tbuckley/cabot-search huggingface dataset:
Tolerability and preliminary efficacy of BXQ-350 for refractory solid tumors and high-grade gliomas: First-in-human, first-in-class phase I trial.
Authors: Olivier Rixe, John Charles Morris, Robert Wesolowski, Emrullah Yilmaz, Richard Curry, Trisha Michel Wise-Draper, Vinay K. Puduvalli
Journal: Journal of Clinical Oncology (2020)

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for &gt; 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .
Identifying the most vulnerable areas for the occurrence of new cases and deaths related to cervical cancer in the city of Recife, Brazil: See to act.
Authors: Jurema Telles O Lima, Candice Lima Santos, Carla Rameri Alexandre Silva De Azevedo, Leticia Katz, Andréa Lopes, Rodrigo alves Pinto, Mozart j t Sales
Journal: Journal of Clinical Oncology (2020)

e13628 Background: Cervical cancer (CC) is the second most incident and the most deadly among women from the Northeast’S Brazil and RECIFE-Pernambuco and the third most incident in Brazil. The occurrence of CC expresses a reality of inequality and inequity and should be understood not only as an oncological indicator, but essentially as an indicator of social vulnerability and health care needs. Its distribution occurs heterogeneously. Methods: Determine the geolocation of areas of greatest risk of occurrence of SC from the social and health determinants Considering the high incidence and mortality related to cervical cancer between 2006-2015, in the city of Recife, we used the spatialization technique to identify the most vulnerable territories for our intervention in the city of Recife. Results: 3,844 Cervical Cancer notifications AND 276 OBITUATIONS registered in the period 2006-2015 and the number of deaths in the period from 2009 to 2018, as a result, there are five areas of high influence. from spatialization, the heat zone generated by the 47 deaths that occurred in the north of the city of Recife WAS DETERMANED. Regarding the cytopathological supply, the ratio in 2018 was 0.37, being below the state average, which is 0.41. With a deficit of 45,041 screening cytopathological exams in the age group 25-64 years.the III Health Region was identified, based on the analysis of information from the State Health Secretary, which shows to be one of the areas of great social vulnerability, since 63% of the 22 municipalities that make up this health region and its population is in extreme poverty, according to IBGE (2010). Conclusions: The occurrence of deaths and new cases of cervical cancer in the city of Recife occurs geographically unequally and is associated with indicators of social vulnerability. IS IT POSSIBLE to identify a priority region to intensify public actions for prevention and early diagnosis. A challenging scenario has been found and must be actively addressed.
A study into how ultraviolet radiation from the sun effects genes in the skin
Authors: M. Bustamante, C. Hernandez‐Ferrer, A. Tewari, Y. Sarria, G.I. Harrison, E. Puigdecanet, L. Nonell, W. Kang, M.R. Friedländer, X. Estivill, J.R. González, M. Nieuwenhuijsen, A.R. Young
Journal: British Journal of Dermatology (2020)

The sun emits two main types of ultraviolet radiation (UVR): UVB (~5%) and UVA (~95%). We know that UVR from the sun causes sunburn (inflammation) as well as many other adverse (negative) effects including weakening the skin's immunity, accelerated skin ageing and skin cancer. These effects are caused by UVR altering the activity (expression) of the skin's genes – the so-called ‘transcriptome’. The behaviour of genes determines the body's response to external and potentially damaging stress. Studying skin transcriptome changes in vivo (in humans) can inform us about the pathways in skin cells that are activated after a single UVR exposure (dose). This knowledge is important to develop strategies to prevent the adverse effects of sunlight. In this study, the authors examined skin transcriptome response in seven healthy, fair-skinned volunteers after doses of UVR than could easily be obtained during one day of a sun-holiday. The authors show that doses of UVR typical in holiday situations results in marked changes of expression of thousands of skin genes. Most striking were genes involved in the turnover of the outermost layer of the skin (a protective response), inflammation, immune system responses and accelerated skin ageing. The higher the UVR dose, the larger number of affected genes. One very interesting observation was the suppression (dampening down) of the activity of a gene involved in vitamin D production, suggesting that the body has its own mechanism to control vitamin D toxicity (too much vitamin D) in skin. The study also showed that UVB was generally more effective than UVA at causing changes in gene expression, which is consistent with other studies that show that UVB is much more powerful than UVA at causing molecular and clinical changes in the skin. This is a summary of the study: Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome
SLC3A2 mutation as a genetic biomarker for dMMR in colorectal cancer.
Authors: Jian Xiao, Bo Yang, Ming Liu, Tanxiao Huang, Xiaoni Zhang, Yuanyuan Liu, Jingxian Duan, Shanshan Li, Shifu Chen
Journal: Journal of Clinical Oncology (2020)

e13545 Background: SLC3A2 (solute carrier family member 2) 3 is a member of the SLC3 family Ⅱ transmembrane glycoprotein, which is a key component of heteromeric amino acid transporters (HATs). The association between SLC3A2 and cancer was established, given that the amino acid supply by SLC3A2 is required for the resistance of oxidative stress and the maintenance of cell proliferation. However, whether SLC3A2 mutation plays a role in carcinogenesis remains unclear. Methods: This study enrolled 1000 colorectal cancer patients. Tumor tissues and paired peripheral blood mononuclear cells (PBMC) were collected for the sequencing of cancer-related genes by target capture and next-generation sequencing. Results: p.Lys301Argfs*31 mutation in SLC3A2 were detected in 40(40/1000, 4.0%) patients. low TMB and MSS were reported in 2 cases while the remaining 38 cases exhibited high TMB and MSI-H. 41(41/1000, 4.1%) DNA mismatch repair (dMMR) were identified in 41(41/1000, 4.1%) tumor samples, 27(27/41, 65.9%) of which had p.Lys301Argfs*31 mutation. Moreover, this frameshift mutation (COSM253097) was observed in 28 cases of large intestine cancer, 1 case of peritoneum cancer, 1 case of Stomach cancer, 1 case of biliary tract cancer and 1 case of ovary cancer in the COSMIC database. Conclusions: p.Lys301Argfs*31 mutation of SLC3A2 was identified in the majority of colorectal cancer cases with dMMR events, suggesting that this mutation may be a biomarker of dMMR.
Anlotinib in patients with recurrent platinum-resistant or refractory ovarian carcinoma: A prospective, single-arm, single-center, phase II clinical study.
Authors: Huaying Wang, Wenbin Shen, Boer Shan
Journal: Journal of Clinical Oncology (2021)

e17524 Background: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and its anti-tumor targets include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and c-kit. This phase II study aims to evaluate the safety and efficacy of anlotinib monotherapy in patients with recurrent or refractory ovarian carcinoma. We have previously reported primary results (objective response rate (ORR) 35.7%, 95%CI: 12.8-64.9; and disease control rate (DCR) 85.7%, 95%CI: 57.2-98.2) in 14 patients), and we now present the updated ORR, DCR and safety data in more patients. Methods: Patients who have previously received second-line or more chemotherapy, with histopathologically confirmed ovarian high-grade serous gonadal ovarian carcer (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2 were considered eligible for enrollment. Anlotinib was administered orally (12 mg qd, d1-14; 21 days per cycle) till disease progression, death or intolerant toxicity. Therapeutic effects are evaluated every 6 weeks. The primary endpoint was ORR and the secondary endpoints included DCR, progression-free survival (PFS), overall survival (OS), safety and quality of life (QoL). Results: Between March 2019 and January 2021, 31 patients (female) with FIGO histopathological stage IC (1, 3.2%), IIC (1, 3.2%), IIIC (23, 74.2%) and IV (6, 19.4%) were enrolled and 24 patients were evaluable with a median age of 59 years (range: 37-73). The median treatment period was 4.96 months (95% CI: 4.50-7.56). Therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 4.2%, 25%, 45.8% and 25% respectively, yielding the ORR of 29.2% (7/24; 95% CI: 14.6-57.0) and the DCR of 75.0% (18/24; 95% CI: 53.3-90.2). The median PFS was 6.34 months (95% CI: 3.14-9.54). The median OS was not reached. Most of the occurring adverse events (AEs) were grade 1 and grade 2, and ≥10% grade 1 AEs included hypertention (45.83%), fatigue (29.17%), hand-foot syndrome (33.33%) and hoarseness (12.50%). Grade 2 AEs only included gingival bleeding (4.2%), hand-foot syndrome (4.2%), renal dysfunction (4.2%) and cancer pain (4.2%). No higher grade AEs were observed. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib showed a promising efficacy with an acceptable safety profile for patients with recurrent platinum-resistant or refractory ovarian carcinoma. Further evaluation of PFS and OS is ongoing. Clinical trial information: ChiCTR2000029654.
Assessment of quality and clinical similarity (pharmacokinetic and safety) of HD204, a biosimilar of bevacizumab.
Authors: Jocelyn Hii, Martin Demarchi, Pierre Coliat, Michael J Kim, Kuo Wei Chan, Peggy Feyaerts, Felicia Ang, Roland Schott, Philippe Barthelemy, Meher Benabdelghani, Filip Deforce, Marie_Paule Derde, Xavier Pivot, Lisa Soyeon Park
Journal: Journal of Clinical Oncology (2020)

e21556 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.
脊源性颈、腰痛的诊断
Authors: 刘延青
Journal: BMJ (2008)

颈、腰痛是多种疾病的常见症状.许多临床医生听到患者最多的主诉之一就是我颈部疼痛或我腰背部疼痛.这种情况在现代社会更加普遍,几乎每个人在一生中至少经历过一次明显的颈、腰疼痛发作.但是,临床上对颈、腰痛的诊疗仍有许多不尽人意之处。
Reflux esophagitis after resection of esophageal carcinoma with instrument anastomosis at superior aperture of thorax
Authors: Ting-hai Li, Dong-yong Zhao, Lan-peng Wang
Journal: BMJ (2011)

One hundred and ninety one patients with esophageal carcinoma underwent surgical resection from January 2004 to January 2009. The gastroesophageal anastomosis was performed with auto suture instrument at superior aperture of the thorax in 107 cases (group A) and the instrument anastomosis was performed above or below the aorta arch in 84 cases ( group B ). The electron gastroscopy was performed and biopsy of mucosa at 3cm above the anastomosis was taken during the postoperative follow-up in all patients. Results showed that the incidence rate of reflux esophagitis in group A ( 5% ) was much lower than that in group B (51% ).

Key words: 
Esophagectomy;  Gastroesophageal reflux
繁殖期杀菌药与快速抑菌药的联合应用
Authors: 杜长军, 武焱旻
Journal: BMJ (2009)

中,建议CAP的最初经验治疗使用β-内酰胺类(繁殖期杀菌药)联合大环内酯类(快速抑菌药).然而,迄今仍有不少临床工作者不同意此观点[1-2].作者依据临床实践体会,结合相关文献,概述如下,有些实属管见,以求同道斧正。
Performance of polygenic risk scores for cancer prediction in an academic biobank.
Authors: Heena Desai, Anh Le, Ryan Hausler, Shefali Verma, Anurag Verma, Renae Judy, Abigail Doucette, Peter Edward Gabriel, Scott Damrauer, Marilyn Ritchie, Daniel Rader, Rachel Kember, Kara Noelle Maxwell
Journal: Journal of Clinical Oncology (2020)

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p&lt;0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p&lt;0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]
Combination of anlotinib and irinotecan in the second-line treatment of patients with advanced colorectal cancer: An open-label, multicenter phase I/II study.
Authors: Bo Zhang, Xi Wang, Lingjun Zhu, Qun Li, Yun Liu, Ling Qi, Yongqian Shu, Jing Huang
Journal: Journal of Clinical Oncology (2020)

e16036 Background: Efficacious therapeutic options for advanced colorectal cancer (CRC) are limited, and treatment outcomes remain to be improved in the second-line setting. Anlotinib is a multi-target antiangiogenic small molecule that primarily inhibits VEGFR1/2/3. We conducted this open-label, multi-center phase 1/2 study to evaluate the safety and efficacy of anlotinib plus irinotecan in patients with previously treated advanced CRC. Methods: We enrolled patients with advanced CRC whose disease had progressed after first-line systemic therapy and had not previously received irinotecan. In the 3+3 dose escalation (phase 1) part of the trial, patients received anlotinib (8mg, 10mg and 12mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180mg/m 2 , iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the dose-expansion (phase 2) part, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and disease control rate (DCR). Results: A total of 31 patients were enrolled from 2 centers between May 2018 and Jan 2020. The median follow-up duration was 12.48m (95% CI 7.43-15.24). Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1 part, and the RP2D was therefore 12mg. Twenty-eight patients were evaluable for efficacy analysis. Eight patients achieved partial response (PR), in which 6 had confirmed PR and 2 were unconfirmed. The ORR was 21.4% (95%CI 8.3%-41.0%) and the DCR was 100% (95%CI 87.7%-100%). The median PFS and OS were 6.97m (95%CI 3.71-11.20) and 13.87m (95%CI 11.47-NR), respectively. All patients were included in the safety analysis. The most common grade 3 treatment-related adverse events (AEs) (≥5%) were diarrhea (16.1%), neutropenia (12.9%), fatigue (6.5%) and hypertension (6.5%). Grade 4 AEs included neutropenia (6.5%) and thrombocytopenia (3.2%). There were no treatment-related deaths. Conclusions: The combination of anlotinib and irinotecan had promising anti-tumor activity in the second-line treatment of advanced CRC with a manageable safety profile. Clinical trial information: NCT03545711 . [Table: see text]
Combined OX40 agonist and PD-1 inhibitor immunotherapy improves the efficacy of vascular targeted photodynamic therapy in a urothelial tumor model.
Authors: Ricardo Alvim, Lucas Nogueira, Petrina M Georgala, Alexander Somma, Karan Nagar, Jasmine Thomas, Souhil Ledbai, Christopher Hudges, Avigdor Joshua Scherz, Saeid M Zanganeh, Kwanghee Kim, Jonathan Coleman
Journal: Journal of Clinical Oncology (2020)

e17004 Background: In patients with low-grade, small upper tract urothelial carcinomas (UTUC), as well as those in whom preservation of kidney function is critical, local ablative therapies such as vascular targeted photodynamic (VTP) therapy have emerged as a means of reducing treatment-related morbidity. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Methods: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and metastasis and prolonged survival to a much greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.