tbuckley/cabot-search huggingface dataset:
Interaction between the <i>p53</i> genotype of lung cancer and response to mTOR inhibitor combined with irradiation therapy
Authors: Y. Nagata, T. Tojo, K. Ohnishi, A. Takahashi, T. Ohnishi, S. Taniguchi
Journal: Journal of Clinical Oncology (2009)

e22028 Background: Frequent activation of the PI3K/Akt/mTOR pathway and aberrations of tumor suppressor gene p53 are associated with therapeutic resistance in lung cancer. Nevertheless, the possibility of the variants of p53 genotype to affect response to mTOR inhibitor combined with irradiation therapy remains still unclear. Methods: Human non-small lung cancer cell line H1299 with p53 null genotype, was transfected with wild type or mutated p53 gene (H1299/wtp53 (WT), H1299/mp53 (MT)). Both cell survival and cell proliferation were estimated by colony formation assay to assess differences between WT and MT in sensitivity to rapamycin and ability of rapamycin to enhance radiation sensitivity. Cells were treated according to the individual study; DMSO (control), rapamycin (100 nM for 1 hour), irradiation (IR) (increasing doses), combination (RR) (rapamycin followed by irradiation). Changes in the cell cycle were also analyzed by flow cytometry. Results: Rapamycin decreased cell survival only in WT (P &lt; 0.01, vs. control). MT was resistant to rapamycin exhibiting slightly inhibited cell proliferation. Compared with IR, RR with no less than 6 Gy radiation enhanced inhibitory effects on both cell survival and proliferation independent of p53 genotype (P &lt; 0.01 in WT and P &lt; 0.01 in MT, respectively), that indicating additive interaction. Cell cycle analysis demonstrated rapamycin induced G 1 cell cycle arrest in both types of cells compared with controls (P &lt; 0.01 in WT and P &lt; 0.05 in MT, respectively) at 24 hours after treatment. Enhancement of G 1 arrest by RR was observed in both WT (P &lt; 0.01, vs. IR) and MT (P &lt; 0.01, vs. IR) at the same time point. In addition, RR caused a greater reduction of cells in S phase than that of IR regardless of p53 gene status (P &lt; 0.01 in WT and P &lt; 0.01 in MT, respectively). Conclusions: Rapamycin is an effective radiosensitizer in a p53 independent manner, in which increased G 1 cell cycle arrest and decrease in S phase cells are responsible for increased growth inhibitory effect. It will enable us to provide more appropriate treatment to patients with mutated p53 gene. No significant financial relationships to disclose.
Molecular Profiling Defines Distinct Prognostic Subgroups in Chilhood Acute Myeloid Leukemia: A Report from the French ELAM02 Study Group
Authors: Alice Marceau-Renaut, Nicolas Duployez, Benoit Ducourneau, Myriam Labopin, Arnaud Petit, Alexandra Rousseau, Sandrine Geffroy, Maxime Bucci, Wendy Cuccuini, Odile Fenneteau, Brigitte Nelken, Stéphane Ducassou, Virginie Gandemer, Thierry Leblanc, Gerard Michel, Yves Bertrand, Andre Baruchel, Guy Leverger, Claude Preudhomme, Hélène Lapillonne
Journal: Blood (2017)
Comparison of surgeon gaze behaviour against objective skill assessment in laparoscopic cholecystectomy-a prospective cohort study
Authors: Keane Evans-Harvey, Simon Erridge, Urvi Karamchandani, Sala Abdalla, Jasmine Winter Beatty, Ara Darzi, Sanjay Purkayastha, Mikael H. Sodergren
Journal: International Journal of Surgery (2020)
Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer
Authors: Min Wang, Jun Liu, Yan Zhao, Ruizhi He, Xiaodong Xu, Xingjun Guo, Xu Li, Simiao Xu, Ji Miao, Jianpin Guo, Hang Zhang, Jun Gong, Feng Zhu, Rui Tian, Chengjian Shi, Feng Peng, Yechen Feng, Shuo Yu, Yu Xie, Jianxin Jiang, Min Li, Wenyi Wei, Chuan He, Renyi Qin
Journal: Molecular Cancer (2020)

Abstract Background Pancreatic cancer is one of the most lethal human cancers. N 6 -methyladenosine (m 6 A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive. Methods LC/MS was used to profile m 6 A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m 6 A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14. Results We found that the m 6 A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m 6 A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo , via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m 6 A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells. Conclusions Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m 6 A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.
Bevacizumab combined with taxanes in second-line or more for metastatic breast cancer: Efficacy and predictive factors of response
Authors: A. Vanneuville, J. Gentil, C. Vautravers-Dewas, S. Guiu, L. Favier, S. Causeret, F. Mayer, B. Coudert, P. Fumoleau
Journal: Journal of Clinical Oncology (2009)

1122 Background: In metastatic breast cancer (MBC), bevacizumab (BEVA) and taxanes (TAX) (paclitaxel or docetaxel) are very efficient as first line metastatic therapy. However, such combination is questionable in subsequent lines of therapy. Aims: evaluate the efficacy and the factors of response of BEVA and TAX combination in second line or more for MBC. Methods: A retrospective study was done on all the MBC patients treated with BEVA combined with TAX, between July 2007 and November 2008, in the medical oncology department. Statistics were descriptive for the population and the efficacy. Univariate and multivariate analysis were used to determine the predictive factors of response. Results: 31 patients received BEVA combined with paclitaxel in 30 cases (96.7%) or docetaxel in one case (3.3%). Mean age was 55.3 years (IC95% [50.8–59.7]). Median number of previous lines was 4 (range [2–10]). 14 patients had already progressed under TAX therapy. Mean follow up was 7.1 months (IC 95% [5.9–8.4]). Thirteen (41.9%) patients had a clinical response, partial in 12 (38.7%) and complete in 1 (3.2%) patients. Four (12.9%) additional patients were stabilized therefore clinical benefit (CR+PR+SD) was obtained in 17 (60.7%) patients. The mean duration of the clinical benefit, measured as the delay between the first day of BEVA-TAX treatment and the date of progression or last news date, was of 5.8 months (IC95% = [4.4–7.1]). The progression delay, for patients who presented a progression and needed the introduction of a new therapy, was of 2.4 months (IC95% = [1.7–3.1]). Eleven (35.5%) patients had no clinical benefit and readily progressed under therapy. Multivariate analysis showed that age less than 65 (OR = 14.5 IC95% = [1.6–128.7]; p = 0.016) and a number of previous lines less than 6 (OR = 11.0 IC95% = [1.2–102.7]; p = 0.036) were related to the clinical benefit. Previous TAX resistance had no significant influence on the efficacy of the combination. Conclusions: In pretreated MBC patients, the combination of BEVA and TAX can be effective with a mean duration of clinical benefit around 6 months. Age over than 65 and a number of previous lines over 5 could be considered as factors of resistance to such a combination. These results have to be confirmed in larger studies. [Table: see text]
BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine
Authors: Deepak Kanojia, Wojciech K. Panek, Alex Cordero, Jawad Fares, Annie Xiao, Solomiia Savchuk, Krishan Kumar, Ting Xiao, Katarzyna C. Pituch, Jason Miska, Peng Zhang, Kwok-Ling Kam, Craig Horbinski, Irina V. Balyasnikova, Atique U. Ahmed, Maciej S. Lesniak
Journal: Science Translational Medicine (2020)

Combination of BET inhibitor and vinorelbine improves survival in preclinical models of brain metastases.
Neoadjuvant chemoradiation therapy with capecitabine (X) plus cetuximab (C), and external beam radiotherapy (RT) in locally advanced rectal cancer (LARC): ABCSG trial R03
Authors: W. M. Eisterer, A. De Vries, D. Oefner, R. Greil, H. Rabl, J. Tschmelitsch, R. Schmid, K. Kapp, F. Zehentmayr, J. Thaler
Journal: Journal of Clinical Oncology (2009)

4109 Background: Pre-operative chemoradiation is a standard treatment for LARC. X and C are synergistic with radiotherapy and active in colorectal neoplasms. This phase II multicenter trial was designed to assess the feasability and tolerability of a preoperative combination of X, C, plus RT in patients with LARC. Secondary endpoints were downstaging-rate and induction of complete pathological response (CPR). Only patients (pts.) with MRT-documented T3/T4-tumours were included. Methods: Pts. with potentially resectable cT4 or cT3 LARC (lower/mid rectum) were enrolled. Chemoradiotherapy consisted of X (825mg/sqm twice daily on RT-days weeks 1–4), C (400mg/sqm loading dose once per week, 200mg/sqm weekly x 4) and pelvic RT 3D conformation technique (1.8Gy/day, 45Gy total). Surgery was performed 28–42 days after completion of RT. Results: 31 pts. were enrolled, median age was 61 years (range 41 to 80), PS 0: 22 pts. (71%), PS 1: 8 pts. (26%), PS 2: 1 pt. (3%). 21 pts. (68%) presented with cT4, 10 pts. (32%) with cT3 tumors. 25 pts. (81%) had positive lymph nodes (LN) by imaging, 2 pts. were LN-negative, 4 pts. (13%) are not evaluable for N-stage. 28 pts (90%) are available for evaluation of toxicity and efficacy. Treatment with X and C plus RT was well tolerated, in only 4 pts. grade 3 toxicity was observed: acneiform skin rash 2 pts (7%), diarrhea 3 pts (11%), 1 pt. (4%) suffered from grade 4 diarrhea. Median dose intensity of X and C was &gt;95% during the entire treatment period. Tumor downstaging was observed in 14 pts. (50%) total, 12/19 (63%) T4 tumours and 2/9 (22%) T3 tumors responded. While no patient achieved a CPR, in 14 pts. a lymph node clearing (ypN0) was observed. Conclusions: The combination of capecitabine and cetuximab plus radiotherapy is a well tolerated preoperative treatment regime for LARC (cT3/4). The main toxicity consisted of diarrhea. The combination is effective in the primary tumor as well as in the lymph nodes, both with possible impact on therapy outcome. No significant financial relationships to disclose.
FRI0155 Different schemes of conservative therapy in patients with thrombangiitis obliterans
Authors: MS Gurieva, AA Baranov, SV Bagrakova, PV Shiryaev, AA Kurdjukov
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To compare changes of the Birmingham vasculitis activity score (BVAS) and some laboratory parameters in thrombangiitis obliterans patients (pts) treated with antiplatelet agents and vasodilators in usual doses (first group) and with standard three-days scheme glucocorticoid and cyclophosphamide pulse-therapy (second group). <h3>Methods</h3> The first group included 12 male (mean age 37.9 ± 6.9 years) and the other one – 16 male (mean age 41.3 ± 7.5 years). Duration of disease and clinical symptoms before the treatment were comparable in both groups, excepting the frequency of joints pain (n1 = 41.7% v.s. n<sup>2</sup> = 6.3%; p &lt; 0.05) and migratory superficial phlebitis (n1 = 66.7% v.s. n<sup>2</sup> = 18.8%; p &lt; 0.05), which were observed significantly more often in pts of the first group. Inspection of the pts was carried out before treatment and in a month. An estimation of clinical activity has carried out on BVAS. Serum levels of C-reactive protein (CRP) by ELISA and ESR at the same time were determinated as well. <h3>Results</h3> Before the start of treatment there were no significant differences in values of BVAS (8.2 ± 3.5 -first group; 8.4 ± 3.2 – second group), ESR and CRP between both groups. In a month BVAS was significantly lower in pts of the second group, then in the first one (6.8 ± 3.3 – first group v.s. 3.9 ± 1.7 – second group; p &lt; 0.05). The mean values of CRP were not significantly changes during follow-up in both groups, but high serum levels of CRP were founded significantly more often in pts of the first group then in the second after the treatment (n1 = 58.3%; n<sup>2</sup> = 56.3% – before; n1 = 66.7%; n<sup>2</sup> = 18.8%; p &lt; 0.05 – after the treatment, respectively). The similar features were observed for the frequency of amputations (n1 = 58.33% v.s. n<sup>2</sup> = 12.5%; p &lt; 0.05). <h3>Conclusion</h3> So, the pulse-therapy has more considerable anti-inflammatory effect comparing to antiplatelet agents and vasodilators, therefore it is necessary to include it in the scheme of therapy pts with thrombangiitis obliterans.
Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion
Authors: Valerie Clerin, Hiroshi Saito, Kevin J. Filipski, An Hai Nguyen, Jeonifer Garren, Janka Kisucka, Monica Reyes, Harald Jüppner
Journal: Journal of Clinical Investigation (2020)

The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.
Assessment of Postprostatectomy Radiotherapy as Adjuvant or Salvage Therapy in Patients With Prostate Cancer
Authors: Sean Sachdev, Peter Carroll, Howard Sandler, Paul L. Nguyen, Eileen Wafford, Gregory Auffenberg, Edward Schaeffer, Mack Roach, Christopher P. Evans, Maha Hussain
Journal: JAMA Oncology (2020)

After radical prostatectomy, adverse pathologic features and postoperative prostate-specific antigen (PSA) levels can herald disease recurrence or progression. Postoperative radiotherapy (RT) remains beneficial in this setting.To examine the evidence supporting the use of postoperative RT as well as recent advances that help determine timing, scope, and use in combination with androgen deprivation therapy (ADT) with or without lymphatic irradiation.A search was conducted of MEDLINE (Ovid), Embase (Elsevier), and the Cochrane Library (Wiley) databases, in addition to clinical trial registries. The reference list of included studies was reviewed for relevant articles. The search was limited to studies published between January 1, 2014, and December 31, 2019.After 548 citations were screened, 27 articles were selected for inclusion. In addition to conventional imaging, positron-emission tomographic (PET)-based radiotracers can aid in disease localization. While PET imaging may influence management with RT, studies are underway examining this issue, and several limitations must be considered, such as limited detectability at lower PSA levels and regional sensitivity. Available genomic classifiers can risk stratify patients or assess potential added benefit of RT. Prospective validation is underway with cooperative group trials. Adjuvant RT, on the basis of adverse pathologic features (such as extraprostatic extension or positive margins) is beneficial in terms of disease control, but it is unclear whether this therapy translates into more meaningful clinical benefit (eg, improved overall survival and a reduction in metastasis), which has been demonstrated by only 1 older, prospective randomized study. Preliminary data suggest that for a relatively favorable-risk population (low Gleason score but with positive margins), PSA monitoring may be a reasonable alternative in some men. Use of androgen deprivation therapy and lymphatic irradiation should be considered in higher-risk cohorts (those with high PSA, high Gleason score, seminal vesicle invasion or node positivity) in conjunction with postoperative RT.The findings of this review suggest that postprostatectomy RT should be considered for men with prostate cancer in the setting of adverse pathologic features; in carefully selected patients with favorable characteristics, close PSA monitoring is an option. Androgen deprivation therapy and pelvic lymphatic irradiation should be considered for higher risk cohorts (eg, higher PSA values, higher Gleason score). PET imaging and molecular studies remain unproven as decision tools.
Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia
Authors: Lindsey E. Roeker, David A. Knorr, Melissa S. Pessin, Lakshmi V. Ramanathan, Meghan C. Thompson, Lori A. Leslie, Andrew D. Zelenetz, Anthony R. Mato
Journal: Leukemia (2020)
False-positive diagnosis of breast cancer by diffused optical tomography with ultrasound
Authors: X. Wang, Y. Li, X. Cao
Journal: Journal of Clinical Oncology (2009)

e22085 Background: Breast cancer is one of the most common cancer in women. Early detection, early diagnosis and early treatment play key role in fighting against breast cancer. OPTIMUS system is a system of diffused optical tomography with ultrasound. It provides dual modality images for early diagnosis of breast cancer. The aim of this study was to evaluate the OPTIMUS system on diagnosis of breast disease. Methods: OPTIMUS system was applied to 160 breast tumor patients. All patients had received surgical treatment and had definite pathological diagnosis. OPTIMUS system was evaluated as diagnostic tool of breast tumor in this study. Results: There were 42 cases diagnosed as benign breast disease and 118 cases diagnosed as breast cancer by OPTIMUS system. Pathology confirmed 60 cases of benign disease and 100 cases of breast cancer. False positive rate of breast cancer was 30% (18/60). False negative rate of breast cancer was 0% (0/100). The pathology of false positive cases was mild and severe papillomatosis (6/18), non-typical hyperplasia (4/18), chronic inflammation (3/18), fibroadenoma (3/18) and fat necrosis (2/18). Papillomatosis and non-typical hyperplasia are precancerous lesions and often difficult for clinical diagnosis. In this study the false positive diagnostic rate of mammography and ultrasonography is 13% and 11.1% respectively. Conclusions: OPTIMUS system is a non- invasive and highly effective diagnostic tool for breast disease. Its sensitivity is reached to 100% and specificity is about 70% on the diagnosis of breast cancer. OPTIMUS system could be used as assistant diagnostic tool for breast tumor. No significant financial relationships to disclose.
Changes in Performance of More Than 1000 Minimally Invasive Liver Resections
Authors: Forat Swaid, Iswanto Sucandy, Samer Tohme, James W. Marsh, David L. Bartlett, Allan Tsung, David A. Geller
Journal: JAMA Surgery (2020)

fewer patients with thyroid nodules per year, compared with more than 50 such patients, were less likely to schedule ultrasonography examinations for positive thyroid antibody test results (OR, 0.41 [95% CI, 0.18-0.93]).Most surveyed physicians (428 [69.3%]) reported recently published clinical guidelines as most influential in their decisions for treating patients with thyroid nodules and thyroid cancer.Discussion | To our knowledge, this is the first survey study to evaluate use of thyroid ultrasonography by a diverse cohort of physicians involved in the care of a population-based cohort of patients with thyroid cancer.A substantial number of physicians endorsed use of ultrasonography for reasons not supported by clinical guidelines and in conflict with the Choosing Wisely recommendations. 2,5,6ur study has limitations in that direct links between physician-reported practice patterns and unnecessary thyroid cancer diagnoses were not possible, and physicians were not asked if they personally performed thyroid ultrasonography examinations or specific details about patients' ultrasonography requests.Despite limitations, this study highlights the need for focused physician education on clinically supported and unsupported indications for use of thyroid ultrasonography, with potential roles for future clinical practice guidelines, patient decision-making aids, and clinical decision-making support tools.
Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19
Authors: Girish N. Nadkarni, Anuradha Lala, Emilia Bagiella, Helena L. Chang, Pedro R. Moreno, Elisabet Pujadas, Varun Arvind, Sonali Bose, Alexander W. Charney, Martin D. Chen, Carlos Cordon-Cardo, Andrew S. Dunn, Michael E. Farkouh, Benjamin S. Glicksberg, Arash Kia, Roopa Kohli-Seth, Matthew A. Levin, Prem Timsina, Shan Zhao, Zahi A. Fayad, Valentin Fuster
Journal: Journal of the American College of Cardiology (2020)
Accelerated Partial-Breast Irradiation Compared With Whole-Breast Irradiation for Early Breast Cancer: Long-Term Results of the Randomized Phase III APBI-IMRT-Florence Trial
Authors: Icro Meattini, Livia Marrazzo, Calogero Saieva, Isacco Desideri, Vieri Scotti, Gabriele Simontacchi, Pierluigi Bonomo, Daniela Greto, Monica Mangoni, Silvia Scoccianti, Sara Lucidi, Lisa Paoletti, Massimiliano Fambrini, Marco Bernini, Luis Sanchez, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Stefania Pallotta, Lorenzo Livi
Journal: Journal of Clinical Oncology (2020)

To report the long-term results of external-beam accelerated partial-breast irradiation (APBI) intensity-modulated radiation therapy (IMRT) Florence phase III trial comparing whole-breast irradiation (WBI) to APBI in early-stage breast cancer.The primary end point was to determine the 5-year difference in ipsilateral breast tumor recurrence (IBTR) between 30 Gy in 5 once-daily fractions (APBI arm) and 50 Gy in 25 fractions with a tumor bed boost (WBI arm) after breast-conserving surgery.Five hundred twenty patients, more than 90% of whom had characteristics associated with low recurrence risk, were randomly assigned (WBI, n = 260; APBI, n = 260) between 2005 and 2013. Median follow-up was 10.7 years. The 10-year cumulative incidence of IBTR was 2.5% (n = 6) in the WBI and 3.7% (n = 9) in the APBI arm (hazard ratio [HR], 1.56; 95% CI, 0.55 to 4.37; P = .40). Overall survival at 10 years was 91.9% in both arms (HR, 0.95; 95% CI, 0.50 to 1.79; P = .86). Breast cancer-specific survival at 10 years was 96.7% in the WBI and 97.8% in the APBI arm (HR, 0.65; 95% CI, 0.21 to 1.99; P = .45). The APBI arm showed significantly less acute toxicity (P = .0001) and late toxicity (P = .0001) and improved cosmetic outcome as evaluated by both physician (P = .0001) and patient (P = .0001).The 10-year cumulative IBTR incidence in early breast cancer treated with external APBI using IMRT technique in 5 once-daily fractions is low and not different from that after WBI. Acute and late treatment-related toxicity and cosmesis outcomes were significantly in favor of APBI.