tbuckley/cabot-search huggingface dataset:
Real-time PCR detection of BRCA1 5382insC mutation by melting curve analysis on the Lightcycler
Authors: Kostas Christopoulos, Laura Devetzoglou, Christos Kroupis, Ioannis Tsiagas, Evi S. Lianidou
Journal: Cancer Research (2006)

205  Aim of the study. BRCA1 gene mutations increase the risk of developing breast and ovarian cancer. BRCA1 5382insC mutation is the most common mutation in the Greek population as well as in Eastern Europe. Our objective was to develop a reliable and rapid real time-PCR method for the detection of 5382insC BRCA1 mutation from whole genomic material (either from peripheral blood or tissue sample). Materials and methods. We used two pairs of hybridization probes (TIB Molbiol, Germany): a common anchored probe (labeled with LC Red 640), and either a wild-type or a mutant probe (labeled with fluorescein). Amplification was followed by melting curve analysis on the LightCycler (Roche). The primers were designed to amplify the region where the mutation lies. An in-silico study was conducted to verify the efficiency of the primers and probes. After PCR amplification, the melting curves were analyzed for melting point (Tm) differences between wild-type and mutant alleles. Results. Under optimized conditions by using the wild type probe the Tm9s were found to be 65,93+0,55°C (n=16, CV=0,83%) for the wild-type alleles and 63,74+0,70°C (n=4, CV=1,10%) and 67,20+0,29°C (n=4, CV=0,43%) for the mutant alleles, while by using the mutant probe the Tms were found to be 62,58+0,46°C (n=16, CV=0,73%) and 63,44+0,62°C (n=4, CV=0,99%) and 68.04 + 0.73°C (n=4, CV=1,07%) for the wild type and the mutant allele respectively. Also by using asymmetric PCR (primer ratio: 1/10), the Tm9s differences between homoduplexes and heteroduplexes of DNA increased in comparison with symmetric PCR. A total number of 20 patient samples were analyzed. These samples were selected based on our previous analysis by a reference Primer Specific Mutagenesis (PSM-PCR) method. By using the mutant probe, significant melting point differences (ΔTm: 5.07°C) enabled us to identify wild-type from mutant alleles as well as heterozygotes from homozygotes. With the use of asymmetric PCR melting point differences increased (ΔTm: 5,96°C). There was a 100% concordance of our results with those of the PSM-PCR method. Conclusions. Our newly developed method enables a reliable, cost effective and rapid detection of 5382insC mutation for BRCA1 and eliminates the need of post-amplification electrophoresis or DNA sequencing.
The prognostic role of body-mass index (BMI) for advanced EGFR positive non-small cell lung cancer (NSCLC) patients treated with osimertinib.
Authors: Andrea De Giglio, Alessandro Di Federico, Giada Donati, Chiara Deiana, Giacomo Nuvola, Benedetta Fragomeno, Francesca Sperandi, Barbara Melotti, Francesco Gelsomino, Andrea Ardizzoni
Journal: Journal of Clinical Oncology (2021)

e21078 Background: In advanced EGFR-mutated non-small cell lung cancer (NSCLC) population, osimertinib represents the standard of care both for EGFR tyrosine kinase (TK) inhibitor-naive patients and for those with EGFR-mutated NSCLC harboring the T790M mutation and progressed following prior EGFR-TK inhibitor. No clear data supports the relationship between body mass index (BMI) and osimertinib's efficacy. Methods: We conducted a single-center, retrospective study including advanced EGFR-mutated NSCLC patients treated with Osimertinib as second or subsequent lines from February 2016 to December 2020. We examined survival outcomes according to BMI among a BMI-low group ( &lt; 25 Kg/mq2) and BMI-high group (≥25 Kg/mq2). Results: A total of 37 consecutive patients received osimertinib as second- or subsequent line at our Institution. The mean age was 63.5 years (range 34-83 years), 24 (65%) patients were female, 16 (59%) were former or never smokers, and 25 (67%) had three or more metastatic sites at the start of therapy. The BMI-low group includes 25 (67%) patients and the BMI-high group 12 (33%), respectively. Globally, the median overall survival (mOS) was 29.9 mo. (95% CI, 18.2 – NR) and median progression-free survival (mPFS) was 17.5 mo. (95% CI, 15.7-33.3). The median follow-up was 32.5 mo. (IQR, 13.35-42.06). The mPFS was 21.0 mo. (95 CI, 16.8 – NR) within the BMI-low group and 16.8 mo. (95 CI, 4.4 – NR) within the BMI-high group, respectively (p = 0.03). Analogously, the mOS within the BMI-low group was 29.9 mo. (95 CI, 20.8 – NR) versus 18.2 mo. (95 CI, 11.7- NR) for the BMI-high group (p = 0.01). A BMI ≥25 Kg/mq2 constituted an independent risk factor for mortality [HR 3.99, (95 CI, 1.2 – 13.2), p 0.02] at multivariate analysis, including also age and number of metastatic sites. The BMI-high group showed a non-significant tendency to progression [HR 2.76, (95 CI, 0.9 - 8.3), p 0.06] at the same multivariate analysis. Conclusions: In our experience, a BMI ≥25 Kg/mq2 negatively influenced survival outcomes of 2nd-line osimertinib' treated NSCLC patients. More comprehensive studies are warranted to confirm these findings.
Association Between Hospital Voluntary Participation, Mandatory Participation, or Nonparticipation in Bundled Payments and Medicare Episodic Spending for Hip and Knee Replacements
Authors: Joshua M. Liao, Atul Gupta, Yueming Zhao, Jingsan Zhu, Joseph Martinez, Deborah S. Cousins, Amol S. Navathe
Journal: JAMA (2021)

This study uses Medicare claims data to compare spending for hip and joint replacements among hospitals with voluntary vs mandatory participation vs nonparticipation in the Medicare Bundled Payments for Care Improvement program between 2011 and 2017.
Short-term efficacy and long-term survival of limited-stage small cell lung cancer treated with large fractionation radiotherapy and conventional fractionation radiotherapy.
Authors: Cheng Chen, Yingying Jiang, Ning Jiang, Kang He, Cheng Chen, Lijun Zhao, Cheng Kong, Xue Song, Xiaohua Wang, Xia He, Xiangzhi Zhu
Journal: Journal of Clinical Oncology (2021)

e20586 Background: Hyperfractionation (1.5Gy per dose twice a day, total dose 45Gy) or conventional fractionation (2Gy per dose once a day, total dose 60-70Gy) is the recommended dose fractionation for LS-SCLC. However, the optimal segmentation mode and dose of radiotherapy have not been determined. In this study, we evaluated the short-term efficacy and toxic and side effects of macrofractionation to explore the feasibility of macrofractionation radiotherapy in the treatment of LS-SCLC patients. Methods: From May 2011 to February 2020, 52 patients with LS-SCLC admitted to Jiangsu Cancer Hospital were retrospectively analyzed. The patients were divided into two groups according to the dose separation mode, including 29 cases in the large division group (3-4Gy per dose once a day, total dose 45-60Gy) and 23 cases (2Gy per dose once a day, total dose 50-68Gy) in the conventional division group. The short-term efficacy, 1-year survival rate and some other aspects of the two groups were compared. Results: The short-term overall response rate of large segmentation group was 79.3%, and there was significant difference compared with 52.2% of conventional segmentation group ( χ2 =4.293, P&lt;0. 05) (Table). The 1-year survival rate of the large segmentation group was similar to that of the conventional segmentation group (82.8% vs．82.6%). The median survival time of large segment group was 30 months,which was not significantly different from the 34 months of conventional segment group (χ2=0.417, P&gt;0.05). In terms of the effect of the two fractionated dose modes on long survival, 31.0% of patients in the large fractionation group survived more than 48 months, compared with only 13% in the conventional fractionation group. In addition, in the subgroup analysis of this study, it was found that compared with conventional fractionation radiotherapy, patients aged 45-65 years with ECOG score of 0-1 and lesions less than 5cm before radiotherapy could obtain more significant survival benefit from large fractionation radiotherapy, with statistically significant difference between the two groups (χ2=4.874, P&lt;0.05). Conclusions: Large segmentation radiotherapy in the treatment of patients with LS-SCLC can improve the therapeutic effect and prolong the survival, especially for patients aged 45-65 years with ECOG score of 0-1 and lesions less than 5cm before radiotherapy , the survival benefit is more significant. In addition, large fractionated radiotherapy showed certain advantages in the long-term survival of patients with LS-SCLC, which is worthy of further clinical application.[Table: see text]
Head-to-head comparison of first-line FOLFIRINOX versus gemcitabine plus nabpaclitaxel (GN) in advanced pancreatic cancer (APC): A target trial emulation using Canadian real-world data.
Authors: Devon J. Boyne, Darren Brenner, Alind Gupta, Eric Mackay, Paul Arora, Radek Wasiak, Winson Y. Cheung, Miguel Hernan
Journal: Journal of Clinical Oncology (2021)

e18713 Background: When randomized trials are not available, observational real-world data can be used to emulate a (hypothetical) target trial. The procedure starts with the specification of the protocol of the target trial, whose components are then explicitly emulated using observational data. This approach prevents biases that are common when using more conventional methods for real-world data. Advanced pancreatic cancer represents an opportunity for trial emulation since two main frontline therapies, FOLFIRINOX and GN, have never been directly compared in a randomized fashion. The choice between the two regimens is largely based on physician discretion and patient preference rather than direct comparison of effectiveness. Methods: We emulated a target trial using linked data from the provincial cancer registry, electronic health records and various administrative databases from Alberta, Canada. Eligible individuals had locally advanced or metastatic pancreatic cancer diagnosed between Jan. 2015- Dec. 2018, no prior treatment, and adequate hematologic and serum creatinine values. They were followed from diagnosis until March 2020, death, or date of last known contact with the healthcare system. We estimated the effect of initiating FOLFIRINOX vs. GN within 8 weeks of diagnosis on overall survival. Cloning, artificial censoring, and inverse probability weighting were used to address unknown treatment assignment at baseline, non-adherence, and confounding. Adjusted Kaplan-Meier survival curves and hazard ratios were estimated. Results: Of 298 eligible individuals, 70 adhered to the FOLFIRINOX strategy and 147 to the GN strategy. The mean age was 65 years, 173 (58%) were male, and 247 (83%) had metastatic disease. The adjusted median survival, 1-year survival, and 2-year survival for FOLFIRNOX was 8.2 months (95% CI: 5.3 to 9.4), 36.9% (22.2 to 55.8), and 14.1% (4.8 to 32.2), respectively; and for GN was 4.8 months (3.3 to 5.3), 22.2% (13.6 to 35.9), and 4.7% (1.7 to 13.0), respectively. The adjusted difference in median survival was 3.4 months (0.6 to 11.1) and the adjusted hazard ratio was 0.79 (0.56 to 1.05). Conclusions: Target trial emulations can help to inform medical decision making in situations where head-to-head randomized trial data are unavailable or unfeasible. Findings from this real-world trial emulation suggest improved overall survival with FOLFIRINOX over GN.
Increase in Population
Journal: JAMA (1934)

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TrxR1 to promote adriamycin resistance in MCF-7 breast cancer cells by upregulating both gene expression level and enzyme activity: Reversed by shikonin.
Authors: JinQing Yang, Jinhai Tang
Journal: Journal of Clinical Oncology (2021)

e15070 Background: Adriamycin is one of the effective drugs commonly used in the treatment of advanced breast cancer, but its high incidence of drug resistance and cardiotoxicity limit the application of doxorubicin. Recent evidence shows that increased antioxidant capacity of cancer cells is associated with resistance to chemotherapy. Shikonin, a derivative of Lithospermum erythrorhizon Sieb.et Zucc, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that shikonin was enabled to directly binding and inhibiting TrxR1, which significantly downregulates intracellular ROS in cancer cells, suggesting that shikonin might be a promising drug candidate. In this study, we identified the relationship between TrxR1 and chemotherapeutic drug resistance in cancer cells and effects of shikonin with and without adriamycin on adriamycin-resistance cells. Methods: The direct DTNB reduction assay was employed to test the enzyme activity of TrxR1. Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an CCK8 assay and Annexin V-FITC/PI-labeled flow cytometry. Drug resistance was evaluated by inhibitory concentration (IC50) values and immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). TrxR1 knockdown was silenced by siRNA, leading to reducing the IC50 value of ADR-resistant MCF-7 cells. Dysfunctional endoplasmic reticulum was measured by western blot analysis of endoplasmic reticulum (ER) stress signaling pathways and observation of morphology using a transmission electron microscope. Results: We found that the TrxR1 was significantly enhanced in adriamycin-resistant (ADR/MCF7) cells.Furthermore, the decreased TrxR1 function by TrxR1-knockdown or TrxR1 inhibitor piperlongumine increased MCF-7 cells sensitivity to adriamycin. Treatment of ADR/MCF7 cells with shikonin (2.5,5,10,20,40 μM) dose-dependently inhibited TrxR1 enzyme activity and the clearance of dysfunctional endoplasmic reticulum, and induced cell apoptosis. Conclusions: Our results suggest that TrxR1 is critical for adriamycin resistance in breast cancer cells(ADR/MCF7),and shikonin or other inhibitors of TrxR1 would be potential in the treatment of cancer cells with adriamycin resistance.
Hospital variation in cancer treatments and survival outcomes of advanced melanoma patients: Nationwide quality assurance in the Netherlands.
Authors: Jesper van Breeschoten, Alfonsus Johannes Maria van den Eertwegh, Liesbeth De Wreede, Erik W. van Zwet, Doranne Hilarius, John B. A. G. Haanen, Christian U. Blank, Maureen J.B. Aarts, Franchette Van Den Berkmortel, Jan Willem de Groot, Geke Hospers, Ellen Kapiteijn, Djura Piersma, Rozemarijn Van Rijn, Astrid Aplonia Maria Van Der Veldt, Gerard Vreugdenhil, Marion Stevense, Marye Boers-Sonderen, Karijn Suijkerbuijk, Michel W.J.M. Wouters
Journal: Journal of Clinical Oncology (2021)

e18641 Background: The introduction of new systemic treatments for advanced melanoma has markedly changed the outcome of patients with metastatic melanoma. To assure high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes are evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013-2017 in the Netherlands. Methods: We selected patients diagnosed between 2013-2017 with unresectable stage IIIC or IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers’ performance on 2-year survival was compared by means of a multivariable Cox proportional hazards model with a random effect for center ID. Variation between centers was expressed by median hazard ratios. Therapy with BRAF/MEK inhibitors, anti-PD-1 antibodies or ipilimumab plus nivolumab was added to the Cox proportional hazards model as a time dependent covariate to assess the influence of new systemic therapies on center variation. Results: Between 2013-2017, 3820 patients were diagnosed with unresectable stage IIIC or IV melanoma. For patients diagnosed between 2013-2015, significant center variation in 2-year survival probabilities was observed. Median hazard ratio was 1.17 (95%CI: 1.09-1.31) for patients diagnosed between 2013-2015 after correcting for case-mix and treatment with BRAF/MEK inhibitors, anti-PD-1 antibodies or ipilimumab plus nivolumab. Use of new systemic therapies had a significant effect on up to 2-year survival (hazard ratio = 0.83, 95%CI (0.73-0.94)) with no use of the new systemic therapies as a reference. From 2016 onwards, no significant difference in 2-years survival was observed between centers. Conclusions: The different use of new cancer treatment of metastatic melanoma had an effect on survival outcomes in the Netherlands. A platform such as the Dutch Melanoma Treatment Registry, in which melanoma centers collaborate and have insight in variation in treatment patterns and outcomes between centers, results in fast implementation of new clinical developments across all Dutch melanoma centers.
Assembly of a spatial circuit of T-bet–expressing T and B lymphocytes is required for antiviral humoral immunity
Authors: Alejandra Mendoza, William T. Yewdell, Beatrice Hoyos, Michail Schizas, Regina Bou-Puerto, Anthony J. Michaels, Chrysothemis C. Brown, Jayanta Chaudhuri, Alexander Y. Rudensky
Journal: Science Immunology (2021)

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.
Inducible MyD88/CD40 (iMC) Costimulation Enhances Polyclonal Epstein-Barr Virus-Specific Cytotoxic T Lymphocyte (EBV-CTL) Proliferation and Anti-Tumor Activity
Authors: Mariam Khalil, Eric Yvon, Aruna Mahendravada, David M. Spencer, Aaron Foster
Journal: Blood (2017)
Relapsed Breast Implant–Associated Anaplastic Large-Cell Lymphoma Presenting as Refractory Fluid Collections With Low Uptake on FDG PET/CT Scan
Authors: Hussein S. Alsa’di, Joseph S. Donald
Journal: Clinical Nuclear Medicine (2021)

Breast implant-associated anaplastic large-cell lymphoma is a rare type of non-Hodgkin lymphoma that occurs years after placement of textured surface breast implants. Patients typically present after the development of pain, a palpable mass, or swelling. We present a case of a 45-year-old woman with recurrent breast implant-associated anaplastic large-cell lymphoma presenting as refractory fluid collections, and the unusual finding of low uptake on FDG PET/CT scan despite being confirmed by cytology.
Durable Outcomes of a Prospective Double Cord Blood Transplantation Trial in Adults with Acute Lymphoblastic Leukemia: Different Outcomes According to the Presence of Philadelphia Chromosome
Authors: Jae-Ho Yoon, Sung-Soo Park, Young-Woo Jeon, Sung-Eun Lee, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Hee-Je Kim, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Seok Lee
Journal: Blood (2017)
CNS activity of poziotinib in NSCLC with exon 20 insertion mutations.
Authors: Xiuning Le, Marina Chiara Garassino, Robin Cornelissen, Mark A. Socinski, Nishan Tchekmedyian, Julian R. Molina, Christina S Baik, Sharon Leu, Lyndah Dreiling, Francois M. Lebel, Jeffrey Melson Clarke
Journal: Journal of Clinical Oncology (2021)

9093 Background: Treatment addressing non-small cell lung cancer (NSCLC) harboring EGFR or HER2 exon 20 insertion mutations remains an unmet need. These tumors are associated with a high incidence of CNS metastases and unfavorable survival rates. Poziotinib is a potent, irreversible, tyrosine kinase inhibitor (TKI) with a structure that can overcome the steric hindrance of the exon 20 limited binding pocket. Preclinical data suggest poziotinib CNS penetration, and here we show meaningful poziotinib CNS activity in patients with NSCLC harboring exon 20 insertion mutations in an ongoing multi-cohort, multi-center Phase 2 study (ZENITH20; NCT03318939). Methods: ZENITH20 enrolled previously treated and naïve patients with advanced/metastatic NSCLC and EGFR or HER2 exon 20 insertion mutations in several cohorts: Cohort 1 (C1) EGFR previously treated; Cohort 2 (C2) HER2 previously treated and Cohort 3 (C3) EGFR treatment-naïve. All patients with stable CNS metastases at baseline were included. Poziotinib (16 mg) was administered orally QD, with follow-up for up to 24 months. The primary endpoint was Objective Response Rate (ORR) evaluated centrally using RECIST v1.1 by an independent image review committee. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS) and safety. Primary efficacy results have been previously released. Intracranial response was determined based on the modified RECIST criteria. Results: A total of 284 patients across 3 cohorts (C1 n=115; and C2 n=90; and C3 n=79) with a median age of 60.5 years were enrolled. The median follow-up was 7.3, 8.3, and 9.2 months for all patients in C1, C2, and C3, respectively. In NSCLC patients that had baseline CNS lesions (N=36), the analysis showed a patient-based ORR of 22.2% (8/36) and a DCR of 88.9% (32/36). One patient in each cohort had a complete intracranial response and stable disease was 80.6% across 3 cohorts and 92.9% in C2. Two patients each in C1 and C3 had progressive disease (PD) and none had CNS progression in C2 (Table). Conclusions: Poziotinib exhibited clinically meaningful CNS activity in patients with EGFR or HER2 exon 20 mutations in ZENITH20 Cohorts 1-3. The majority of the patients had no CNS progression and 3/36 patients had intracranial complete responses. The preliminary data suggest that poziotinib may provide a meaningful treatment alternative for patients with NSCLC that harbor EGFR or HER2 exon 20 mutations and who present with CNS metastases that have poor prognosis. Clinical trial information: NCT03318939. [Table: see text]