group. A large number of cell disintegration phenomenon, observed lymphocytes, leukocytes, the presence of high electron density granular, suggesting that there may be drugs enter into cancer cells. Conclusions: Intratumoral injection of chemotherapy drugs with hapten can exhibit significant anti-tumor effect. In the DNP sustained-release drug group, abscopal effect is more obvious. After the use of PCR quantitative detection of various tumors and fibroplasia, inflammatory factors and immune-related factors have changed significantly to further confirm abscopal effect by intratumoral injection of combination drugs.
Generation of dendritic cells using viral lysate of tumor cells in vitro.
Authors: Sergey A. Kolpakov, Elena P. Kolpakova, Anastasia O. Sitkovskaya, Elena Yu. Zlatnik, Svetlana Yu. Filippova, Elena S. Bondarenko, Vladimir E. Kolesnikov, Nairi B. Oganyan, Vladislav K. Pavlov, Timofey S. Karasev, Oleg I. Kit
Journal: Journal of Clinical Oncology (2020)

e15202 Background: The purpose of the study was to investigate the effect of a new unclassified rotavirus on the effectiveness of maturation of dendritic cells (DC) and their activation of lymphocytes in vitro. Methods: Strain No.100 of the RVK virus was isolated by S.A. Kolpakov and characterized as rotavirus. U87MG cell lysate (glioblastoma) was obtained by incubation with 10 8 RVK particles in the DMEM medium with L-glutamine for 72 hours; a cytopathic effect was observed. Immature DCs were cultured for 7 days in the presence of IL-4 and GM-CSF. For antigen loading of DCs, we used the following options for 48 h: a) U87MG lysate obtained by repeated freeze-thaw cycles (TL); b) U87MG lysate obtained by co-cultivation with RVK (VTL); c) RVK. To assess the DC ability to activate autologous lymphocytes, they were co-cultured for 5 days in a 3:1 ratio. Results: The use of VTL culture for DC loading caused an increase in the expression of mature DC (mDC) markers compared to TL: the number of CD83+/CD86+ cells increased by more than 2 times, CD83+/CD80+ by 1.2 times, CD83+HLA-DR - by 5.5 times. With VTL, expression of markers of immature DCs (CD1a, CD14) was minimal. The use of RVK as an antigen induced the generation of DCs from monocytes, but their maturation was much less pronounced: a significant increase in the membrane expression of CD86, but not CD83, was determined. These DCs demonstrated a higher expression of markers of immature DCs, compared to stimulation with cell lysates (both TL and VTL): CD1a and CD14; CD80+/CD86+ level was the highest among all options. Analysis of the DC effect on co-cultivated lymphocytes showed that DCs loaded with RVK, both alone and as part of VTL, stimulated predominantly the NKT subpopulation. The same samples contained more T lymphocytes, activated CD4+ and CD8+ compared to samples stimulated by TL. However, the samples co-cultivated with VTL contained the maximal amount of CD4+/CD25+/CD127dim phenotypically corresponding to Tregs. Conclusions: The antigen loading of immature DCs with RVK alone causes their activation, but not maturation, which is not realized in typical terms of the DC generation from blood monocytes. The presence of RVK, including in VTL, has a stimulating effect on NKT lymphocytes suggesting the possible generation of specific highly active cytotoxic lymphocytes.
FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages
Authors: Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian Sheridan, Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
Journal: Journal of Clinical Investigation (2020)

FTY720 is a treatment for relapsing remitting multiple sclerosis (MS). It is an analog of sphingosine-1-phosphate (S1P) and targets S1P receptors 1, 3, 4, and 5. Recent reports indicate an association between long-term exposure to FTY720 and cases of cryptococcal infection. Here, we studied the effect of FTY720 and its derivative, BAF312, which only target S1P receptors 1 and 5, in a mouse model of cryptococcal infection. We found that treatment with FTY720, but not with BAF312, led to decreased survival and increased organ burden in mouse cryptococcal granulomas. Both FTY720 and BAF312 caused a profound CD4+ and CD8+ T cell depletion in blood and lungs but only treatment with FTY720 led to cryptococcal reactivation. Treatment with FTY720, but not with BAF312, was associated with disorganization of macrophages and with M2 polarization at the granuloma site. In a cell system, FTY720 decreased phagocytosis and production of reactive oxygen species by macrophages, a phenotype recapitulated in the S1pr3–/– knockout macrophages. Our results suggest that FTY720 reactivates cryptococcosis from the granuloma through a S1P receptor 3–mediated mechanism and support the rationale for development of more-specific receptor modulators for therapeutic use of MS.
头晕、眩晕与后循环缺血
Authors: 张茁, 刘伟竹
Journal: BMJ (2011)

张茁:眩晕有旋转感,而头晕没有.有人认为,若颈椎X线片发现骨质增生,就是颈椎病导致的脑供脑不足,每年定期输液可以预防并治疗头晕,这个观点是绝对错误的,没有任何科学证据.45岁以上的正常人拍颈椎X线片都会有骨质增生,但不是所有人都会有后循环缺血,只有椎动脉粥样硬化的病理基础才可能导致后循环缺血,那些觉得输液后症状好转多数是患者的心理作用.目前国际上广泛用后循环缺血替代脑供血不足这一提法。
CoupledCAR technology for treating thyroid cancer.
Authors: Lei Xiao, Xingchen Liu, Keshu Zhou, Yu Liu, Yong Huang, Chengfei Pu, Zhiyuan Cao, Cheng Lu, Yang Hang, Xi Huang, Xiaogang Shen, Yongping Song, Renbin Liu, Zhao Wu
Journal: Journal of Clinical Oncology (2020)

e15027 Background: Significant challenges restrict CAR-T cell therapy to treat solid tumors. Methods: Here, we generated CAR-T cells using a novel CoupledCAR technology. Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-thyroid stimulating hormone receptor (TSHR) CAR molecule, and anti-TSHR CAR-T cells showed anti-tumor activities in vitro and in vivo experiments. Further, we treated refractory/relapsed post-thyroidectomy thyroid cancer patients using anti-TSHR CoupledCAR T cells, and observed the rapid expansion of CAR-T cells and the enhanced killing of tumor cells. Results: Both patients achieved PR (Partial Response). Patient Profile: Patient 1 Male, 64Y, Papillary Thyroid Carcinoma. In May 2017, thyroid cancer was diagnosed, bilateral total thyroidectomy, and right cervical lymph node functional dissection were performed in June, followed by iodine 131 isotope therapy. In December 2018, bilateral multiple cervical lymph nodes were enlarged. In February 2019, right neck lymphadenectomy was performed. Patient 2 Female, 60Y, Thyroid Carcinoma. In Aug 2013, a "double lobectomy of the thyroid gland” was performed. From Oct 2013 to Jan 2014, she received iodine 131 isotope therapy. In Sep 2014, she was diagnosed with iodine-resistant thyroid cancer. In 2016, 5 cycles of chemotherapy were performed. In Mar 2019, multiple metastases in both lungs and multiple enlarged lymph nodes were observed. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR: lymph node metastasis became undetectable and the size of the thoracic paratracheal tumor nodules decreased significantly. Three months after infusion (M3), the patient was evaluated as having a durable response, and the tumor tissue was substantially smaller than M1. Patient 2: M1, the patient was evaluated as PR (Partial Response): the tumor volume in the right lower lobe of the lung was reduced by approximately 67.51% (decreased from 65*55mm to 42*39mm). Three months after infusion (M3), compared with that before, the tumor volume was reduced by approximately 73.54% and SUV max value decreased from 14.9 to 2.8, therefore, the patient was evaluated as nCR (near complete remission). Conclusions: We show that TSHR is a good target for treating thyroid cancer, and our anti-TSHR CoupledCAR T cells are safe and effective for treating thyroid cancer. Recruitment is ongoing to evaluate the safety and efficacy of our CoupledCAR T cells. Further, since our CoupledCAR technology is a platform technology, we are developing it to treat other solid tumors using different target markers.
Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis
Authors: Hanwen Zhang, Andi Xu, Xuan Sun, Yaqing Yang, Lai Zhang, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Wei Wu, Di Yang, Yongjie Zhang, Yong Xu, Qi Chen
Journal: Circulation Research (2020)

Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. Methods and Results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a proinflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of SR-A1 (class A1 scavenger receptor) inhibited proliferation of cardiac resident reparative macrophages and, therefore, exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc (Avian myelocytomatosis virus oncogene cellular homolog), a key transcriptional factor for the SR-A1-P38-SIRT1 (Sirtuin 1) pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.
药物性肝病68例临床分析
Authors: 胡国信, 郑洁, 杨小兰, 曾昭琳
Journal: BMJ (2004)

回顾性分析1993年1月～2002年10月收治的68例药物性肝病患者的临床资料,总结诱发药物性肝病的药物种类、临床特点、诊断、治疗和预后.结果显示多种药物可引起肝损害,尤以中药最多见(38.2%,26/68);临床以肝实质损害型最多见(61.7%,42/68);肝功能检查是早期诊断方法,分子吸附再循环人工肝对药物性重型肝炎是一种安全、有效的辅助治疗措施。
Radiotherapy with sequential αnti-PD-1 mAb compared with concurrent αnti-PD-1 mAb for enhancing the abscopal effect by promoting the inflammatory tumor microenvironment.
Authors: Xiaoxia Zhu, Shangbiao Li
Journal: Journal of Clinical Oncology (2020)

e15122 Background: Radiotherapy (RT) is one of the main approaches for treatment of lung cancer. A large number of preclinical and several clinical studies revealed that RT can activate the host’s anti-tumor immune system and induce abscopal effect. However, the optimal timing and its underlying mechanism of the combination of RT and immune checkpoint inhibitor (CHI) are unclear. Methods: MC38 cells were used for subcutaneous tumor formation in the left lower limbs (irradiation field) and the right lower limbs (non-irradiation field) of six-eight weeks old male C57BL/6 mice. When the tumor volume reached 150mm 3 , the mice were randomly assigned to receive RT (8Gy × 3F) with concurrent anti-PD-1 monoclonal antibody (mAb) or RT with sequential (1 week after the first irradiation) anti-PD-1 mAb (group B). The changes of immune microenvironment in irradiated and non-irradiated tumors in the two groups were analyzed by flow cytometry. Results: Both RT with concurrent anti-PD-1 mAb and RT with sequential anti-PD-1 mAb could inhibit the growth of tumors in non-irradiation field. The number of CD4+T cells (CD45+CD44+CD4+T) and effector CD4+T cells (CD44+CD4+IFNγ + T) in non-irradiated tumors in the sequential group was significantly higher than that in the concurrent group, but which showed no significant difference between the two groups in irradiated tumors. Interestingly, CD8+T cells (CD45+CD44+CD8+T) and effector CD8+T cells (CD44+CD8+IFNγ + T) increased both in the irradiation and non-irradiation field in the sequential group compared with that in the concurrent group, while tumor associated macrophages (TAM, F4/80+CD11b+) and Treg cells (CD4+FoxP3+) in the sequential group decreased significantly. RT with sequential anti-PD-1 mAb reduced more exhausted CD8+T cells (PD-1+Eomes+of CD8+T) and induced more reinvigoration of exhausted T cell (Ki-67+PD-1+Emoes+CD8+T). The decrease of MDSCs (Gr1+CD11b+) in the non-irradiated tumors was observed in both groups, but there was no difference in the extent of this decrease between two groups. Conclusions: Compared with the concurrent combination, RT with sequential anti-PD-1 mAb is more effective in promoting the inflammatory tumor microenvironment in out-field tumors and inducing the abscopal effect, which provides a new perspective for further exploring the mechanism of optimal timing of combination. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033.
Clinical outcomes of pancreas cancer patients with peritoneal spread: Results from the chord consortium.
Authors: Mehrnoosh Pauls, Abdulaziz AlJassim AlShareef, Winson Y. Cheung, Rachel Anne Goodwin, Brandon M. Meyers, Christina Kim, Michael M. Vickers
Journal: Journal of Clinical Oncology (2020)

e19268 Background: Prior studies have demonstrated that clonal cells that give rise to pancreatic peritoneal metastases (PM) are geographically and genetically distinct from clonal cells, giving rise to lung and liver metastases. The objective of this study was to assess if there is a distinct difference in prognosis and therapeutic response among patients with pancreatic cancer with (PM compared to the lung/liver. Methods: Using a retrospective cohort design, medical records from adult patients diagnosed with metastatic adenocarcinoma of the pancreas at five Canadian academic cancer centers (2014 - 2019) were reviewed. Prognostic variables including age, Charlson comorbidity index, ECOG, cigarette smoking, nodal status, sites of metastases, and first line chemotherapy were collected. Cox proportional hazards model (MVA) was used to examine the association between peritoneal involvement and survival, adjusted for measured confounders. Analyses were completed using SAS, where alpha of 0.05 was defined as the level of significance. Results: A total of 1161 patients were included. Metastatic sites included peritoneum (n = 170, 14.6%), lung (n = 145, 12.5%) and liver (n = 563, 48.5%). Patients with PM received first-line FOLFIRINOX (FFX, n = 31), Gemcitabine + nab-paclitaxel (G/N, n = 20), Gemcitabine (G, n = 18), and no treatment (n = 97). In univariate analyses, worse ECOG PS was associated with PM (p = 0.002). The majority of patients died (89%), with a median overall survival (OS) of 3 vs 7 months for patients with PM and those without PM (p &lt; 0.001), respectively. The median OS in patient whom receive first-line chemotherapy was 7 months in FFX group (95% CI 1.66-12.33), 6 months in G/N (95% CI 4.54-7.45) and 2 months in G group (95% CI 1.42-2.57). Patients had significantly better OS when treated with FFX or G/N compared to G alone (p = 0.002). Time to treatment failure was significantly shorter among patient treated with G alone compare to patients treated with FFX and G/N (P &lt; 0.005). Conclusions: In the setting of combination chemotherapy for advanced pancreatic cancer, patients with PM continue to have a poor prognosis. This may be due to the impact of PM on PS and the inability to administer palliative chemotherapy. For eligible patients, FFX or G/N results in a higher OS than G monotherapy.