tbuckley/cabot-search huggingface dataset:
Development of a personalized ex vivo drug screening test for patients with ovarian cancer.
Authors: Luzi Brückner, Annika Reinshagen, Bahriye Aktas, Ingo Bechmann, Ivonne Nel, Sonja Kallendrusch
Journal: Journal of Clinical Oncology (2020)

e18090 Background: The standard therapy of patients with ovarian cancer consists of primary surgery followed by chemotherapy. Initial response rates are very high, but recurrence occurs in 85% of the cases. Personalized ex vivo analyses of various anti-tumor compounds in a standardized tissue slice culture system (1) might be a very promising approach for individualized therapeutic decisions. In comparison to cell culture, tumor slice cultures maintain the direct tumor microenvironment which plays a role in resistance mechanisms and thus therapy response. Methods: Patient derived tumor cultures (1) are grown under standardized conditions and are analyzed semi-automated. Patient’s tumor samples were collected during surgery, cut into standardized slices and were cultivated in triplicates for 2, 4, 7 and 14 days and treated with standard therapy for 7 days. A baseline control was prepared at day 0. The cultured tissue is PFA-fixated and paraffin embedded. Hematoxylin eosin staining was performed for microscopic evaluation of morphologic structures. Subsequently, immunohistochemical staining against CD3 was applied to examine the immune setting of the tumor and its environment. Results: Ovarian tumor tissues remained their morphological properties over a period of 14 days. Parameters like cellular formation, proliferation and heterogeneity were adequately represented in the cultures.. Staining against CD3 revealed T-cells in ovarian tumor tissue slices up to 14 days ex vivo and individual response to treatment was observable. Conclusions: Correlation to clinical data is ongoing to analyze the tissue culture model of ovarian cancer for clinical usage. Different approaches, concerning mutational burden, immunological signature and histology are considered for decision of response and non-response.
The role of an open-label non-intervention design versus a placebo-control arm in oncology randomized trials.
Authors: Igal Kushnir, Mark J. Clemons, Dean Fergusson, Dominick Bosse, M. Neil Reaume
Journal: Journal of Clinical Oncology (2020)

e14099 Background: Randomized trials are considered the gold standard when assessing the efficacy of new therapeutic agents. In settings where there is no known effective agent available, a randomised study could compare the investigational agent with either a placebo arm or an open-label non-intervention arm (i.e. best supportive care). The use of placebo arm can result in additional inconvenience and time commitments for patients, as well as increased administrative and regulatory costs. We conducted a survey among Canadian medical oncologists to assess whether an open-label non-intervention arm would be an acceptable alternative control to placebo in randomized trials. Methods: Members of the Canadian Association of Medical Oncologists were invited to participate in an anonymous online survey. Standardized case scenarios were used to determine participants’ attitudes regarding the role of open-label randomized-controlled trials instead of a placebo. Results: Eighty-six medical oncologists and trainees responded (response rate was 27%). Eighty-one (94%) of respondents worked at university-affiliated centres and 41 (48%) had been in practice for at least 10 years. Fifty-one (59%) respondents believed that it is acceptable to use an open-label design instead of a placebo arm when assessing a therapeutic agent in the adjuvant setting. Thirty-eight (49%) felt it was acceptable to compare the investigational agent to an open-label arm instead of a placebo to assess overall survival in the metastatic setting. Twenty-eight (38%) of respondents felt using an open-label design when assessing quality of life endpoints was acceptable. Most physicians (75%) were unsure whether or not the US Food and Drug Administration requires a placebo-controlled arm in cancer clinical trials. Conclusions: We report disagreement and uncertainty among Canadian medical oncologists regarding the acceptability of an open-label design in randomized-controlled trials where no standard therapy is approved. Clearer guidance from regulatory bodies on the adequacy of different trial designs could help reduce this equipoise.
Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase
Authors: Umut Cagin, Francesco Puzzo, Manuel Jose Gomez, Maryse Moya-Nilges, Pauline Sellier, Catalina Abad, Laetitia Van Wittenberghe, Nathalie Daniele, Nicolas Guerchet, Bernard Gjata, Fanny Collaud, Severine Charles, Marcelo Simon Sola, Olivier Boyer, Jacomina Krijnse-Locker, Giuseppe Ronzitti, Pasqualina Colella, Federico Mingozzi
Journal: Molecular Therapy (2020)

Pompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa-/-) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa-/- mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa-/- mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa-/- mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.
Time to label sodium in drug treatments?
Authors: David R J Jarrett
Journal: BMJ (2008)

A soluble tablet of 500 mg paracetamol can contain 388 mmol sodium, the equivalent of 1 g salt. Here lies a more likely cause for the association between regular paracetamol use and hypertension.1 It is hard to find out how much salt is hidden in our patient‘s polypharmacy. Do medications need to label salt content in a similar way to food labelling? Would it not be possible to manufacture salt-free medications similar to the sugar-free paediatric preparations?
Clinical application of selective salpingography and fallopian tube recanalization in diagnosis and treatment for obstructive infertility
Authors: Rui-xia Zhang, Hong-guang Liu, Yong-kui Wang, Fu-min Zhang
Journal: BMJ (2008)

Objective To evaluate the significance of selective salpingography(SSG)and fallopian tube recanalization(FTR)in diagnosis and treatment for obstructive infertility.Methods Totally, 268women with infertility caused by obstruction of the fallopian tube were divided randomly into two groups, one (Group A)with a non-operative hysterosalpingeal system by insertion of co-axial cannula and guiding filament made by COOK Corporation in the US and another(Group B)with a self-prepared hysterosalpingeal system modified based on the apparatus of COOK Corporation, for SSG and FTR.Then, efficacy of SSG and FTR for the infertile women was evaluated by one-year cumulative pregnancy rate and reeanalization rate of the fallopian tube.Resnits One hundred and seventy of 198 fallopian tubes were recanalized in Group A, with a recanalization rate of 85.8%, and 290 of 320 tubes in Group B were recanalized.with a recanalization rate of 90.6%.reaching statistically significant difference.Furthermore, recanalization rate varied with different sites of occlusion of the fallopian tube.Pregnancy rate was 35.3%(36/102)in Group A, significantly higher than that in Group B(47.6%, 79/166).As the same, pregnancy rate varied with different sites of occlusion of the fallopian tube.Conclusion Selective salpingography and fallopian tube recanalization with self-prepared hysterosalpingeal system have dual effects on diagnosis and treatment for tubal infertility of women, which are simpler, safer and more reliable, worth to be clinically applied.

Key words: 
Fallopian tube obstruction; Infertility,female; Hysterosalpingography; Fallopian tube recanalization
Immune-checkpoint genes as predictive biomarkers of trabectedin in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) translational study.
Authors: David Silva Moura, Nadia Hindi, Maria Lopez-Alvarez, Paloma Sanchez-Bustos, Irene Carrasco-Garcia, Paloma Santos-Fernandez, Paula Martinez-Delgado, Serena Lacerenza, Elena Blanco-Alcaina, Jose Lucinio Mondaza-Hernandez, Antonio Gutierrez, Rosa Maria Alvarez, Magda Cordeiro, Luis Miguel De Sande González, Gloria Marquina, Juana Maria Cano, Josefina Cruz Jurado, Claudia Maria Valverde Morales, Javier Martinez-Trufero, Javier Martin Broto
Journal: Journal of Clinical Oncology (2020)

11546 Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.
上颌窦韧带样瘤一例
Authors: 甘艳, 时荣新
Journal: BMJ (2008)

患者女,36岁,已婚.因右面部不适,牙齿松动1年就诊.专科检查:双侧面部对称无畸形,双侧上颌窦无压痛,张口度正常,右侧磨牙开(牙合),右上第6和第7松动,无叩痛,右侧上颌前庭沟未见异常.CT提示右侧上颌窦占位肿块界限清晰,周围骨质未见明显破坏.全身麻醉下手术探查,术中冰冻检查:右侧上颌窦韧带样瘤.扩大手术,右侧上颌骨部分切除.
神经外科防治应激性溃疡的整体护理对策
Authors: 杨传琨, 王淑珍, 许艳
Journal: BMJ (2004)

我科自2000年5月～2003年4月收治的重症神经外科患者134例,在实施整体护理后,仅发生应激性溃疡34例,报告如下. 1.对象与方法:134例中,男95例,女39例,年龄2个月～83岁,平均(38±9)岁.重型颅脑损伤63例,自发性脑出血18例,大面积脑梗死12例,颅内感染7例,脑肿瘤34例,其中接受颅脑手术治疗者93例。
NivoCUP: An open-label phase II study on the efficacy of nivolumab in cancer of unknown primary.
Authors: Junko Tanizaki, Kan Yonemori, Kohei Akiyoshi, Hironobu Minami, Hiroki Ueda, Yuichi Takiguchi, Chihiro Nakayama Kondoh, Yoshihiko Segawa, Shin Takahashi, Yasuo Iwamoto, Yasuhiro Kidera, Kazuya Fukuoka, Yasushi Nakamura, Yasutaka Chiba, Kazuto Nishio, Kazuhiko Nakagawa, Hidetoshi Hayashi
Journal: Journal of Clinical Oncology (2020)

106 Background: CUP has a poor prognosis with a median survival of less than 12 months. Given the recent approval of immune checkpoint inhibitors in several cancer types, we performed a multicenter phase II study of nivolumab in CUP patients (pts). Methods: The main population of this study is CUP pts who were previously treated with more than one line of systemic chemotherapy. Previously untreated CUP pts were also enrolled for exploratory analysis. Pathological examination (including IHC), CT, FDG-PET, gastroscopy and colonoscopy and medical examination were mandatory for diagnosis of CUP before enrollment. CUP pts belonging to favorable prognosis groups were excluded from the trial. Nivolumab (240 mg/body) was delivered as an intravenous infusion every 2 weeks for up to 52 cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 by an Independent Endpoint Review Committee in previously treated pts. The secondary objectives include investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety and the association between the efficacy of nivolumab and PD-L1 expression. Results: A total of 56 CUP pts, 45 previously treated and 11 previously untreated pts, were enrolled in this trial. The median age was 65.5 years, 22 pts were male. Median follow-up was 8.05 mo (range, 0.1 to 20.7 mo). Of 45 previously treated pts, 2 and 9 had an investigator-assessed complete response and partial response (ORR 24.4%, 95% CI: 12.9-39.5%), with a median PFS (mPFS) and OS (mOS) of 5.4 mo (95% CI: 2.6-6.9) and 15.1 mo (95% CI: 8.3-NR), respectively. Among 11 previously untreated pts, 1 pt had partial response (ORR 9.1%, 95% CI: 0.2-41.3%). The mPFS was 3.9 mo and the mOS was not reached in untreated pts (95% CI: 1.1-5.6, and 95% CI: 2.6-NR, respectively). Nivolumab demonstrated a mPFS of 5.1mo (95% CI: 2.7-5.6) and a mOS of 15.9 mo (95% CI: 8.4-NR) in an overall population. Immune-related adverse events occurred in 57% of overall pts with 5% of grade 3 or higher, and the most common were rash (27%), hypothyroidism (16%), and diarrhea/colitis (16%). No treatment related death was observed. Conclusions: In pts with previously treated and untreated CUP, nivolumab demonstrated durable antitumor activity with a manageable safety. Clinical trial information: UMIN000030649.
Targeting glioblastoma with novel immunocytokines.
Authors: Patrick Roth, Tobias Weiss, Emanuele Puca, Manuela Silginer, Teresa Hemmerle, Shila Pazahr, Andrea Bink, Dario Neri, Michael Weller
Journal: Journal of Clinical Oncology (2020)

2558 Background: There is an urgent need for novel treatment options for patients with glioblastoma, the most frequent malignant primary brain tumor. In contrast to other types of cancer, immunotherapeutic approaches have so far not been successful against glioblastoma. Converting the glioma microenvironment from a "cold" and immunosuppressive status into a more "hot" and immunopermissive phenotype may allow for clinically meaningful anti-tumor immune responses. Methods: We explored the activity of novel immunocytokines based on the L19 antibody, specific to a tumor-associated epitope of extracellular fibronectin, for the targeted delivery of three pro-inflammatory cytokines (IL-2, IL-12, TNF) to the microenvironment of gliomas. Following an extensive preclinical assessment in 2 orthotopic immunocompetent mouse glioma models, we used a fully-human L19-hTNF fusion protein to treat human patients with recurrent glioblastoma. Results: Intravenous administration of L19-mIL12 or L19-mTNF prolonged survival and cured a proportion of tumor-bearing mice while no effect was seen with L19-IL2. When L19-mIL12 or L19-mTNF were administered to glioma-bearing RAG −/− mice, no therapeutic activity was observed which suggests adaptive immunity as an underlying mechanism. On a mechanistic level, both immunocytokines induced the infiltration of the tumor site with lymphocytes and promoted the expression of pro-inflammatory cytokines in the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Based on these preclinical findings, we initiated a phase I/II clinical trial with a fully-human L19-hTNF fusion protein for patients with isocitrate dehydrogenase (IDH1R132H) wildtype WHO Grade III or IV glioma at first relapse (NCT03779230). Treatment was safe and well tolerated in the first three glioblastoma patients. Administration of L19-hTNF resulted in reduced regional blood perfusion in the tumor region and was associated with more necrotic areas within the tumor as well as an increased number of tumor-infiltrating CD4 and CD8 T cells. Conclusions: The data obtained with the comprehensive preclinical characterization and subsequent clinical translation form the basis for future studies with immunocytokines as novel treatment option for patients with malignant brain tumors. Clinical trial information: NCT03779230 .
Advances of diagnosis and treatment for hand-foot-mouth disease with nervous system infection in children
Authors: 刘春和, 张迎春, 杨莲荣, 李守超
Journal: BMJ (2008)

手足口病(Hand-foot-mouth disease)是肠道病毒感染引起的常见传染病之一,多发生于5岁以下的婴幼儿,除可引起发热、皮疹外,还可导致无菌性脑膜炎、脑干脑炎和脊髓灰质炎样麻痹等多种与神经系统相关的疾病,致死、致残率较高,从而引起全社会恐慌.现就其流行病学、临床和病理表现、实验室检查及治疗等方面作-综述。
通心络胶囊治疗2型糖尿病伴脂代谢紊乱60例
Authors: 高孝斗, 王宪, 马香稳, 吴瑞婷, 张洪梅
Journal: BMJ (2005)

将入选2型糖尿病伴脂代谢紊乱患者随机分为治疗组和对照组各60例.在维持原糖尿病治疗方案的同时,治疗组加用通心络胶囊每日3次,每次4粒;对照组不服用通心络胶囊.4周后,治疗组胆固醇、甘油三酯和低密度脂蛋白胆固醇均明显下降(P 0.05).
Association between diabetic retinopathy with atherosclerosis cardiovascular disease
Authors: Lu Gao, Zhong Xin, Mingxia Yuan, Xi Cao, Jianping Feng, Jing Shi, Xiaorong Zhu, Jinkui Yang, Mingzhao Qin
Journal: BMJ (2018)

Objective
To investigate the association between diabetic retinopathy (DR) and atherosclerosis cardiovascular disease (ASCVD).


Methods
Clinical data of 654 patients with type 2 diabetic mellitus (T2DM) were collected from a cross sectional, population based survey on chronic diseases and risk factors which was conducted in Beijing Changping district from July 2010 to March 2011. Among 654 T2DM patients, there were 73 patients with ASCVD (ASCVD group) and 581 patients without ASCVD (non-ASCVD group). The association between DR and ASCVD was analyzed.


Results
Patients with ASCVD had significantly older age[58.5(53.9, 65.9) years], more female sex[52(71.2%)], higher proportion of ASCVD history [45(61.6%)], higher levels of PG 2 h[16.26(11.08, 19.20) mmol/L], HbA1c[7.20(6.55, 8.85)%], systolic pressure [151(133, 165) mmHg(1 mmHg=0.133 kPa)] and lower eGFR[87.2(75.0, 103.0) ml·min-1·1.73 m-2] than non-ASCVD patients[52.4(46.5, 58.3) years, Z=-5.86, P=0.00; 307(52.8%), χ2=-8.86, P=0.00; 256(44.1%), χ2=8.07, P=0.01; 13.10(8.99, 17.93) mmol/L, Z=-2.35, P=0.02; 6.70(6.00, 7.90)%, Z=-3.33, P=0.00; 143(131, 158) mmHg, χ2=-2.28, P=0.02; 94.6(84.8, 106.3) ml·min-1·1.73 m-2,Z=- 3.47, P=0.00]. The trend to develop DR in ASCVD group was significantly higher than that in non-ASCVD group [19.2%(14/74) vs. 8.3%(48/581), χ2=9.01, P=0.00]. DR was an independent statistical indicator of the presence of ASCVD [OR(95%CI): 2.64 (1.37-5.06), P=0.00]. Furthermore, when DR was divided into NPDR and PDR according to its severity, only PDR was significantly associated with incident ASCVD [OR(95%CI): 12.05 (2.63-55.12), P=0.00]. After adjusting for traditional ASCVD risk factors, such an association still existed, with the risk of having ASCVD increasing by 718% [OR (95% CI): 8.18(1.56-42.81), P=0.01]. DR associates strongly with ASCVD in the Chinese population with T2DM.


Conclussion
With the severity of DR increasing, the risk of ASCVD also grows. After adjustment for traditional risk factors, PDR is still associated with the risk of prevalent ASCVD.


Key words: 
Diabetes mellitus; Diabetic retinopathy; Cardiovascular diseases, atherosclerosis
Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.
Authors: Marija Staninova Stojovska, Katerina Kubelka Sabit, Dzengis Jasar, Rubens Jovanovic, Nadica Matevska, Biljana Angelovska, Nenad Mitrevski, Milco Panovski, Aleksandar J Dimovski
Journal: Journal of Clinical Oncology (2020)

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C &gt; T (p.Ala21Val) and c.244A &gt; G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T &gt; C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G &gt; T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.