tbuckley/cabot-search huggingface dataset:
Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825)
Authors: Jeffrey S Wefel, Terri S Armstrong, Stephanie L Pugh, Mark R Gilbert, Merideth M Wendland, David G Brachman, Kevin S Roof, Paul D Brown, Ian R Crocker, H Ian Robins, Grant Hunter, Minhee Won, Minesh P Mehta
Journal: Neuro-Oncology (2021)

Abstract Background Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. Methods NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. Results A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. Conclusion The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.
AB0041 Comparison of ultrasound findigs of knee joint synovitis and disease activity in rheumatoid arthritis patients
Authors: VD Skakic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Proliferative synovitis is very common finding in patients with rheumatoid arthritis (RA). Among imaging methods ultrasound is very useful instrument for detection of synovial abnormalities. Using this method we can measure thickness of synovium, it's morphology and localisation. During examination we also can detect joint effusion in knee and presence of Baker's in popliteal fossa. As a sign of synovial inflammation we can detect enhanced blood flow in proliferated synovium. <h3>Objectives</h3> The aim of our study was to detect and measure the thickness of synovial proliferated tissue in suprapatellar recess and to try to find correlation between this finding and disease activity. We also used power doppler to observe blood flow in small vessels of synovial tissue. <h3>Methods</h3> In our study we included 20 patients with clinically affected both knees. Using modern equipment for ultrasound examination (Acceuson Sequoia 5–8 MHz with power doppler), we measured thickness of the synovium in the middle of suprapatellar recess in longitudinal approach. We also detected presence of joint effusion as well as Baker's cyst in popliteal fossa. Disease activity was estimated by sedimentation rate. <h3>Results</h3> We found the thickness of synovial tissue range 1, 3–6 mm (X average = 3,6 mm). Joint effusion was presented in all patients. In 46% of patients we found Baker's cyst with the same synovial pattern. Sedimentation rate in our patients was ranged 19–110/h. We didn't find any significant correlation between synovial thickness and such estimated disease activity. We also found presence of extensive blood flow in small vessels of synovium. <h3>Conclusion</h3> Ultrasound is very objective instrument for detection and measuring of synovial proliferation. This information is useful for practicioner to indicate corticosteroidal injections, synoviorthesis or surgical synovioctomy. This method is also necessary to estimate the results of those procedures. <h3>References</h3> Strome GM, Bouffard JA, van Holsbeek M. Synovial abnormalities. In: Fornage BD, ed. <i>Muskuloskeletal ultrasound</i>. Churchill Livingstone, New York, Edinburgh, London, Melbourne, Tokyo, 1995:203 Cozzi, <i>et al</i>. Ultarsound in monitoring knee joint synovitis [abstract]. Arthritis Rheum. 1998;41(Suppl 9):S50 Wolfgang A, <i>et al</i>. Color Duplex ultrasonography to detect pannus in knee joint effusion [abstract]. Arthritis Rheum. 1998;41(Suppl 9):S49 Helbich TH, <i>et al</i>. Baker's cysts ultrasonographic diagnosis. Rheumatol Eur. 1997;26(3):96–9
MMED PROJECT The Clinical Profile of Takayasu Disease at Tygerberg Academic Hospital – a retrospective study
Authors: Amani Kaawan
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Takayasu’s arteritis (TA) is a disease of unknown etiology that causes chronic inflammation of the large blood vessels and usually involves the aorta and its branches. The inflammatory process initially leads to thickening of the arterial wall and may result in stenosis, occlusion, dilatation or aneurysm formation. Although TA occurs more commonly in certain regions such as Asia, it is a global disease. Currently, there is a dearth of information on this condition in African countries, including South Africa. Results: We have identified 50 patients meeting the ACR criteria for the diagnosis of TA. Data was drawn from the records of the Division of Rheumatology as well as the angiographic records of TA. This included patient demographics, mode of presentation, classification, co-morbidities, complications, clinical and laboratory features, radiological findings, drug therapy as well as outcomes. The cohort comprised 34 of mixed race, 12 black and 4 white patients. The mean age at diagnosis was 16-56 (28.2) years. The most common presention was hypertension, followed by CVA, heart failure, and syncope. Angiography revealed Type V (most of aorta) and Type I (aortic arch branches) lesions to be the most common and that stenosis was much more common than aneurysm formation. Two patients had concomitant antiphospholipid syndrome. Another two had concomitant internal jugular vein thrombosis. Six patients had significant mediastinal lymphadenopathy, only one of whom had TB. Corticosteroids and additional immunosuppressive therapy were used to control disease activity in most patients. Biological treatment was used in two patients. Surgical intervention consisted mainly of renal auto transplantation. Twelve percent of patients had repeated admissions, which included planned surgical intervention. We had two mortalities, both as a result of massive strokes. The mortality rate was 6%. Only 3 patients had active TB. Conclusion: The study revealed gender and age characteristics similar to previous studies, confirming that TA affects mainly young females. The mortality rate of 6% in this cohort is significantly lower than that of previous series. The unusual findings in this study were: Significant chest lymphadenopathy in 12% of the cases,the significantly lower percentage of active TB of only 6%, two cases of a rare finding of venous thrombosis as well as 2 cases of an uncommon finding in TA of antiphospholipid syndrome.
CRISPR/Cas9 screening identifies a kinetochore‐microtubule dependent mechanism for Aurora‐A inhibitor resistance in breast cancer
Authors: Ailin Chen, Shijun Wen, Fang Liu, Zijian Zhang, Meiling Liu, Yuanzhong Wu, Bin He, Min Yan, Tiebang Kang, Eric W‐F Lam, Zifeng Wang, Quentin Liu
Journal: Cancer Communications (2021)

Abstract Background Overexpression of Aurora‐A ( AURKA ) is a feature of breast cancer and associates with adverse prognosis. The selective Aurora‐A inhibitor alisertib (MLN8237) has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients. Thus, identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome. Methods Here, we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237. Then, we performed competitive growth assays, colony formation assays, cell viability assays, apoptosis assays, and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin ( GSG2 ) depletion or inhibition with MLN8237. For mechanistic studies, immunofluorescence was used to detect the state of microtubules and the localization of Aurora‐B and mitotic centromere‐associated kinesin (MCAK). Results Among the hits, we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237. Mechanistic studies showed that co‐treatment with Aurora‐A and Haspin inhibitors abolished the recruitment of Aurora‐B and mitotic centromere‐associated kinesin (MCAK) to centromeres which were associated with excessive microtubule depolymerization, kinetochore‐microtubule (KT‐MT) attachment failure, and severe mitotic catastrophe. We further showed that the combination of MLN8237 and the Haspin inhibitor CHR‐6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth. Conclusions These findings establish Haspin as a synthetic lethal target and demonstrate CHR‐6494 as a potential combinational drug for promoting the therapeutic effects of MLN8237 on breast cancer.
Increased risk of COVID-19-relateddeath among cancer survivors
Authors: J. Shen, H. Zhao
Journal: Clinical Cancer Research (2020)

Significant variations in experience of the COVID-19 pandemic have been observed in the United States  Increasedrisk of COVID-19-related death has been reported among cancer survivors, but due to limited sample size in thosestudies, to what extent the previous cancer diagnosis may play a role in the determination of COVID-19-relateddeath is still unclear  In this study, using aggregated real-world data extracted from TriNetx electronic medical recorddata from 34 hospitals around United States, we assessed the relationship between prior cancer diagnosis in thepast 5 years and COVID-19-related death within one month after the diagnosis of virus contraction  A total of 24,534patients aged 18-80 years old who contracted COVID-19 were identified from January 20th to May 4th, 2020 Among them, 3,619 were cancer survivors  In the univariate analysis, we found that cancer patients had 2 55-foldincreased risk ratio (RR) of death than those without cancer (RR=2 55, 95% Confidence Interval (CI): 2 25, 2 88), although the risk was decreased but still significant (RR=1 42, 95% CI: 1 21, 1 67) after adjustment fordemographics (e g , age, gender, and race) and other pre-existing chronic diseases, including obesity, diabetes, hypertension, chronic ischemic heart disease, chronic kidney disease, asthma, and COPD  When stratified bycancer sites, significant associations were observed between respiratory and intrathoracic, oral, digestive, breast, male genital, urinary, blood, and skin cancers with COVID-19-related death in the univariate analysis  As expected, the most significant cancer site was respiratory and intrathoracic cancer with an RR of 6 49 (95% CI: 5 21, 8 07) However, after adjustment for demographics and other pre-existing chronic diseases, the significant associationsremained for respiratory and intrathoracic, digestive, and blood cancers (RR=1 89, 95% CI: 1 31, 2 73;RR=1 59, 95% CI: 1 06, 2 38;RR=2 08, 95% CI: 1 51, 2 86, respectively)  In addition, among cancer survivors, men werefound to have higher RR of death than women (RR=1 41, 95% CI: 1 12, 1 78), but the RR did not differ betweenBlacks and Whites  In summary, our data show significant increased COVID-19-related death among cancersurvivors  The elevated risk was particularly evident among those who had respiratory and intrathoracic, digestive, and blood cancers
Phase II study of ipilimumab, nivolumab, and panitumumab in patients with <i>KRAS</i>/<i>NRAS</i>/<i>BRAF</i> wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Michael Sangmin Lee, Patrick J. Loehrer, Iman Imanirad, Stacey Cohen, Kristen Keon Ciombor, Dominic T. Moore, Cheryl Ann Carlson, Hanna Kelly Sanoff, Autumn Jackson McRee
Journal: Journal of Clinical Oncology (2021)

7 Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.
EMT‐associated microRNAs and their roles in cancer stemness and drug resistance
Authors: Guangtao Pan, Yuhan Liu, Luorui Shang, Fangyuan Zhou, Shenglan Yang
Journal: Cancer Communications (2021)

Abstract Epithelial‐to‐mesenchymal transition (EMT) is implicated in a wide array of malignant behaviors of cancers, including proliferation, invasion, and metastasis. Most notably, previou studies have indicated that both cancer stem‐like properties and drug resistance were associated with EMT. Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance. Therefore, understanding the relationship between EMT‐associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment. In this review, we preliminarily looked into the various roles that the EMT‐associated miRNAs play in the stem‐like nature of malignant cells. Then, we reviewed the interaction between EMT‐associated miRNAs and the drug‐resistant complex signaling pathways of multiple cancers including lung cancer, gastric cancer, gynecologic cancer, breast cancer, liver cancer, colorectal cancer, pancreatic cancer, esophageal cancer, and nasopharyngeal cancer. We finally discussed the relationship between EMT, cancer stemness, and drug resistance, as well as looked forward to the potential applications of miRNA therapy for malignant tumors.
Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): Results from a phase I study.
Authors: Funda Meric-Bernstam, Diana L. Hanna, Anthony B. El-Khoueiry, Yoon-Koo Kang, Do-Youn Oh, Jorge M Chaves, Sun Young Rha, Erika P. Hamilton, Shubham Pant, Milind M. Javle, Kanwal Pratap Singh Raghav, Allison Fortenberry, Todd Gray, Joseph Woolery, Keun Wook Lee
Journal: Journal of Clinical Oncology (2021)

299 Background: Treatment options are limited for patients with unresectable, locally advanced or metastatic BTCs progressing after first line treatment. Standard second line chemotherapy yields objective response rates (ORR) of &lt; 10% and median overall survival of these patients is &lt; 6 months. Human epidermal growth factor receptor 2 (HER2) overexpression/ amplification is observed in 5–19% of BTCs. Zanidatamab is a bispecific HER2-targeted antibody that has demonstrated durable single agent activity with good tolerability in a range of HER2-overexpressing cancers. Methods: In the expansion cohort of this phase I study (NCT02892123), the primary objective is to characterize safety and tolerability of zanidatamab and secondary objectives include evaluation of anti-tumor activity. This cohort includes BTC patients with centrally confirmed HER2 overexpression (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]+), disease progression after standard of care therapy, and measurable disease per RECIST 1.1. Zanidatamab is administered at the previously identified recommended dose of 20 mg/kg every 2 weeks (Q2W). Tumors are assessed every 8 weeks (response confirmed at ≥ 4 weeks). Results: As of the data cutoff date (Jul 28, 2020), 20 patients (median age: 63 years [range, 42–78]) with BTC (11 gallbladder cancers, 5 intra- and 4 extra-hepatic cholangiocarcinomas) have been treated with zanidatamab. The median number of prior systemic therapies was 2.5 (range, 1–8), including five patients who had received prior HER2-targeted therapy (trastuzumab). Fourteen (70%) patients experienced zanidatamab-related adverse events (AEs), all of which were grade 1 or 2 in severity. The most common (occurring in ≥ 20%) zanidatamab-related AEs were diarrhea (n = 9) and infusion-related reactions (n = 6). A single treatment-related serious AE of grade 2 fatigue was reported in one patient. Among patients evaluable for response (n = 17), the confirmed ORR was 47% (n = 8; 95% confidence interval [CI]: 23, 72), the disease control rate was 65% (n = 11; 95% CI: 38, 86) and the median duration of response was 6.6 months (95% CI: 3.2, not estimable). Conclusions: Zanidatamab is well tolerated with promising and durable anti-tumor activity in patients with HER2 overexpressing BTC. Based on these data, zanidatamab is now being evaluated in an ongoing global Phase 2b study in patients with advanced HER2+ BTC that have progressed after treatment with a gemcitabine-containing regimen (NCT04466891). Clinical trial information: NCT02892123.
Cost effectiveness of <i>DPYD</i> genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.
Authors: Gabriel A. Brooks, Stephanie Tapp, Allan T. Daly, Jonathan Busam, Anna N.A. Tosteson
Journal: Journal of Clinical Oncology (2021)

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.
Abstract 15693: A Novel Rabbit Model of Plaque Erosion With Spontaneous Atherothrombotic Occlusion
Authors: Yoshibumi Antoku, Tetsuya Matoba, Takeo Yufu, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira
Journal: Circulation (2013)

Background: Plaque erosion is known to be a major cause of coronary atherothrombosis that leads to acute coronary syndrome. However, the mechanism of atherothrombosis on plaque erosion remains poor...