tbuckley/cabot-search huggingface dataset:
ZEB1 expression in tumor tissues in patients with localized and advanced Ewing's sarcoma.
Authors: Darya Yu. Yurchenko, Elena P. Ulianova, Oleg I. Kit, Inna A. Novikova, Dmitriy V. Burtsev, Aleksandr B. Sagakyants, Sergei A. Kuznetsov, Tatiana O. Lapteva, Oksana G. Shulgina, Olga P. Popovyan
Journal: Journal of Clinical Oncology (2020)

e22511 Background: Ewing's sarcoma is the second most common malignant tumor of bones and soft tissues in children and adolescents; it is characterized by an aggressive clinical course and extremely high metastatic potential. The process of its onset is well studied, but the processes of metastasis are of great interest both from a scientific point of view and in clinical practice. Epithelial-mesenchymal transition plays an essential role in tumor progression, and the ZEB1 protein is one of its key regulators. Our purpose was to evaluate the expression of ZEB1 as a prognostic factor in patients with localized and advanced Ewing's Sarcoma (ES) in children and adolescents. Methods: The study included 50 samples of primary ES of various locations. The patients (0-18 years) were divided into groups 1 (localized ES, n = 27) and 2 (advanced ES, n = 23). Rabbit polyclonal antibodies to ZEB1 (Biorbyt Ltd.) at a dilution of 1:200 and the Reveal Polyvalent HRP-DAB Detection System were used for IHC. The percentage and intensity of staining were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: The average ZEB1 expression was in group 1 - 30.0±3.5%, in group 2 - 41.7±11.1%. The maximal accumulation of ZEB1 in the nuclei of tumor cells was observed in patients with advanced ES - 1.4 times (p = 0.248) higher than in patients with localized ES. However, the difference was not statistically significant (the Mann-Whitney U-test, p &gt; 0.05). Conclusions: An IHC analysis revealed a tendency toward increased expression of ZEB1 in patients with advanced ES. However, a more extensive study is needed to evaluate the possible prognostic value of this marker.
特发性范可尼综合征一家二例
Authors: 曹宗新, 曹广平
Journal: BMJ (2008)

例1 男,2个月.因反复低热、喂养困难、消瘦3周就诊.患儿系第2胎,足月顺产,出生体重3120 g,发育无畸形;生后母乳喂养,20 d后渐发现患儿哺乳量减少,满月后出现明显的喂养困难、渐渐消瘦、反复低热.于2005年9月26日来我院就诊,并以中度贫血,营养不良,败血症?收住院.父母非近亲婚配,否认家族遗传病病史及结核病接触史.查体:体温37.8℃,体重2950 g,神志清,外型消瘦,贫血貌,无黄染;心、肺、肝、脾无异常,四肢肌力、肌张力低下。
CDK4/6 inhibitors beyond second line, is it worthy? A real-world data experience.
Authors: Alejandro Falcón, Javier Salvador Bofill, Alvaro Montaño, Marta Benavent, Rosario Gonzalez, Manuel Ruiz Borrego
Journal: Journal of Clinical Oncology (2020)

e13033 Background: CDK4/6 inhibitors as Palbociclib, Ribociclib and Abemaciclib has become the first or second line in advanced or metastatic luminal breast cancer HER2 negative. We only have data about the use of Abemaciclib in monotherapy beyond second line. Methods: We have analyzed 200 patients treated in our center with CDK4/6 inhibitors since 2017. All of them belong to clinical practice, out of clinical trial context. The effect of CDK4/6 inhibitors was analyzed using logistic regression analyses. Results: 34 patients were treated beyond second line of treatment with a medium follow-up of 18 months. CDK4/6 inhibitors were used as fourth line as medium (range 3-9), median age of 45 years, 1 male. 52% patients had visceral disease and 8.8% were primary hormone resistance. 64.6% were treated with palbociclib, 26.5% with ribociclib and 8.8% with abemaciclib. 52.9% were asociated with Fulvestrant, 44.1% with Letrozol and 2.9% with tamoxifen. Clinical benefit of 67.6% and response rate of 32.3%. Similar toxicities to previosly published trials were observed. Median progression-free survival was 14.2 months and median overal survival was 26.6 months. Non statistical difference were observed by luminal subtype, number of prior lines, type of hormonal therapy or CDK4/6 inhibitor used. Conclusions: Despite of the small population, we can summarized that CDK4/6 inhibitors associated to hormonal therapy is a good option for patients previosly treated in the metastatic setting. We need further investigation to understand which patient will benefit from treatment with this drugs in advanced lines.
Adjuvant systemic therapies for melanoma in Alberta: An early descriptive analysis of population characteristics and treatment outcomes.
Authors: Rodrigo Rigo, Kim Koczka, Atul Batra, Winson Y. Cheung, Jose Gerard Monzon, Tina Cheng
Journal: Journal of Clinical Oncology (2020)

e22013 Background: Adjuvant immunotherapies and adjuvant targeted therapy for melanoma became available in clinical practice in 2018 in Alberta, Canada. We describe the delivery of adjuvant systemic therapy, local-regional treatment, recurrence patterns, and treatment toxicity, in tertiary academic centers. Methods: We conducted a retrospective chart review of patients who received adjuvant systemic therapy for melanoma in Alberta. Adjuvant systemic treatment options included Nivolumab, Pembrolizumab, and Dabrafenib/Trametinib. Results: From September 2017 to January 2020, 71 patients were identified. Forty-one (61%) were male with a median age of 60 years (15-88). Seven (9.8%), 26 (36.6%), 27 (38%), 4 (5.6%), and 3 (4.2%) patients were stage IIIA, IIIB, IIIC, III-unspecified, and IV, respectively. BRAF mutations were detected in 31 (50.8%) patients. The median time from last surgical procedure to start of treatment was 10.8 weeks (4-28), with a median follow up time of 12 months. Sixty-one patients (85.9%) received Nivolumab, four (5.6%) patients received Pembrolizumab, and four (5.6%) Dabrafenib/Tremetinib. Twenty-eight (87.5%) of 32 patients with a positive sentinel lymph node biopsy did not complete elective regional lymph node dissection. Only two patients received adjuvant radiation. Local-regional surveillance with regular nodal ultrasound was not consistently performed. Seven (9.8%) patients had clinical or radiographic finding of enlarged regional lymph node while on treatment. At time of analysis, thirteen (18.3%) patients have completed adjuvant therapy, 18 (25.3%) discontinued therapy, and 39 (54.9%) patients were still on treatment. Eleven (15.4%) patients discontinued treatment due to toxicity, 8 (13.1%) from Nivolumab, 3 (75%) from Dabrafenib/Trametinib. Nine (12.6%) patients relapsed on treatment, of those, five (55.5%) had incidental findings on baseline imaging. Hypothyroidism affected 11 (15.4%) patients, hypophysitis and other immune-related side effects were described in 14 (19.7%) cases. Conclusions: Our cohort reflects excellent patient selection and delivery of adjuvant therapy consistent with clinical trial data. Surgical and radiation oncology care has adapted, and differs from trial procedure. Adjuvant immunotherapy was used in most patients. There appears to be a higher rate of discontinuation due to toxicity with Dabrafenib/Trametinib. Toxicity and recurrence findings are preliminary and will be updated.
Maternity unit under investigation for baby deaths was often operating without senior doctor
Authors: Clare Dyer
Journal: BMJ (2020)

A hospital trust under the spotlight over avoidable baby deaths provided inadequate antenatal care, with inexperienced junior midwives working alone and doctors not always available to assess high risk women, the Care Quality Commission (CQC) has found.

The latest CQC report on maternity services at East Kent Hospitals University Foundation Trust follows a report last month by the NHS Healthcare Safety Investigation Branch on 24 maternity care investigations at the trust. That report found that the trust was slow to learn lessons from …
Evaluation of prognostic significance of microRNA in tumors of luminal, primary operable breast cancer without Her2 neu overexpression in postmenopausal women.
Authors: Elena P. Ulianova, Vasilij V. Tokmakov, Iuliana S. Shatova, Aleksandr B. Sagakyants, Anna S. Goncharova, Ekaterina V. Zaikina, Elena N. Chernikova, Svetlana M. Bakulina, Tatiana F. Pushkareva, Oleg I. Kit, Aleksandr E. Lisutin
Journal: Journal of Clinical Oncology (2020)

e12558 Background: Breast cancer (BC) is associated with miRNAs, the qualitative and quantitative analysis of which shows significant differences between molecular subtypes, as well as between miRNAs circulating in the bloodstream and detected in tumor tissue. Since there is no clear characteristics for markers of luminal B primary operable BC without Her 2 neu overexpression, our purpose was an evaluation of prognostic significance of miRNA-21, 221, 20a, 200a, 196a in such postmenopausal patients in order to create a diagnostic panel. Methods: The study included 120 samples of healthy tissues of patients with luminal A BC (group 1, mean age 76.16±3.14 years) and tumor tissues of patients with luminal B BC (group 2, mean age 69.5±3.2 years); invasive ductal carcinoma in all patients. The expression status was analyzed using 5 mioRNA markers associated, according to the literature, with various molecular subtypes of BC (miRNA-21, 221, 20a, 200a, 196a). The Thermo Scientific PureLink RNA Mini Kit was used for the total RNA isolation. The reverse transcription reaction was performed using the ImProm-II Reverse Transcriptase kit (Promega). The Livak/2 method was used to assess the relative expression of miRNAs. Results: The average relative expression was: miRNA-21 in group 1 – 0.2±0.01, group 2 – 1.5±0.05; miRNA- 221 in group 1 – 0.19±0.02, group 2 – 0.43±0.04; miRNA -20a in group 1 – 0.12±0.01, group 2 – 0.13±0.01, miRNA -200a in group 1 – 0.22±0.02, group 2 – 0.96±0.06; miRNA- 196a in group 1 – 1.06±0.02, group 2 – 1.56±0.04. The differences between the groups were statistically significant (p = 0.0001); the difference was statistically insignificant only for miRNA -20a (p = 0.159955). Conclusions: Results of the study allow considering the overexpression of miR-21, 221, 200a and 196a and the relatively low expression of miR-20a as diagnostic markers for a diagnostic panel for luminal B BC without overexpression of HER2/neu.
Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.
Authors: Mallika Sachdev Dhawan, Roshun Rahimi, Silpa Karipineni, Lauren Wilch, Erika Zigman, Rahul Raj Aggarwal, Jennifer A. Grabowsky, Pamela N. Munster
Journal: Journal of Clinical Oncology (2020)

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .
BRAF mutation in Chinese biliary tract cancer patients.
Authors: Wendong Li, Yanzhi Cui, Fei Yin, Li Peng, Xiaogang Liu, Yunzhi Shen, Yuntong Guo, Shiwang Wen, Junping Shi, Mengping Lei, Milind M. Javle, Kai Wang, Da Jiang
Journal: Journal of Clinical Oncology (2020)

e16678 Background: Biliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA), and extrahepatic (ECC) cholangiocarcinoma. In the ROAR basket trial, dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, demonstrated promising efficacy in patients with BTCs with an overall response rate (ORR) of 41% and a favorable safety profile. The frequency of BRAF mutations reported in BTC varies widely, and BRAF V600E mutations have been reported in 0% to 20% of BTCs. However, the frequencies of BRAF mutations in Chinese BTCs are not clear. Methods: A total of 926 BTC patients (203 ECC, 195 GBC, 59 HCCA, and 469 ICC) were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from these patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions and deletions, copy number variations, and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: BRAF activating mutations were detected in 5.5% of Chinese BTC patients. There were 5.1% in ICC cases, 8.9% in ECC cases, 5.1% in HCCA cases, and 3.1% in GBC cases. BRAF V600E, the most common hotspot mutation, was detected in ICC and GBC with frequencies of 1.5% and 0.5%, respectively. No BRAF V600E was detected in ECC or HCCA. The top-ranked co-mutation genes with BRAF were TP53 (54%), ARID1A (40%), and SMAD4 (32%). Compared with BRAF wild-type cohort, the frequencies of ARID1A and SMAD4 mutations were significantly higher in patients with BRAF mutations cohort (40% vs 17%, P&lt; 0.001; 32% vs 14%, P&lt; 0.001), while KRAS mutations were mutually exclusive with BRAF mutations. Conclusions: To our knowledge, this is the largest BTCs cohort used to study the characterization of BRAF mutations in the Chinese patients. BRAF mutations occurred in 5.5% of patients, and BRAF V600E in 0.9%. These patients could benefit from treatment with a BRAF inhibitor combined with a MEK inhibitor. Analysis of BRAF V600E should be considered in patients with BTCs, especially in ICC and GBC. Clinical trial information: NCT03892577 .
Real-world data on adjuvant bisphosphonate use in a breast cancer center in Mexico.
Authors: Omar Peña-Curiel, Cynthia Villarreal-Garza, Héctor Díaz-Pérez, Enrique Francisco Martinez Trevino
Journal: Journal of Clinical Oncology (2020)

e12544 Background: Results from the Early Breast Cancer Trials Collaborative Group (EBCTCG) meta-analysis published in 2015 showed a significant reduction in risk of distant recurrence, bone recurrence and a 10-year breast cancer mortality reduction 1 . Moreover, Cancer Care Ontario and ASCO issued a guideline regarding the use of adjuvant bisphosphonates (AB) in breast cancer postmenopausal patients 2 . While these data are compelling, we have no information to support the implementation of this recommendation at Hospital San José’s Breast Cancer Center (HSJBCC). Methods: A retrospective analysis was performed to evaluate our compliance to the current recommendations for AB administration from 2015 through 2019. Inclusion criteria were based on the ASCO guidelines and comprised invasive breast cancer, postmenopausal status and early or locally advanced stage. Furthermore, in AB-treated patients we assessed the percentage of baseline calcium and creatinine measurement, prior dental evaluation, and concurrent calcium and vitamin-D supplementation during AB use. Results: A total of 106 patients met the inclusion criteria. Within the 4-year timeframe, AB was prescribed to 28/106 (26%) patients. Stratifying by year, we observed an increase of AB use rate from 4% in 2015 to 32% in 2019. Moreover, we observed a 93% baseline calcium and creatinine measurement, a 60% prior dental evaluation, and a 43% concurrent calcium and vitamin-D supplementation in the AB-treated population. Conclusions: HSJBCC recommendation for AB use is less than expected in the evaluated eligible patients in the 4-year timeframe. Despite an increase in our compliance to current ASCO guidelines it is not yet the standard of care at HSJBCC. Based on these results, we are currently planning a quality improvement initiative to undertake our low percentage of AB usage. [Table: see text]
Early cancer detection using multi-omic approach including epigenetic signal from ultra-small fragments.
Authors: Johnny Wu, Xin-Xing Li, Huabang Zhou, Wendi Liu, Fenfen Wang, Qianqian Yao, Dongsheng Lu, Huiqi Lu, Hongyan Wang, Tobias Wittkop, Paul Tang, Heping Hu, Xiaodong Cheng, Zhiqian Hu, Malek Faham, Li Weng
Journal: Journal of Clinical Oncology (2020)

e13561 Background: Genetic and epigenetic signals from plasma cell-free DNA (cfDNA) as well as proteins have been shown to detect cancer early. We have previously developed Circular Ligation and Amplification (CLAmp-seq) to detect mutations very sensitively and demonstrated higher performance than molecular barcode-based methods. The same single strand based technology yielded a much larger proportion of small fragments ( &lt; 100 bp) than traditional methods typically relying on double stranded ligation, allowing us to investigate epigenetic signature of cancer in ultra-short fragments. We sought to measure the performance using a multi-omics approach of these genetic and epigenetic changes as well as proteins in detecting colorectal cancer (CRC), ovarian cancer (OC) and hepatocellular carcinoma (HCC). Methods: A healthy and a late stage cancer sample were assessed by whole genome sequencing (WGS) using CLAmp-seq. Then we analyzed cfDNA from plasma samples of 731 patients, including 69 CRC, 57 HCC, 49 OC patients and 556 age-matched healthy individuals. Out of the diseased samples, the numbers for stages I-IV are 49, 39, 71, and 16, respectively. CLAmp-seq WGS was performed on 58 healthy and 66 cancer samples to discover cancer epigenetic signature. In addition, all the samples were analyzed for a panel of proteins and a CLAmp-seq targeted panel that includes known mutation sites. Results: Using CLAmp-Seq in late stage cancer showed 33% of its fragments as smaller than 100 bp compared to 15% in healthy and &lt; 1% in late stage by double stranded library prep. In addition, the difference in fragment size between late stage cancer and healthy was 29bp using CLAmp-Seq and 12bp using traditional double stranded prep. This focused our attention to detect epigenetic signature specific to cancer on the small fragments using CLAmp-Seq. Using data from whole genome analysis we demonstrated a performance using the epigenetic signature alone of 50% sensitivity at 97% specificity. Combined with mutations and proteins, we obtained at specificity of 97% sensitivities of 50%, 88%, 88%, and 100% in stage I, II, III, and IV, respectively. At the same 97% specificity we obtained the sensitivities of 73%, 100%, and 85% in CRC, OC, and HCC, respectively. Conclusions: We have demonstrated that CLAmp-Seq detects small fragments that are enriched in cancer. We have found predictive epigenetic signature in these small fragments. When combined with mutations and proteins we obtained a performance of 80% sensitivity at 97% specificity.
Integrating breast cancer screening into a cervical cancer screening program in three rural districts in Rwanda.
Authors: Lydia E. Pace, Jean Marie Vianney Dusengimana, Jean Paul Balinda, Origene Benewe, Vestine Rugema, Cyprien Shyirambere, Jean Bosco Bigirimana, Chuan-Chin Huang, Tharcisse Mpunga, Nancy Lynn Keating, Lawrence N. Shulman, Francois Uwinkindi
Journal: Journal of Clinical Oncology (2020)

2025 Background: In low-income countries where mammography is not widely available, optimal strategies to facilitate earlier breast cancer detection are not known. We previously conducted a cluster randomized clinical trial of clinician trainings in Burera District in rural Rwanda to facilitate earlier diagnosis among symptomatic women; 1.3% of women evaluated at intervention health centers (HCs) were diagnosed with cancer. Early stage breast cancer incidence was higher in intervention areas. Subsequently, Rwanda Biomedical Centre, Rwanda’s national health implementation agency, adapted the program in 3 other districts, offering screening clinical breast exams (CBE) to all women aged 30-50 years receiving cervical cancer screening and any other woman requesting CBE. A navigator facilitated patient tracking. We sought to examine patient volume, service provision and cancer detection rate in the adapted program. Methods: We abstracted data from weekly HC reports, facility registries, and the referral hospital’s electronic medical record to determine numbers of patients seen, referrals made, biopsies, and cancer diagnoses from July 2018-December 2019. Results: CBE was performed at 17,239 visits in Rwamagana, Rubavu and Kirehe Districts (total population 1.34 million) over 18, 17 and 7 months of program implementation respectively. At 722 visits (4.2%), CBE was abnormal. 571 patients were referred to district hospitals (DH); their average age was 35 years. Of those referred, 388 (68.0%) were seen at DH; 32% were not. Of those seen, 142 (36.6%) were referred to a referral facility; 121 of those referred (85.2%) actually went to the referral facility. Eighty-eight were recommended to have biopsies, 83 (94.3%) had biopsies, and 29 (34.9% of those biopsied; 0.17% of HC visits) were diagnosed with breast cancer. Conclusions: Integrating CBE screening into organized cervical cancer screening in rural Rwandan HCs led to a large number of patients receiving CBE. As expected, patients were young and the cancer detection rate was much lower than in a trial focused on symptomatic women. Even with navigation efforts, loss-to-follow-up was high. Analyses of stage, outcomes, patient and provider experience and cost are planned to characterize CBE screening’s benefits and harms in Rwanda. However, these findings suggest building health system capacity to facilitate referrals and retain patients in care are needed prior to further screening scaleup. In the interim, early diagnosis programs targeting symptomatic women may be more efficient and feasible.